HRP20040932A2 - Aerosol formulation for inhalation comprising a tiotropium salt - Google Patents

Description

The proposed invention relates to an aerosol formulation of a pharmaceutically acceptable salt of tiotropium dissolved in water and without propellant gas. The formulation according to the invention is particularly suitable for atomizing the active substance using an atomizer for inhalation application of the active substance. Indications are primarily asthma and/or COPD.

Tiotropium, chemical (1α,2β,4β,5a,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo-[3.3.1.02,4]nonane , is known as tiotropium bromide from European patent application EP 418 716 A1. The bromide salt of tiotropium has the following chemical structure:

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This compound has valuable pharmacological properties and is known as tiotropium bromide. Tiotropium and its salts are highly effective anticholinergics and can therefore be used to treat asthma or COPD (chronic obstructive pulmonary disease). Pharmacologically, tiotropium bromide monohydrate is also interesting.

Both compounds are the subject of the proposed invention to which preference is given.

The proposed invention relates to liquid formulations of the active substance of these compounds, which can be applied by inhalation, whereby the liquid formulations according to the invention must meet high quality standards.

In order to obtain an optimal distribution of the active substance in the lungs, it makes sense to use liquid formulations without propellant gas, which are given by means of suitable inhalers. Particularly suitable are those inhalers that can atomize a small amount of liquid formulation in a therapeutically necessary dosage into an aerosol suitable for therapeutic inhalation in a few seconds. Within the framework of the proposed invention, preference is given to those atomizers, in which the amount of active substance solution smaller than 100 microliters, preferably smaller than 50 microliters, preferably smaller than 20 microliters, preferably smaller than 20 microliters, preferably with one or two activations, can be atomized into an aerosol with an average particle size smaller than 2 0 microns, preferably less than 10 microns, so that the portion of the aerosol that can be inhaled already corresponds to a therapeutically effective amount.

Such devices for administering a metered amount of liquid medicine for inhalation use without propellant gas are described in detail, for example, in International Patent Application WO 91/14468, "Atomizing Device and Methods", as well as in WO 97/12687, Figures 6a and 6b and in the corresponding description. In such an atomizer, the drug solution is transformed under high pressure up to 500 bar into an aerosol that can enter the lungs and be expelled. Within the scope of the description of the proposed invention, the mentioned publications are taken into account in their entirety and exclusively as literature.

In such inhalers, the solution formulations are in a container. It is important that the active substance formulations used are sufficiently stable during storage and that they are made so that they can be directly applied in accordance with the medical purpose, preferably without any further manipulation. Furthermore, they must not contain any ingredients that could interact with the inhaler, thereby damaging the inhaler or impairing the pharmaceutical quality of the solution, i.e. the aerosol produced in question.

For the atomization of the solution, special nozzles are used, such as, for example, those described in WO 94/07607 or in WO 99/16530, which publications are expressly incorporated herein by way of reference.

WO 98/27 959 describes solution formulations for the inhaler described above, which additionally contain the disodium salt of editic acid (ie disodium ethylenediamine-tetra-acetate dihydrate or sodium edetate). Among the formulations of aqueous solutions that are to be converted into an inhalation aerosol by means of the inhaler described in the introduction, preference is given to a minimum sodium edetate concentration of 50 mg/100 ml in order to limit accidental irregularities in the ejection of the spray. Among the described examples, there is a formulation with tiotropium bromide, which has a pH value of 3.2 and 3.4, respectively. In that formulation, the active substance is dissolved in water. The proportion of sodium edetate is also 50 mg/100 ml.

It has now surprisingly been found that aqueous solution formulations of tiotropium salts are particularly stable when their pH value is below 3.2, preferably below 3.1.

