HK1078793B - Aerosol formulation for inhalation comprising a tiotropium salt - Google Patents

Description

Aerosol formulation for inhalation comprising tiotropium salt

The present invention relates to a propellant-free aerosol formulation of a pharmaceutically acceptable tiotropium salt dissolved in water. The formulations according to the invention are particularly suitable for administration of the active substance by inhalation by means of nebulization of the active substance by means of a nebulizer. Preferred indications are asthma and/or COPD.

Tiotropium salts of formula (1 α, 2 β, 4 β, 5 α, 7 β) -7- [ (hydroxydi-2-thiopheneacetyl) oxy]-9, 9-dimethyl-3-oxa-9-azonia tricyclo [3.3.1.0^2，4]Nonane, in EuropeThe continental patent application EP 418716a1 is known as tiotropium bromide. Tiotropium bromide has the following chemical structure

This compound has valuable pharmacological properties and is known as tiotropium bromide. Tiotropium and its salts are highly effective anticholinergic agents. Thus providing therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease). Tiotropium bromide monohydrate is also of value pharmacologically.

Both compounds are preferred objects of the present invention.

Disclosure of Invention

The present invention provides a pharmaceutical formulation comprising

One or more tiotropium salts as active substance in a concentration of between 0.023 ± 0.001 g per 100ml of formulation and 0.045 ± 0.001 g per 100ml of formulation, based on tiotropium, wherein the one or more tiotropium salts are present in the pharmaceutical formulation in completely dissolved form

Water is the only solvent and the solvent is,

adjusting the pH value to between 2.8 and 3.05 with an acid,

benzalkonium chloride as a pharmacologically acceptable preservative,

ethylenediaminetetraacetic acid or a pharmacologically acceptable salt thereof as a pharmacologically acceptable complexing agent in an amount of from 5 mg to 20 mg per 100ml of the preparation.

The above pharmaceutical preparation according to the invention is characterized in that the tiotropium salt is a salt with hydrobromic acid, hydrochloric acid, hydroiodic acid, monomethyl sulfate, methanesulfonic acid and/or p-toluenesulfonic acid.

The above-mentioned pharmaceutical preparation according to the present invention is characterized by not comprising any other excipients and additives other than water, tiotropium salt, benzalkonium chloride, disodium edetate, hydrochloric acid and optionally sodium chloride.

The invention relates to liquid active substance formulations for the general administration of these compounds by inhalation, wherein the liquid formulations according to the invention meet high quality standards.

To achieve an optimal active substance distribution of the active substance in the lungs, propellant-free liquid preparations are administered using suitable inhalers. A particularly suitable inhaler is one that is capable of aerosolizing a small quantity of a liquid formulation having the dose required for therapeutic purposes in a few seconds to form an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, a preferred nebulizer is one that is preferably capable of nebulizing less than 100 microliters, preferably less than 50 microliters, most preferably less than 20 microliters of liquid active substance in one or two puffs to form an aerosol having an average particle size of less than 20 micrometers, preferably less than 10 micrometers, such that the respirable fraction of the aerosol corresponds to a therapeutically effective amount.

Such metered dose liquid pharmaceutical compositions are administered in propellant-free manner by apparatus such as the "atomising device and method" of international patent application WO 91/14468 and also in WO97/12687, the figures 6a and 6b of which and the description relating thereto are detailed. In this nebulizer, the drug solution is converted into an aerosol by high pressure up to 500 bar, and is ejected toward the lungs. The above references are expressly incorporated in their entirety within the present specification.

In this inhaler, the solution formulation is stored in a storage tank. The active substance preparations used are necessarily sufficiently stable on storage and can be administered directly, if possible without further treatment, to suit their medical purpose. Furthermore, they must be free of any components that may interact with the inhaler so as to impair the inhaler or the solution quality of the aerosol produced.

For atomizing the solution, special nozzles are used, as already described in WO 94/070607 or WO 99/16530, both of which are incorporated herein by reference.

