BG66315B1 - Inhalative solution formulation containing a tiotropium salt - Google Patents

Abstract

The invention relates to a propellant-free inhalation of tiotropium bromide monohydrate, which is dissolved in water or in a mixture consisting of water and ethanol, and to propellant-free inhalable aerosols resulting therefrom.

Description

The present invention relates to a pressurized inhalation preparation containing a pharmaceutically acceptable salt of tiotropium dissolved in water and ethanol and to pressurized inhalable aerosols obtained therefrom.

BACKGROUND OF THE INVENTION

Tiotropium-chemical (1 alpha, 2beta, 4beta, 5alpha, 7beta) -7 - [(hydroxides-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:

(I)

The compound has valuable pharmacological properties and is known as tiotropium bromide. Tiotropium and its salts are highly effective anticholinergic agents and therefore may be useful in the treatment of asthma or chronic obstructive pulmonary disease (COPD). Of pharmacological interest is the monohydrate natiotropium bromide. Both compounds are preferred objects of the present invention.

The present invention is concerned with the inhalation of liquid preparations of these compounds, and the liquid preparations according to the invention must meet a high standard of quality. In order to achieve optimal distribution of the active substance in the lung, it is proposed to use a liquid, gas-free preparation using suitable inhalers. Particularly suitable are inhalers that can nebulize a small amount of liquid preparation at a therapeutically necessary dose within a few seconds in the form of a therapeutically and inhalation aerosol. Such nebulizers are preferred in the context of the present invention, in which even an amount of less than 100 microl, preferably less than 50 microl, especially preferably less than 20 microl, of a solution of the substance is pulverized by a single actuation to a medium-sized aerosol of particles less than 20 [mu] m, preferably less than 10 [mu] m, so that the inhalable portion of the aerosol corresponds to the therapeutically effective amount. Such a pressurized gas delivery device for a metered dose of a liquid drug for inhalation administration is described, for example, in international patent application WO 1991/014468 "Atomizing Device and Methods" and in WO 1997/012687, including in the figures 6a and 6b and their description. In such a nebulizer, a solution of a drug substance such as a aerosol passable into the lung is injected and sprayed by high pressure up to 500 bar. The foregoing references are fully understood in the context of the present description of the invention. In such inhalers, the solution solutions are stored in a tank. It is necessary that the solutions used in the formulations have sufficient storage stability and, at the same time, be prepared so that they can be applied to the medical purpose accordingly, without any other manipulation, i. directly. In addition, they should not have ingredients that can interact with the inhaler so that the inhaler or the pharmaceutical quality of the solution or the resulting aerosol is damaged.

A special nozzle is used for spraying the solution as described, for example, in WO 1994/007607 and in WO 1999/016530. And two

66315 Bl are hereby expressly incorporated by reference.

WO 1998/027959 publishes solutions of formulations for the inhaler described above which additionally contain the sodium edithic acid (sodium edetate) disodium salt. The description favors aqueous solutions to be sprayed using the inhaler aerosol dispenser described, with a minimum sodium edetate concentration of 50 mg / 100 ml to reduce the incidence of spray abnormalities. Among the published examples is a preparation with tiotropium bromide. In this preparation the substance is dissolved in water. The proportion of sodium edetate is also 50 mg / 100 ml.

SUMMARY OF THE INVENTION

It has surprisingly been found that solutions of tiotropium salts in water or a mixture of water and ethanol, in which the proportion of the sodium edetate supplement is significantly below 50 mg / 100 ml, have a decrease in the dispersion of the delivered mass compared to the prior art with tiotropium bromide. Additionally, the dust quality is very good. Preferably, water is used as the solvent. The aerosol thus obtained has very good properties for inhalation administration.

Another advantage of the formulation is that, due to the lack, respectively, of reducing the sodium edetate supplement in the formulation, the pH of the solution may be reduced. Lower pH values are required for the long-term stability of the preparation.

The administration of tiotropium salts is preferably by inhalation route. Suitable inhalable powders may be used here to be administered in suitable capsules (inhalers) filled with suitable powder inhalers. Alternatively to this administration, inhalation administration can also be performed by using suitable inhalation aerosols. These also include powdered inhalable aerosols that contain, for example, HFA134a, HFA227 or a mixture thereof as pressurized gas. Inhalation administration may also be carried out by means of suitable solutions of the niotropium salt.