It was also found that such formulations, in comparison with tiotropium bromide formulations which are known from the state of the art, when atomized using the Respimat inhaler, have a reduced deviation of the ejected mass if the amount of sodium edetate ranges between 5 mg and 20 mg per 100 g of the formulation. The quality of the spray formulation according to the invention is very good. The resulting aerosol has very good properties for inhalation application. In addition, the formulation according to the invention has improved stability and patients are less burdened with sodium edetate.

The task of the proposed invention is therefore to produce a formulation of an aqueous active substance with a pharmaceutically acceptable salt of tiotropium that meets the higher standards that are required so that the solution can be optimally atomized using the inhalers mentioned at the outset. At the same time, the active substance formulations according to the invention must also have a sufficiently high pharmaceutical quality, i.e. they must be pharmaceutical stable during a storage time of several years, preferably at least one year, and even better two years.

A further task is to produce propellant-free tiotropium salt solution formulations that can be atomized using a pressurized inhaler, wherein the mass ejected in the generated aerosol is within a reproducibly defined range.

A further task is to prepare an inhalation formulation of the tiotropium salt as a liquid formulation with water as solvent, which is stable and with which the burden of the chemical substances on the patients is reduced to a minimum.

According to the invention, all pharmaceutically acceptable salts of tiotropium can be used for the formulation. If the term tiotropium salt is used within the scope of the proposed invention, it should be understood as tiotropium. A reference to tiotropium, which represents a cation without ammonium, corresponds according to the invention to a reference to tiotropium in the form of such a tiotropium salt which contains an anion as an ion of the opposite charge. As tiotropium salts that can be used within the scope of the proposed invention, compounds which, in addition to tiotropium, contain chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate and/or methylsulfate as an ion (anion) of the opposite charge.

Within the framework of the proposed invention, tiotropium bromide is preferred among the salts.

When tiotropium bromide is mentioned within the scope of the proposed invention, it always means all possible amorphous and crystalline modifications of tiotropium bromide. They can be included, for example, in the crystal structure of the solvent molecule. Of all the crystalline modifications of tiotropium bromide according to the invention, preference is given to those that include water (hydrates). In the framework of the proposed invention, tiotropium bromide monohydrate can be used particularly advantageously.

The formulation preferably does not contain any further active substance, which does not contain tiotropium or its pharmaceutically acceptable salt.

In the formulations according to the invention, tiotropium salts are dissolved in water. No further solvent is used. In particular, the formulation is without propellants.

According to the invention, the formulation preferably contains only one single tiotropium salt, preferably tiotropium bromide or tiotropium bromide monohydrate. However, the formulation may also contain a mixture of various tiotropium salts and solvates.

The concentration of tiotropium salts, calculated as the proportion of tiotropium in the finished pharmaceutical preparation, depends on the desired therapeutic effect. For a number of tiotropium-responsive diseases, the concentration of tiotropium is between 0.01 g per 100 g of formulation and 0.06 g per 100 g of formulation. Since the density of the formulation is 1.00 g/cm3, 100 g of the formulation corresponds to a volume of 100 ml. Within the scope of the proposed description of the invention, the expression "per 100 ml", or V100 ml" means in any case per 100 ml of the formulation, unless otherwise stated. Preference is given to an amount of 0.015 g/100 ml to 0.055 g/100 ml, even better in the amount of 0.02 g/100 ml to 0.05 g/100 ml.The greatest preference is given to the amount of 0.023±0.001 g per 100 ml of the formulation, up to 0.045±0.001 g per 100 ml of the formulation.

The pH value of the formulation according to the invention is between 2.7 and 3.1, preferably between 2.8 and 3.05, even better between 2.80 and 3.0, and most preferably at 2.9.

The pH value is adjusted by the addition of pharmacologically tolerable acids. Examples of such favorable inorganic acids are: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid.

Examples of particularly favorable 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. Favorable inorganic acids are hydrochloric acid and sulfuric acid. Acids that form an acid addition salt with the active substance can also be used.