WO 98/27959 discloses a solution formulation for the above inhaler comprising as an additive a disodium salt of ethylenediaminetetraacetic acid (or disodium ethylenediaminetetraacetate dihydrate or disodium ethylenediaminetetraacetate). For converting a water-soluble solution preparation into an inhalable aerosol using the inhaler described above, the present specification is inclined to use disodium edetate at a minimum concentration of 50mg/100ml to reduce the abnormality of atomization. In embodiments disclosed herein, there is a formulation comprising tiotropium bromide having a pH of 3.2 or 3.4. In such formulations, the active substance may be dissolved in water. The proportion of the disodium ethylene diamine tetraacetate is still 50mg/100 ml.

Surprisingly, it has now been found that water-soluble formulations of tiotropium salt solutions are particularly stable at pH values below 3.2, preferably below 3.1.

In addition, it was found that when Respimat is used^®Such formulations have been shown to provide reduced dispersion of the composition when sprayed by a nebulizer, if the amount of disodium edetate is between 5 mg and 20 mg per 100 g of formulation, as compared to formulations containing tiotropium bromide known in the art. The spray quality of the formulation according to the invention is good. The aerosol thus produced has very good properties for administration by inhalation. In addition, the formulation according to the present invention has improved stability and reduces the burden on patients with disodium edetate.

It is therefore an object of the present invention to provide a desired water-soluble active substance formulation containing a pharmaceutically acceptable tiotropium salt and in a high standard, which is necessary for achieving an optimum spray effect of the solution using the above-mentioned inhaler. The active substance preparations according to the invention must have a sufficiently high drug quality that they should have a drug stability over a storage period of several years, preferably at least one year, more preferably two years.

Another object is to provide a propellant-free tiotropium salt-containing solution formulation, nebulized under pressure using an inhaler, the composition delivered by the generated aerosol being reproducible within a specific range.

Another object is to provide an inhalable formulation of a liquid formulation comprising tiotropium salt in a water solvent that is stable and reduces the burden on the patient of chemicals to a minimum.

According to the present invention, any pharmaceutically acceptable tiotropium salt can be used as a formulation. When the term tiotropium is used within the scope of the present invention, reference is made to tiotropium species. The tiotropium reference corresponds to the cation of the free ammonium. The tiotropium salt thus comprises an anion as the counter ion. Tiotropium salts which can be used within the scope of the present invention are preferably compounds which, in addition to tiotropium, contain as counter-ion (anion) also chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate and/or methosulfate.

Preferred within the scope of the present invention is tiotropium bromide. Within the scope of the present invention reference to tiotropium bromide is generally understood to be a reference to all possible amorphous and crystalline modified tiotropium bromide. For example, these may contain solvent molecules in their crystal structure. According to the present invention, it is preferred to contain water (hydrate) in all crystal modifications of tiotropium bromide. It is particularly preferred within the scope of the present invention to use tiotropium bromide monohydrate.

The present formulation is preferably an active substance which does not contain any other tiotropium-free active substance or a pharmaceutically acceptable salt thereof.

The tiotropium salt of one or more of the formulations according to the invention is dissolved in water. No other solvent was used. In particular, such formulations are devoid of propellant gas.

The formulations according to the invention preferably contain only a single tiotropium salt, preferably tiotropium bromide or tiotropium bromide monohydrate. However, such formulations may also contain mixtures of different tiotropium salts and solvates.

The concentration of tiotropium salt depends on the desired therapeutic effect, depending on the tiotropium ratio of the final pharmaceutical preparation. For most disorders responsive to tiotropium, the concentration of tiotropium is between 0.01 gram per 100 gram of formulation and 0.06 gram per 100 gram of formulation. Because the density of the preparation is 1g/cm³A 100 gram formulation corresponds to a volume of 100 ml. Within the context of the present description, the expression "per 100 ml" or "/100 ml" is, unless stated otherwise, in each case a formulation per 100 ml. Preferably in an amount of 0.015g/100ml to 0.055g/100ml, more preferably in an amount of 0.02g/100ml to 0.05g/100 ml. The optimal amount is 0.023 +/-0.001 g per 100ml of the preparation to 0.045 +/-0.001 g per 100ml of the preparation.