It is therefore an object of the present invention to provide an aqueous composition of substances with a pharmaceutically acceptable tiotropium salt that satisfies the high standard and which is necessary in order to optimally dispense a solution using the inhaler mentioned above. The formulations of the invention must also be of sufficient pharmaceutical quality, i. E. be pharmaceutically stable over a storage period of several years, preferably at least 1 year, more preferably 2 years.

Another object is to create gas-free solutions of tiotropium salt compositions that can be sprayed using a pressurized inhaler, with the mass contained within the aerosol formed being repeated uniformly within a defined area.

According to the invention, all pharmaceutically acceptable tiotropium salts can be used for the preparation. If the term tiotropium salt is used within the scope of the present invention, this should be understood as referring to tiotropium. The reference to titropium, which is the free ammonium cation, corresponds in the invention to the reference to tiotropium in the form of its salt (tiotropium salt), which contains an anion as the opposite ion. As compounds of the present invention, tiotropium salts are preferred compounds which, in addition to tiotropium, contain as the opposite ion (anion) chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methyl sulfate.

Within the present invention, the preferred salt is tiotropium bromide. References to tiotropium bromide in the context of the present invention should always be understood as references to all possible amorphous and crystalline modifications of tiotropium bromide. They may, for example, include solvent molecules in the crystal structure. Of all the crystalline modifications of tiotropium bromide, preferred according to the invention are those which include water (hydrates). Particularly preferred within the scope of the present invention is tiotropium bromide monohydrate. Preferably, the preparation does not contain any substance other than tiotropium or

66315 B1 is a pharmaceutically acceptable salt thereof.

In the compositions of the invention, the tiotropium salts are in a solvent. The solvent may be water only or a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but preferably the maximum limit is up to 70% vol. %, especially up to 60% and especially preferably up to 30%. The remaining volume percent is filled with water. A preferred solvent is ethanol free water.

According to the invention, the preparation preferably contains only one tiotropium salt. However, the preparation may be a mixture of different tiotropium salts and solvates. Preferably, the preparation does not contain any substance other than tiotropium within the meaning of the above definition.

The concentration of the tiotropium salt, referred to as the fraction of tiotropium in the finished drug, depends on the desired therapeutic effect. For most of the titropium-sensitive diseases, the concentration of tiotropium is between 0.0005 and 5 wt. %, preferably between 0.001 and 3 wt. percent. In the case of tiotropium bromide monohydrate or tiotropium bromide, respectively, the preferred amount relative to tiotropium is 0.0005 to 0.5% by weight, more preferably 0.0005 to 0.25% and especially preferably 0.001 to 0.1%.

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

The pH is adjusted by the addition of pharmacologically acceptable acids. Examples of preferred inorganic acids are: hydrochloric acid, bromoic acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are ascorbic, citric, malic, tartaric, maleic, succinic, fumaric, acetic, formic and / or propionic acids, and the like. Preferred inorganic acids are hydrochloric acid and sulfuric acid. Acids that already form an acid-added salt of the substance may also be used. Among organic acids, ascorbic, fumaric and citric acid are preferred, with citric acid being the most preferred. Alternatively, mixtures of said acids may be used, especially in the case of acids which, in addition to their acidic properties, have other properties, such as flavors or antioxidants, such as citric acid or ascorbic acid. Hydrochloric acid is particularly preferred as an inorganic acid.

Pharmacologically acceptable bases may also be used for accurate pH titration. Suitable bases are, for example, alkali hydroxides and alkaline carbonates. Preferred alkali ion is sodium. If such bases are used, care must be taken to ensure that the salts contained in the formulation so prepared are pharmacologically compatible with the acids mentioned above.

According to the invention, the addition of edithic acid (EDTA) or one of its known salts, sodium edetate, as a stabilizer or complexing agent may be avoided in the present preparation.

Another embodiment of the invention contains edithic acid and / or any of its salts.

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

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

In a preferred embodiment, this additive is completely absent.

Similar to what is indicated for sodium edetate is the ratio to other comparable additives which have complexing properties and can be used in place of it, such as nitrile-tracetic acid and its salts.

Composers within the scope of the present invention are preferably understood to be molecules capable of binding into complex compounds. Preferably, cations, especially preferably metal cations, can be formed through these compounds.

The preparations according to the invention

66315 B1 may contain, in addition to ethanol, other co-solvents and / or excipients. Preferred co-solvents are those which contain 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 acids esters of fatty acids or the suspending agent.