Among the organic acids, ascorbic acid, fumaric acid and citric acid are favorable, with citric acid being preferred. If necessary, mixtures of the mentioned acids can also be used, especially in the case of acids which, in addition to their acidic properties, have other properties, for example as substances for flavor correction or as antioxidants, such as citric acid or ascorbic acid.

Of the inorganic acids mentioned above, particular preference is given to hydrochloric acid.

If necessary, pharmacologically tolerable bases can also be used to adjust the correct pH value. Suitable bases are, for example, alkali hydroxides and alkali carbonates. A favorable alkali ion is sodium. If such bases are used, care should be taken that the salts obtained from them are then also found in the finished formulation of the drug and that together with the above-mentioned acids they must be pharmacologically acceptable.

The formulation according to the invention contains editic acid (EDTA) or its known salt, for example sodium-EDTA, i.e. disodium-EDTA-dihydrate (sodium edetate) as a stabilizer or as a complex-forming agent. Sodium edetate is primarily used.

In this case, the content calculated as sodium edetate is between 5 mg/100 ml of the formulation and 20 mg/100 ml of the formulation, preferably between 5 mg/100 ml of the formulation and 15 mg/100 ml of the formulation, preferably between 8 mg/100 ml of the formulation and 12 mg/100 ml formulation, and preferably 10 mg/100 ml formulation. If another editic acid salt or acid is used, then that acid is used as such in an amount analogous to the amount of the complexing agent.

The analogy relating to sodium edetate also applies to other possible additives which are similar but do not have the advantage of EDTA or its salts, and which have complexing properties and can be used instead, such as, for example, nitrilotriooctene acid and its salts.

Within the framework of the proposed invention, means for the formation of complexes are understood primarily as molecules that can form complex bonds. These compounds should preferably have cations that form complexes, especially metal cations.

Other pharmacologically tolerable excipients can also be added to the formulations according to the invention.

In this sense, auxiliary and additional substances mean any pharmacologically tolerable and therapeutically meaningful substance that is not an active substance, but which can be formulated together with the active substance in a pharmacologically suitable solvent, in order to improve the qualitative properties of the formulation of the active substance. These substances primarily do not have any or in terms of the desired therapy they do not have any noticeable effect or at least they do not have any unwanted pharmacological effects. These auxiliary and additional substances include, for example, further stabilizers, complex-forming agents, antioxidants and/or preservatives, which extend the duration of use of the finished drug formulation, substances to improve taste, vitamins and/or other additives known from the state of the art. Additives also include pharmacologically unambiguous salts, such as sodium chloride.

Preferred excipients include antioxidants, such as ascorbic acid, if it has not already been used to adjust the pH value, vitamin A, vitamin E, tocopherol and similar vitamins or provitamins that appear in the shell body.

They can be used as a preservative to protect the formulation from contamination with pathogenic bacteria. Suitable preservatives are those known from the state of the art, especially benzalkonium chloride or benzoic acid, or benzoates such as sodium benzoate at concentrations known from the state of the art. According to the invention, benzalkonium chloride is primarily added to the formulation. In this case, the amount of benzalkonium chloride is between 5 mg/100 ml of the formulation and 20 mg/100 ml of the formulation, preferably between 5 mg/100 ml of the formulation and 15 mg/100 ml of the formulation, preferably between 8 mg/100 ml of the formulation and 12 mg/ 100 ml formulation, and preferably 10 mg/100 ml formulation.

In addition to the solvent water and tiotropium salt, the formulations primarily contain only benzalkonium chloride, sodium edetate and the acid necessary to adjust the pH value, preferably hydrochloric acid.

As already mentioned, tiotropium bromide is described in EP 418 716 A1.

Crystalline tiotropium bromide monohydrate can be obtained by a process which will be described in more detail below.

For the production of crystalline monohydrate according to the proposed invention, tiotropium bromide, obtained for example by the process described in EP 418 716 A1, should be placed in water, heated, cleaned with activated carbon and after separation of activated carbon, tiotropium bromide monohydrate slowly crystallizes upon slow cooling.