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

The pH is adjusted by the addition of a pharmacologically acceptable acid.

Examples of preferred inorganic acids for this purpose include: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids are ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid and the like. Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which form acid addition salts with the active substance. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred, and citric acid is most preferred. Mixtures of the above acids may also be used, if desired, especially in the case of acids which have other properties in addition to their acidifying properties, for example as flavoring agents or antioxidants, such as citric acid and ascorbic acid.

Among the acids mentioned above, hydrochloric acid and citric acid are clearly indicated as being particularly preferred.

If necessary, a pharmacologically acceptable base can be used to precisely titrate the pH. Suitable bases include, for example, alkali metal hydroxides and alkali metal carbonates. The preferred alkali metal ion is sodium. If such bases are used, care must be taken to ensure that the final salt contained in the final pharmaceutical formulation is pharmacologically compatible with the above-mentioned acids.

According to the invention, the formulation comprises ethylenediaminetetraacetic acid (EDTA) or one of its known salts, such as sodium ethylenediaminetetraacetate or disodium ethylenediaminetetraacetate dihydrate, as a stabilizer or complex former. Disodium edetate is preferably used.

According to the content of the disodium edetate, the content is between 5 mg per 100ml of the preparation and 20 mg per 100ml of the preparation, preferably between 5 mg per 100ml of the preparation and 15 mg per 100ml of the preparation, more preferably between 8 mg per 100ml of the preparation and 12 mg per 100ml of the preparation, and most preferably 10 mg per 100ml of the preparation.

If a different salt of ethylenediaminetetraacetic acid or acid is used, a similar amount of complexing agent is used.

It is noted that other additives, which are less preferred than ethylenediaminetetraacetic acid or a salt thereof, but which have complexing properties such as nitrilotriacetic acid and salts thereof, may similarly be used in relation to disodium ethylenediaminetetraacetate.

In the context of the present invention, complexing agents preferably mean molecules which are capable of entering into a coordinate bond. Preferably, the complexation is performed by cations of these compounds, most preferably metal cations.

Other pharmacologically acceptable adjuvants may also be added to the formulations according to the invention.

Auxiliaries and additives in this context mean any pharmacologically acceptable, therapeutically useful substance which 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 quality of the active substance preparation. Preferably, these substances have no pharmacological effect or have no equivalent or at least no desired pharmacological effect under the desired therapeutic conditions. Such adjuvants and additives may include, for example, other stabilizers, complexing agents, antioxidants, and/or preservatives, flavoring agents, vitamins, and/or other additives known in the art that may prolong the shelf life of the final pharmaceutical formulation. Such additives also include pharmaceutically acceptable salts, such as sodium chloride.

Preferred adjuvants include antioxidants, such as ascorbic acid, but with the proviso that they are not used to adjust the pH, vitamin a, vitamin E, tocopherol and similar vitamins or vitamin precursors present in the human body.

Preservatives may be added to protect the formulation from contamination by pathogenic bacteria. Suitable preservatives are known from the prior art, in particular benzalkonium chloride, or benzoic acid, or benzoates, for example sodium benzoate, in concentrations known from the prior art. Preferably, according to the invention, benzalkonium chloride is admixed to the preparation. The amount of benzalkonium chloride is between 5 mg per 100ml of formulation and 20 mg per 100ml of formulation, preferably between 5 mg per 100ml of formulation and 15 mg per 100ml of formulation, more preferably between 8 mg per 100ml of formulation and 12 mg per 100ml of formulation, most preferably 10 mg per 100ml of formulation.

Preferred formulations contain only benzalkonium chloride, disodium ethylenediaminetetraacetate and the acid required to adjust the pH, preferably hydrochloric acid, in addition to the aqueous solvent and the tiotropium salt.

As already mentioned, tiotropium bromide is described in EP 418716a 1.

Crystalline tiotropium bromide monohydrate can be obtained using the preparation process detailed below.

According to the invention, to prepare the crystalline monohydrate, tiotropium bromide obtained by the preparation method disclosed in EP 418716a1 is, for example, first dissolved in water, heated, purified with activated carbon, and after removing the activated carbon, slowly crystallized upon slow cooling.