Excipients and additives in this context are understood to mean any pharmacologically acceptable and therapeutically correct substance which is not an active ingredient but may be formulated together with the substance in a pharmacologically acceptable solvent to improve the qualitative characteristics of the preparation. Preferably, these substances do not have or exhibit, in the context of the desired therapy, insignificant or at least not undesirable pharmacological actions. Excipients and additives include, for example, surfactants, such as soy lecithin, butyric acid, sorbitan esters such as sorbitan triolate, polyvinylpyrrolidone and other stabilizers, complexing agents, antioxidants and / or preservatives, which provide or extend the drug's life. , flavors, vitamins and / or other known additives. Additional substances include pharmacologically acceptable salts such as sodium chloride.

Preferred excipients include antioxidants, such as ascorbic acid, if it is no longer used to adjust pH, vitamin A, vitamin E, tocopherols and the like, vitamins or provitamins found in the human body.

Preservatives can be used to protect the preparation from contamination with bacteria. Suitable preservatives are those known in the art, especially benzalkonium chloride or benzoic acid, respectively, benzoates such as sodium benzoate, in the known state of the art.

Preferred preparations contain, in addition to the solvent, water and the tiotropium salt only benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate is avoided.

As already stated repeatedly, tiotropium bromide is described in EP 418 716 A1, as crystalline tiotropium bromide monohydrate can be prepared according to the production method, which will be described in detail hereinafter.

In order to obtain crystalline tiotropium bromide monohydrate according to the invention, it is necessary that the tiotropium bromide obtained according to the manufacturing method published in EP 418 716 A1 be dissolved in water, heated, purified with activated carbon and after separation of the active charcoal and slow cooling slowly crystallized the tiotropium bromide monohydrate.

Preferably proceed as follows.

In a suitably sized reaction vessel, a solvent is mixed with tiotropium bromide, which has been prepared according to the production method published in EP 418 716 A1. 0.4 to 1.5 kg, preferably 0.6 to 1 kg, especially preferably 0.8 kg of water as solvent are used per mole of tiotropium bromide used. The resulting mixture is stirred with stirring to above 50 ° C, especially preferably to above 60 ° C. The maximum temperature is determined by the evaporation point of the water used as solvent. Preferably the mixture is heated to 8090 ° C. Dry or wet charcoal is added to this solution. Preferably 10 to 50 g, especially preferably 15 to 35 g, most preferably about 25 g of activated carbon, are used per mol of tiotropium bromide. Optionally, the charcoal is soaked in water before being placed in the solution of tiotropium bromide. 70 to 200 g, preferably 100 to 160 g, particularly preferably about 135 g of water, are used per mol of tiotropium bromide applied to soak the activated carbon. If the charcoal is soaked in water before being placed in the solution of tiotropium bromide, it is recommended that it is then washed with the same amount of water.

At constant temperature, after the addition of activated carbon, stirring is continued for 5 to 60 minutes, preferably between 10 and 30 minutes, especially preferably about 15 minutes, and the resulting solution is filtered to remove the activated carbon. The filter is then

66315 Bl washed with water. For this purpose, 1 mol of tiotropium bromide 140 to 400 g, preferably 200 to 300 g, most preferably about 270 g of water, are used.

The filtrate is then cooled slowly, preferably at a rate of 1 to 10 ° C every 10-30 minutes, preferably 2 to 8 ° C every 1030 minutes, most preferably 3 to 5 ° C for about 20 minutes. Optionally, after cooling to 2025 ° C, additional cooling to below 20 ° C can be performed, especially preferably up to 10-15 ° C.

After cooling is complete, stirring is continued for between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, especially preferably for about 1 hour until crystallization is complete.

Finally, the formed crystals are isolated by filtration or suction of the solvent. If further washing of the crystals is required, this is preferably done with a solvent of water or acetone. Per mol of crystals of tiotropium bromide monohydrate are used 0.1 to 1 l, preferably 0.2 to 0.5 l, especially preferably about 0.3 l solvent. The flushing may be repeated. The product obtained is dried in vacuo or by means of heated rotating air to achieve a water content of 2.5 to 4%.

Thus, one aspect of the present invention relates to compositions of the above kind, which use crystalline tiotropium bromide monohydrate, which is prepared according to the described procedure.

The tiotropium salt formulations of the invention are preferably used in an inhaler of the above kind to produce free aerosols without pressurized gas. The patent documents explicitly described in the beginning should be mentioned here again.