The procedure is primarily as described below. In a reaction vessel of appropriate dimensions, the solvent is mixed with tiotropium bromide, which was produced, for example, by the process described in EP 418 716 A1.

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

The resulting mixture is heated with stirring, preferably above 50°C, especially preferably above 60°C. The highest temperature that can be selected depends on the boiling point of the solvent (water) used. The mixture is preferably heated to a temperature in the range of 80 to 90°C.

Activated carbon, dry or moistened with water, is added to this solution. Per mole of tiotropium bromide used, preferably 10 to 50 g, particularly preferably 15 to 35 g, most preferably approximately 25 g of activated carbon are used. If necessary, the active substance is mixed in water before being introduced into the solution containing tiotropium bromide. 70 to 200 g, preferably 100 to 160 g, preferably approx. 135 g of water. If the activated carbon is mixed with water before being introduced into the solution containing tiotropium bromide, it is recommended to rinse it with an equal amount of water.

After the addition of activated carbon is complete, it is stirred at a constant temperature for between 5 and 60 minutes, preferably between 10 and 30 minutes, particularly preferably for approximately 15 minutes, and the resulting mixture is filtered to remove the activated carbon. The filter is then rinsed with water. For this purpose, 140 to 400 g, preferably 200 to 320 g, preferably approx. 270 g of water.

The filtrate is then slowly cooled, preferably to a temperature of 20-25°C. Cooling is carried out preferably at a rate of 1 to 10°C for 10 to 30 minutes, preferably 2 to 8°C for 10 to 30 minutes, particularly advantageously from 3 to 5°C for 10 to 20 minutes, most advantageously from 3 to 5°C for approx. every 20 minutes. If necessary, when the mixture has cooled to 20 to 25°C, it can be continued with further cooling to below 20°C, especially advantageously to 10 to 15°C.

After the cooling is complete, the mixture is stirred for another 20 minutes to 3 hours, preferably between 40 minutes and 2 hours, especially preferably for approximately one hour, until the crystallization is complete.

The resulting crystals are then separated from the solvent by filtration or suction. If necessary, the obtained crystals are washed, whereby it is recommended to use water or acetone for washing. 0.1 to 1.0 1, preferably 0.2 to 0.5 1, particularly preferably approximately 0.3 1 of solvent can be used per mole of tiotropium bromide used for washing the obtained crystals of tiotropium bromide monohydrate. Rinsing can be repeated if necessary. The resulting product is dried in a vacuum or with heated air until a water content of 2.5-4.0% is reached.

One aspect of the proposed invention therefore also relates to a formulation in the form of a solution of the type described above, in which crystalline tiotropium bromide monohydrate is used, which can be obtained in accordance with the previously described process.

Formulations of the drug according to the invention containing tiotropium salts are primarily used in an inhaler of the type described above, in order to produce an aerosol from it according to the invention without propellant gas. For this reason, the patent documents mentioned in the introduction are expressly referred to at this point, which are taken into account.

As mentioned in the introduction, a further developed form of the inhaler of WO 97/12687 and its figure 6, which is preferred, will be described. According to the invention, this atomizer (Respimat) can be usefully used to create an inhalation aerosol that contains tiotropium salt as an active substance. Due to its cylindrical shape and size suitable for handling, it has a length of less than 9 to 15 cm and a width of 2 to 4 cm, this device can always be carried by the patient. An atomizer ejects a defined volume of drug formulation through a small nozzle under high pressure, creating an aerosol that can be inhaled.