Preferably described in the following steps:

in a suitably sized reaction vessel, the solvent is mixed with tiotropium bromide, for example prepared by the method of preparation described in EP 418716a 1. For each mole of tiotropium bromide added, 0.4 to 1.5 kg of water is used as solvent, preferably 0.6 to 1 kg, most preferably about 0.8 kg. The resulting mixture is heated with stirring, preferably to above 50 ℃, optimally to above 60 ℃. The maximum temperature that can be selected is determined by the boiling point of the solvent (water) used. Preferred mixtures are heated to a temperature in the range of 80 to 90 ℃.

Activated carbon, either dry or wet with water, is added to this solution. Preferably, from 10 to 50 grams, more preferably from 15 to 35 grams, and most preferably about 25 grams of activated carbon are added per mole of tiotropium bromide added. If desired, the activated carbon is suspended in water before addition to the aqueous solution containing tiotropium bromide. To suspend the activated carbon, 70 to 200 grams of water, preferably 100 to 160 grams, and more preferably about 135 grams, are used per mole of tiotropium bromide added. If the activated carbon is pre-suspended in water, it is advisable to rinse again with an equal amount of water before adding the aqueous solution containing tiotropium bromide.

After the addition of the activated carbon, stirring is continued at a constant temperature for 5 to 60 minutes, preferably 10 to 30 minutes, more preferably about 15 minutes, and the resulting mixture is filtered to remove the activated carbon. The filter paper was then rinsed with water. For each mole of tiotropium bromide used, 140 to 400 grams of water, preferably 200 to 320 grams, most preferably about 270 grams, are used.

The filtrate is then slowly cooled to a temperature preferably of 20 to 25 ℃. The preferred cooling rate for cooling is 1 to 10 ℃ per 10 to 30 minutes, preferably 2 to 8 ℃ per 10 to 30 minutes, more preferably 3 to 5 ℃ per 10 to 20 minutes, most preferably 3 to 5 ℃ per 20 minutes. If desired, cooling to 20 to 25 ℃ may be followed by further cooling to less than 20 ℃, preferably 10 to 15 ℃.

After completion of the cooling, stirring is continued for 20 minutes to 3 hours, preferably 40 minutes to 2 hours, more preferably about 1 hour to complete the crystallization.

The solvent is then removed by filtration or suction filtration to isolate the crystals obtained. The crystals obtained are further washed, and it is recommended to use water or acetone as a solvent for washing. To wash the crystalline tiotropium bromide monohydrate obtained, 0.1 to 1.0 liter of solvent, preferably 0.2 to 0.5 liter, more preferably about 0.3 liter, per mole of tiotropium bromide is added. The washing step may be repeated as necessary. The product obtained is dried under vacuum or with air heated with circulation until a water content of 2.5 to 4.0% is obtained.

According to one aspect, the present invention relates to the above solution formulation using the crystalline tiotropium bromide monohydrate obtained in the above step.

The pharmaceutical formulations according to the invention comprising tiotropium bromide salts preferably use the above mentioned inhalers to produce a propellant-free aerosol according to the invention. The above-described patent documents are again expressly mentioned here as reference.

As mentioned at the outset, a further embodiment of a preferred inhaler is disclosed in WO97/12687 and its figure 6. This sprayer (Respimat)^®) It is advantageously possible to produce inhalable aerosols according to the invention which comprise tiotropium salts as active substance. The device can be carried by a patient at any time based on its cylindrical shape and size of the hand less than 9 to 15cm long by 2 to 4cm wide. The nebulizer ejects a fixed volume of the pharmaceutical formulation through a small nozzle under high pressure to produce an inhalable aerosol.

The preferred sprayer consists essentially of a housing upper part, a pump housing part, a nozzle, locking pliers, a spring housing part, a spring and a reservoir, characterized by:

a pump housing fixed to an upper portion of the housing and a nozzle body having a nozzle or an array of nozzles at one end,

-a hollow piston having a valve body,

a drive flange located in the upper part of the housing and fixing the hollow body,

a locking pliers located in the upper part of the housing,

a spring housing with a spring therein, rotatably mounted with a rotational bearing in an upper part of the housing,

a housing lower part, fixed to the spring housing part in the direction of the axis.