As described in the beginning, the further preferred embodiment of the preferred inhaler is published in WO 1997/012687 and its Figures 6. This nebulizer (Respimat®) can be advantageously used to prepare the inhaled aerosols with the tiotropium salt as the active ingredient. Due to its cylindrical shape and size that is less than 9 to 15 cm long and 2 to 4 cm wide, this device can be worn at any time by the patient. The nebulizer dispenses a certain volume of the drug using high pressure through small nozzles, so that inhaled aerosols are generated.

In essence, the preferred dispenser comprises an upper outer housing, a pump housing, a nozzle, a closure, a spring housing, a spring and a content chamber, characterized by

- a pump housing attached to the upper housing, one end of which carries the nozzle body with the nozzle or nozzle device respectively;

- hollow piston with valve;

- a pressure flange in which the hollow piston is mounted and which is located at the top of the outer housing;

- a live closure device located at the top of the outer housing;

- a spring housing with a spring located inside the upper part of the outer housing by means of a rotary bearing;

- the lower part of the outer housing which is inserted into the spring housing in an axial direction.

The hollow piston with the valve corresponds to one of the published devices in WO 1997 / 012687. It partially enters the cylinder of the pump housing and is mounted axially in the displacement cylinder. In particular, the features in Figures 1-4, especially Figure 3, and the corresponding descriptions should be taken into account. During the actuation of the spring, the hollow piston exerts high pressure on the fluid side - the measured solution of the substances - a pressure of 5 to 60 MPa (about 50 to 600 bar), preferably 10 to 60 MPa (about 100 to 600 bar). Preferably, volumes of 10 to 50 microl, particularly preferably 10 to 20 microl, most preferably a volume of 15 microl, are separated.

The valve is preferably positioned at the end of the hollow piston, which faces the nozzle body.

The nozzle is preferably micro-constructed, i.e. produced by microtechnology.

66315 Bl

Microstructured nozzle bodies are published, for example, in WO 1994/007607; this description is referenced, especially in Figure 1 and its description.

The nozzle body consists, for example, of two rigidly fixed glass and / or silicon plates, at least one of which has one or more microstructured grooves that connect the interior to the exit side of the nozzle. At least one circular or non-circular opening with a depth of 2 to 10 micrometer and a width of 5 to 15 micrometer, with a depth of 4.5 to 6.5 micrometer and a length of 7 to 9 micrometer, is provided on the starting side.

In the case where there are more nozzle openings, preferably two, the nozzle flow directions are parallel to each other or inclined opposite to each other in the nozzle opening direction. For one nozzle body with at least two nozzle openings on the outlet side, the flow directions may be inclined relative to each other at an angle of 20 ° to 160 °, preferably 60 to 150 °, especially preferably 80 to 100 °.

The nozzle openings are preferably spaced from 10 to 200 micrometer apart, more preferably spaced from 10 to 100 micrometer, especially preferably from 30 to 70 micrometer. Most preferably a distance of 50 µm.

The flow directions are found, respectively, in the area around the nozzle openings.

As already mentioned, the liquid drug composition enters the body of the nozzle under pressure up to 600 bar, preferably 200 to 300 bar, and is sprayed over the nozzle openings as an inhalable aerosol. Preferred particle sizes or aerosol droplets are up to 20 µm, preferably 3 to 10 µm, respectively.

The pressurized device comprises a spring, preferably a cylindrical pressurized coil spring, as a reserve for mechanical energy. The spring acts on the pressure flange as a bouncing part, the movement of which is determined by the position of the closing part. The path of the actuating flange is precisely limited by one upper and one lower stop. The spring is tensioned by a force-transmitting gear, such as a helical gear, by an external torque that occurs when the upper body of the outer housing rotates against the spring housing in the lower part of the outer housing. In this case, the upper part of the outer housing and the actuating flange also have a one- or two-way wedge gear.

The sealing portion with inlet sealing surfaces is circularly arranged around the actuating flange. It consists, for example, of a radially and elastically changing ring of plastic or metal. The ring is placed in a vertical plane with respect to the sputtering axis. After the spring is pressed, the closing surfaces of the closing device are moved in the path of the actuator and preventing the spring from being released. The closing part is actuated by a button. This button is connected or fixedly connected to the closing part. To activate the closing part, the button is pushed parallel to the plane of the ring and preferably in the atomizer; thus, the changing ring changes its shape in the plane of the ring. The structural details of the closure device are described in WO 1997/020590.