A preferred atomizer consists mainly of an upper housing, a pump housing, a nozzle, a stop member, a spring housing, a spring and a supply tank, and is characterized by

- the pump housing is fixed in the upper part of the housing, and at one end it carries the body of the nozzle, i.e. the assembly with the nozzle,

- has a hollow piston with a valve body,

- has a working flange in which a hollow piston is fixed, and it is located in the upper part of the housing,

- has a locking element located in the upper part of the housing,

- has a spring housing in which a spring is located, which spring housing is pivotally seated in the upper part of the housing by means of a pivot bearing,

- has the lower part of the housing, which is pushed onto the spring housing in the direction of the axis.

A hollow piston with a valve body corresponds to the devices described in WO 97/12687. It partially protrudes into the cylinder of the pump housing and is mounted in the cylinder so that it can be moved axially therein. Figures 1-4 are especially taken into account, especially figure 3 and the corresponding description. A hollow piston with a valve body on its high pressure side at the moment of spring release acts with a pressure of 5 to 60 MPa (approximately 50 to 600 bar), preferably 10 to 60 MPa (approximately 100 to 600 bar) on the liquid, i.e. on the metered solution active substances. At the same time, the volume per stroke is preferably from 10 to 50 microliters, especially advantageously from 10 to 20 microliters, especially advantageously 15 microliters.

The valve body is primarily located at the end of the hollow piston facing the nozzle body.

The nozzle in the nozzle body is primarily micro-structured, i.e. it is produced by micro-technique. Micro-structured nozzle bodies are described, for example, in WO-99/16530; therefore, the contents of that document, in particular Figure 1 in WO-94/07607 and its description, are taken into account.

The body of the nozzle consists, for example, of two plates made of glass and/or silicon oxide firmly connected to each other, of which at least one plate has one or more micro-structured channels, which connect the inlet side of the nozzle with the outlet side of the nozzle. On the exit side of the nozzle there is at least one round or non-round hole of depth. from 2 to 10 micrometers and width b to 15 micrometers, whereby the depth is preferably 4.5 to 6.5 micrometers and the length is 7 to 9 micrometers.

In case there are several nozzle openings, preferably two openings, then the jet directions from the nozzles in the nozzle body can run parallel to each other or they are inclined to each other in the direction of the nozzle openings. In a nozzle body with at least two nozzle openings, the jet directions on the exit side can be inclined to each other at an angle of 20 degrees to 160 degrees, preferably at an angle of 60 to 150 degrees, especially advantageously at an angle of 80 to 100 degrees.

The nozzle openings are preferably spaced at a distance of 10 to 200 microns, more preferably at a distance of 10 to 100 microns, particularly preferably 30 to 70 microns. The best distance is 50 microns.

Accordingly, the directions of the jets meet in the vicinity of the nozzle opening.

The liquid preparation of the drug, as already mentioned, comes to the body of the nozzle with an inlet pressure of 600 bar, preferably 200 to 300 bar and is dispersed through the nozzle openings into an aerosol that can be inhaled. A preferred aerosol particle size is up to 20 microns, preferably 3 to 10 microns.

The locking element includes a spring, preferably a cylindrical screw compression spring, as stored mechanical energy. The spring acts on the working flange as a spring, the movement of which is determined by the position of the locking part. The path of the working flange is exactly bounded by the upper and lower stops. The spring is tensioned via a power transmission gear, such as a screw shift gear, with an external torque, which is generated by turning the upper part of the housing towards the spring housing. In this case, the upper part of the housing and the working flange contain a single or multi-stage wedge gear.

The locking part with the retractable locking surface is annular, to fit the working flange. It consists of a ring that can elastically deform radially inward and is made of plastic or metal. The ring is placed in one plane perpendicular to the axis of the atomizer. After tensioning the spring, the locking surfaces of the locking part move to the path of the working flange and prevent the spring from being unloaded. The locking part is released using a button. The activation button is connected or connected to the locking part. To activate the locking element, the button is moved parallel to the plane of the ring and primarily into the atomizer; in doing so, the ring, which can be deformed, is deformed in the plane of the ring. Details of the construction of the locking element are described in WO 97/20590.