The lower part of the outer casing moves axially on the spring casing and conceals the storage chamber, the spindle (spindle) mechanism and the fluid chamber.

When the nebulizer is actuated, the upper housing is rotated against the lower housing, the lower housing engaging the spring housing. In doing so, the spring is pressed against the screw gear and tensioned and the closing device is released independently. The rotation angle is preferably an entire portion of 360 °, for example 180 °. Simultaneously with the spring tension, the actuating part is moved to the upper part of the housing in a specified way, the hollow piston is moved back inside the cylinder of the spring housing, and a part of the liquid from the storage chamber is sucked into the high pressure space before the nozzle.

Several interchangeable storage chambers containing the liquid may be inserted and used alternately in the nebulizer. The storage chamber contains the aqueous aerosol composition of the invention.

The dusting process starts with a slight push of the actuating button. In that

66315 Bl the closing device releases the path of the actuator. The elongated spring pushes the piston into the cylinder of the spring housing. The fluid enters the nebulizer nozzle in a dusty state.

Other structural details are disclosed in WO 1997/012683 and WO 1997/020590, which are incorporated herein by reference.

The constituent parts of the nebulizer are of function-relevant material. The nebulizer housing and, as far as function permits, other parts are preferably made of plastic, for example obtained by injection molding. Physiologically acceptable materials are used for medical purposes.

Figures 1a / b, which are identical to figures ba / b of WO 1997/012687, describe the nebulizer (Respimat®) by which the aqueous aerosol compositions of the invention can preferably be inhaled.

Figure 1 a shows a longitudinal section through a nebulizer with a spring extended, Figure 2b shows a longitudinal section through a nebulizer with a spring extended.

The upper part of the housing 51 contains the pump housing 52, at the end of which is fitted the handle 53 of the spray nozzle. The nozzle body 54 and one filter 55 are housed in the handle. The hollow piston 57 secured in the actuating flange 56 of the closing device 54 partially enters the pump housing cylinder. The hollow piston carries the valve body 58 at its end. The hollow piston is sealed by a single seal 59. Inside the upper part of the housing there is a stop 60, on which lies the actuating flange with the spring released. On the actuating flange there is a stop 61 on which the actuating flange lies when the spring is pulled. After tensioning the spring, the closing device 62 is moved between the stop 61 and a support portion 63 at the top of the housing. The actuating button 64 is in connection with the closing device. The upper part of the housing ends in mouthpiece 65 and is closed with a sliding protective cap. The spring housing 67 with the spring 68 is arranged to be rotatable by means of a snap finger 69 and a rotary bearing at the top of the housing. The lower housing 70 is inserted above the spring housing. Inside the spring housing, there is a replaceable containment chamber 71 for the spray liquid 72. The containment chamber is closed by a stopper 73 through which the hollow piston enters the containment chamber and sinks with its end into the liquid. (containing the substance solution).

On the outer surface of the spring housing is a spindle 74 for the mechanical counter. At the end of the spindle, which faces the top of the housing, is the drive sprocket 75. The spindle has a movable portion 76.

The nebulizer described above is suitable for spraying aerosol compositions of the invention into an inhalable aerosol.

If the preparation of the invention is nebulized by the technique described above (Respimat®), the delivery mass should be at least 97%, preferably at least 98% of all inhalation triggers (pressures), a certain amount with a tolerance area of at most 25%, preferably 20 % of this amount. Preferably, between 5 and 30 mg of the formulation are delivered for pressing as a specified mass, especially between 5 and 20 mg.

The formulation of the invention may also be nebulized by devices other than the inhaler described above, for example by '' Jet-Stream '' inhalers.

Examples of carrying out the invention

1. An example of the synthesis of tiotropium bromide monohydrate

25.7 kg of water and 15.0 kg of tiotropium bromide are placed in a suitable reaction vessel. The mixture was heated to 80-90 ° C and stirred at constant temperature until a clear solution was obtained. Activated charcoal (0.8 kg), moistened, was swollen in 4.4 kg of water, this mixture was added to the solution of tiotropium bromide and washed with 4.3 kg of water. The resulting mixture was stirred for at least 15 minutes at 80-90 ° C and finally filtered through a heated filter in a preheated to 70 ° C apparatus. The filter was washed with 8.6 kg of water. The contents of the apparatus are cooled by 3-5 ° C every 20 minutes to a temperature of 20-25 ° C. With cold water cooling, the apparatus is still cooled to 10-15 ° C and crystallization is completed by stirring for at least one hour. The crystallizate is isolated

66315 Bl xy filter-dryer, the isolated crystalline slurry was washed with 9 l of cold water (10-15 ° C) and cold acetone (10-15 ° C). The crystals obtained were dried at 25 ° C for 2 h under nitrogen flow.

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

11. Examples of preparations

100 g medicinal composition contains:

Example Amount of tiotropium bromide as a fraction of tiotropium Amount of tiotropium bromide monohydrate as a proportion of tiotropium Amount of benzalkonium chloride Amount of sodium edetate pH-; value set by HCI (1N) 1 0.099 gr - 10 mg 25 mg 3.0 2 0.006 gr 10 mg 25 mg 3.0 3 0.099 gr 10 mg 10 mg 3.0 4 0.006 gr - 10 mg 10 mg 3.0 5 - 0.099 gr 10 mg 25 mg 3.0 ⁶ - 0.006 gr 10 mg 25 mg 3.0 7 - 0.099 gr 10 mg 10 mg 3.0 8 - 0.006 gr 10 mg 10 mg 3.0

The rest is water.

Claims

Claims (19)

1. Propellant-free medicinal composition for inhalation administration, characterized in that it consists of: • tiotropium salt as active substance, in a concentration with respect to tiotropium between 0.0005 and 5 wt. %, • only water or a mixture of water / ethanol as solvent for the active substance, • acid to adjust the pH between 2.0 and 3.1, • a pharmacologically acceptable preservative, • optionally ethylenediaminetetraacetic acid or an ethylenediaminetetraacetic acid salt in an amount of -large from 0 to 25mg / 100 ml, optionally a pharmacologically acceptable complexing agent and / or stabilizer and / or pharmacologically acceptable co-solvent and / or other pharmacologically acceptable excipients and additives, together with a preservative. The composition of claim 1, wherein the tiotropium salt is chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methylsulfonate. Medicament composition according to claim 1, characterized in that the active substance is tiotropium bromide. The pharmaceutical composition according to claim 1, wherein the active substance is tiotropium bromide monohydrate. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the solvent is only water. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the solvent is a mixture of ethanol / water, preferably up to 70% vol. % ethanol, particularly preferably up to 60% vol. % ethanol and most preferably up to 30% vol. % ethanol. 66315 Bl Medicament composition according to any one of claims 1 to 6, characterized in that it is free of complexing agent. Medicament composition according to any one of claims 1 to 7, characterized in that it is stabilizer free. Medicament composition according to any one of claims 1 to 6, characterized in that the ethylenediaminetetraacetic acid salt is in an amount of from 5 to less than 10 mg / 100 ml. A pharmaceutical composition according to any one of claims 1 to 6, characterized in that the ethylenediaminetetraacetic acid salt is in an amount of 10 to 25 mg / 100 ml. A pharmaceutical composition according to claims 1 to 6 or 9 to 10, characterized in that the ethylenediaminetetraacetic acid salt is sodium edetate. Medicament composition according to any one of claims 1 to 11, characterized in that the pH value is between 2.5 and 3.1, preferably between 2.7 and 3.1 and most preferably between 2.7 and 3.0. A pharmaceutical composition according to any one of claims 1 to 12, characterized in that the concentration with respect to tiotropium is between 0.001 and 3 wt. %, preferably between 0.0005 and 0.5 wt. %, especially preferably between 0.0005 and 0.25 wt. % and most preferably between 0.001 and 0.1 wt. %. Medicament composition according to any one of claims 1 to 13, characterized in that it contains benzalkonium chloride as a preservative. A pharmaceutical composition according to any one of claims 1 to 14, characterized in that pharmacologically acceptable excipients and adjuvants are used in addition to the preservative. Medicament composition according to claim 15, characterized in that it contains an antioxidant as an excipient. A pharmaceutical composition according to any one of claims 1 to 16, characterized in that it is free of co-solvents and / or pharmacologically acceptable excipients and additives other than a preservative. Use of a medicament composition according to any one of claims 1 to 17 for the preparation of a medicament for the treatment of asthma and / or COPD. A method for preparing a medicament composition according to any one of claims 1 to 17, characterized in that the individual components are mixed.