The lower part of the housing moves axially over the spring housing and covers the bearing, spindle drive and fluid reservoir.

To activate the atomizer, the upper part of the housing is rotated towards the lower part of the housing, whereby the lower part of the housing engages the spring housing. In doing so, the spring presses together over the screw displacement gear and is tensioned and the locking element engages automatically. The turning angle is primarily a fraction of a whole number of 3 60 degrees, eg 180 degrees. At the same time as the spring is tensioned, the working part moves in the upper part of the housing for a predetermined distance, the hollow piston is pulled back inside the cylinder in the pump housing, which sucks a part of the amount of liquid from the storage tank into the high-pressure space in front of the nozzle.

If necessary, several exchangeable supply containers containing the liquid to be atomized can be pressed into the atomizer and used in succession. The supply container contains the aqueous aerosol preparation according to the invention.

The atomization process is performed by lightly pressing the activation button. In doing so, the locking element clears the way for the working part. A tensioned spring moves the piston into the cylinder of the pump housing. The liquid comes out of the atomizer nozzle in atomized form.

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

Add-on parts of the spray device (atomizer) made of a suitable material that corresponds to its function. The housing of the atomizer and other parts - if this is possible due to the function - are primarily made of plastic, for example by injection molding. Physiologically clear materials are used for medical purposes.

Figures 1a/b, which are identical to Figures 6a/b from WO 97/12687, show an atomizer (Respimat®) with which aqueous aerosol preparations according to the invention can be inhaled.

Figure 1a shows a longitudinal section through the atomizer with the spring under tension, while Figure 1b shows a longitudinal section through the atomizer with the spring unloaded.

The upper part of the housing (51) contains the pump housing (52), at the end of which there is a holder (53) for the atomizer nozzle. The holder contains the nozzle body (54) and the filter (55). The hollow piston (57), which is fixed in the working flange (56) of the locking element, partially protrudes into the cylinder of the pump housing. The hollow piston carries the valve body (56) at its end. The hollow piston is sealed with a gasket (59). Inside the upper part of the housing there is a stop (60), on which the working flange rests when the spring is tensioned. When the spring is tensioned, then the stop member (62) moves in the upper part of the housing between the stop (61) and the support (63). The activation button (64) is connected to the locking member. The upper part of the housing ends in a spout (65) and it is closed with a protective cap (66) that can be put on.

The spring housing (67) with the compression spring (68) is pivoted by means of a snap-in support (69) and a pivot bearing on the upper part of the housing. The upper part of the housing (70) moves over the spring housing. Inside the spring housing is a replaceable container (71) with a supply of liquid (72) to be sprayed. The container with the supply is closed with a plug (73), through which the hollow piston enters the container with the supply and its end is immersed in the liquid (stock solution of the active substance).

There is a spindle (14) for the mechanical dial on the outer surface of the spring housing. At the end of the spindle facing the upper part of the housing there is a drive notch (75). A rider sits on the spindle (76).

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

If the formulation according to the invention is atomized using the previously described technique (Respimat®), the ejected mass with at least 97%, preferably at least 98% of all inhaler activations (displacements) must correspond to a defined amount with a tolerance area of at most 25%, preferably 20% of that amount . Preferably between 5 and 30 mg of the formulation is ejected per shift as a defined mass, particularly preferably between 5 and 20 mg.

However, the formulation according to the invention can also be atomized with inhalers that are different from the inhaler described above, for example with Jet-Stream inhalers.

EXAMPLES

I. Example of synthesis of tiotropium bromide monohydrate

25.7 kg of water is placed in a suitable reaction vessel and 15.0 kg of tiotropium bromide is added. The mixture is heated to 80-90°C and stirred at a constant temperature until a clear solution is obtained. Activated carbon (0.8 kg), moistened with water, is mixed in 4.4 kg of water and this mixture is added to the solution containing tiotropium bromide and supplemented with 4.3 kg of water. The mixture obtained in this way is stirred for at least 15 minutes at 80-90°C and then filtered through a filter into an apparatus whose jacket is preheated to 70°C. The filter is washed with 8.6 kg of water. The contents of the apparatus are cooled to a temperature of 20-25°C at a cooling rate of 3-5°C in 20 minutes. The apparatus is further cooled to 10-15°C by cooling with cold water and crystallization is assisted by stirring for another hour. The crystallisate is isolated by suction, the isolated crystals are washed with 9 l of cold water (10-15°C) and with cold acetone (10-15°C). The obtained crystals are dried for 2 hours at 25°C in a stream of nitrogen.

Yield: 13.4 kg of tiotropium bromide monohydrate (8 6% of theoretical).

II. Examples of formulations

100 ml of the pharmaceutical preparation contains:

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The residue is cleaned with water, that is, with water for injection purposes with a density of 1.00 g/cm and at a temperature of 15°C to 31°C.

Further examples 13 to 24:

Analogous to examples 1 to 12, but with 9 mg sodium edetate.

Further examples 25 to 36:

Analogous to examples 1 to 12, but with 11 mg sodium edetate.

Further examples 37 to 48:

Analogous to examples 1 to 12, but with 9 mg of benzalkonium chloride.

Further examples 4 9 to 60:

Analogous to examples 1 to 12, but with 11 mg of benzalkonium chloride.

In further examples, the amount of benzalkonium chloride is 8 and 12 mg, respectively.

In further examples, the amount of sodium edetate is 8 and 12 mg, respectively.

Among the examples, the greatest preference is given to examples 1 to 4.

Claims (28)

1. Pharmaceutical preparation, characterized in that it contains • one or more tiotropium salts as active substances with a tiotropium-based concentration between 0.01 g per 100 ml of the formulation and 0.06 g per 100 ml of the formulation, whereby the tiotropium salt(s) present in the pharmaceutical preparation is completely dissolved, • water as the only solvent, • acid for adjusting the pH value between 2.7 and 3.1, preferably 2.8 and 3.05, • pharmacologically tolerable preservative, • a pharmacologically acceptable agent for the formation of complexes and/or a stabilizer and/or, if necessary, one or more other pharmacologically acceptable auxiliary and additional substances. 2. Pharmaceutical preparation according to claim 1, characterized in that the tiotropium salt is a salt with HBr, HCl, HI, with monomethyl sulfate, methanesulfonic acid and/or with p-toluenesulfonic acid. 3. Pharmaceutical preparation according to claim 1, characterized in that the active substance is only tiotropium bromide. 4. Pharmaceutical preparation according to claim 1, characterized in that the active substance is only tiotropium bromide monohydrate. 5. A pharmaceutical preparation according to any of claims 1 to 4, characterized in that editic acid or its pharmacologically tolerable salt is used as a complex-forming agent. 6. Pharmaceutical preparation according to any one of claims 1 to 4, characterized in that sodium edetate is used as a complex forming agent. 7. Pharmaceutical preparation according to claim 6, characterized in that sodium edetate is contained in an amount of 5 mg/100 ml of the formulation to 20 mg/100 ml of the formulation, preferably between 8 mg/100 ml of the formulation and 12 mg/100 ml of the formulation. 8. Pharmaceutical preparation according to any of claims 1 to 7, characterized in that the pH value is between 2.8 and 3.0, preferably at 2.9. 9. Pharmaceutical preparation according to any of claims 1 to 7, characterized in that the pH value is adjusted with an inorganic acid, preferably with hydrochloric acid. 10. Pharmaceutical preparation according to any claim 1 to 9, characterized in that the concentration of tiotropium is between 0.02 g/100 ml of formulation and 0.05 g/100 ml of formulation, preferably between 0.023±0.001 g per 100 ml of formulation up to 0.045±0.001g per 100 ml formulation. 11. Pharmaceutical preparation according to any of claims 1 to 10, characterized in that the preparation contains benzalkonium chloride as a preservative. 12. Pharmaceutical preparation according to any claim 1 to 11, characterized in that the formulation does not contain any further auxiliary and additional substances except water, tiotropium salt, benzalkonium chloride, sodium edetate, hydrochloric acid and, if necessary, sodium chloride. 13. Pharmaceutical preparation according to any of claims 1 to 12, characterized in that 100 ml of the formulation is produced by dissolving 0.057 g of tiotropium bromide monohydrate, 10 mg of anhydrous benzalkonium chloride, 10 mg of sodium edetate in water ad 100 ml and 1N hydrochloric acid to adjust the pH values at 2.9. 14. Pharmaceutical preparation according to any of claims 1 to 12, characterized in that 100 ml of the formulation is produced by dissolving 0.028 g of tiotropium bromide monohydrate, 10 mg of anhydrous benzalkonium chloride, 10 mg of sodium edetate in 100 ml of water and 1N hydrochloric acid to adjust the pH values at 2.9. 15. Pharmaceutical preparation according to any of claims 1 to 12, characterized in that 100 ml of the formulation is produced by dissolving the tiotropium salt in an amount of 0.045 g based on tiotropium, 10 mg of anhydrous benzalkonium chloride, 10 mg of sodium edetate in water ad 100 ml and 1N saline acid to adjust the pH value to 2.9. 16. Pharmaceutical preparation according to any of claims 1 to 12, characterized in that 100 ml of the formulation is produced by dissolving the tiotropium salt in an amount of 0.023 g based on tiotropium, 10 mg of anhydrous benzalkonium chloride, 10 mg of sodium edetate in water ad 100 ml and 1N saline acid to adjust the pH value to 2.9. 17. Pharmaceutical preparation according to any of claims 1 to 16, characterized in that it is used as a medicine for inhalation application. 18. The use of a pharmaceutical composition according to any one of claims 1 to 17, characterized in that it is used for atomization in the inhaler according to WO 91/14468 or in the inhaler shown in Figures 6a and 6b and described in WO 97/12687. 19. The use of a pharmaceutical preparation according to any one of claims 1 to 17, characterized in that it is used for atomization in an inhaler, which atomizes a defined amount of the drug formulation by applying a pressure of 100 to 600 bar through a nozzle with at least one opening of a depth of 2 to 10 micrometers and a width of 5 to 15 micrometers to create an inhalation aerosol. 20. Use according to claim 19, characterized in that at least one nozzle opening consists of at least two nozzle openings that are inclined towards each other in the direction of the nozzle opening at an angle of 20 degrees to 160 degrees. 21. Use according to claim 19 or 20, characterized in that the defined amounts amount to 10 to 50 microliters. 22. Use according to any of claims 19 to 21, characterized in that the inhaler has a length of 9 to 15 cm and a width of 2 to 4 cm. 23. Use according to any one of claims 19 to 22, characterized in that the ejected mass of the formulation after at least 97% of all actuations of the inhaler is between 5 and 30 mg with a tolerance range of 25%. 24. Use according to claim 23, characterized in that the mass of the formulation thrown out after at least 97% of all . inhaler activation is between 5 and 30 mg with a tolerance range of 20%. 25. Use according to any claim 23 or 24, characterized in that the ejected mass of the formulation is achieved after at least 98% of all inhaler actuations. 26. Use of a pharmaceutical composition according to any one of claims 1 to 17, characterized in that it is used as a medicine, in particular for the treatment of asthma and/or COPD. 27. A method for the treatment of asthma and/or COPD, characterized in that the pharmaceutical preparation according to any of claims 1 to 17 is used, especially in an inhaler according to any of claims 18 to 25. 28. A method for the production of a pharmaceutical preparation according to any of claims 1 to 17, characterized in that the individual components are mixed together.