The hollow piston with the valve body corresponds to the device disclosed in WO 97/12687. It projects partly in the cylinder of the pump housing part and is axially displaceable in the cylinder. With particular reference to fig. 1 to 4 and in particular fig. 3 and the related description. At the end of the high pressure, the hollow piston with the valve body exerts a pressure of 5 to 60MPa (approximately 50 to 600 bar) on the solution, preferably 10 to 60MPa (approximately 100 to 600 bar), i.e. the measured amount of active substance solution, when the spring is released. The preferred volume per actuation is 10 to 50 microliters, more preferably 10 to 20 microliters, and particularly preferably 10 to 15 microliters.

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

The nozzle in the nozzle body is preferably microstructured, i.e. produced in a microfabrication process. Microstructured nozzle bodies are disclosed for example in WO 99/16530; reference is therefore made to the present description, in particular to fig. 1 and the related description.

The nozzle body comprises, for example, two pieces made of glass and/or silicon and held together in close proximity, at least one of which has one or more microstructured channels connecting the inlet end and the outlet end of the nozzle. At the outlet end of the nozzle there is at least one annular or non-annular opening, 2 to 10 microns deep and 5 to 15 microns wide, preferably 4.5 to 6.5 microns deep and 7 to 9 microns long.

If there are a plurality of nozzle openings, preferably two, the spray directions of the nozzles of the nozzle body may be parallel to each other or inclined relative to each other in the nozzle opening direction. In the case of at least two nozzle openings at the outlet end of the nozzle body, the directions of the sprays can be inclined at an angle of 20 to 160 degrees, preferably 60 to 150 degrees, most preferably 80 to 100 degrees, relative to one another. The nozzle openings are preferably arranged 10 to 200 microns apart, preferably 10 to 100 microns apart, more preferably 30 to 70 microns. Most preferably 50 microns apart.

The direction of the spray thus meets around the nozzle opening.

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

The locking pliers structure includes a spring, preferably a cylindrical helical compression spring, which acts as a mechanical energy reservoir. The spring acts on the drive flange as a spring element, the movement of which is dependent on the position of the locking device. The travel of the drive flange is precisely limited by the upper and lower stops. The spring is preferably tensioned by the external torque from an up gear, such as a helical sliding gear, which is caused by the rotation of the upper part of the housing relative to the spring housing in the lower part of the housing. In this case, the upper portion of the housing and the drive flange contain single or multiple ratio tooth slot gears.

A locking device having an engaging locking surface annularly surrounds the drive flange. Which consists for example of an elastically deformable plastic or metal ring in its radial direction. This ring is mounted on a plane perpendicular to the axis of the atomizer. After locking the spring, the locking surface of the locking device moves into the path of the drive flange and prevents the spring from unwinding. The locking device is activated by a key. The triggering key is connected or coupled with the locking device. For triggering the locking pliers structure, the trigger key is moved parallel to the annular plane, preferably into the spray device, and the deformable ring is thus deformed on the annular plane. Details of the construction of the locking pliers are described in WO 97/20590.

The lower portion of the housing is moved along the shaft toward the spring housing and covers the bearing, acting as a drive for the shaft and reservoir for the solution.

When the sprayer is in operation, the upper part of the housing rotates relative to the lower part of the housing, which brings the spring housing with it. The spring is compressed and tensioned together through the spiral sliding gear, and the locking pliers are automatically meshed. The angle of rotation is preferably an equal fraction of 360 degrees, for example 180 degrees. At the same time as the spring is tightened, the drive member above the housing is moved a given amount and the hollow piston is pulled back into the cylinder of the pump housing, as a result of which part of the solution is sucked from the storage container into the high-pressure chamber in front of the nozzle.

If desired, a plurality of replaceable storage containers containing the solution to be atomized can be moved into the atomizer one after the other and then used. The storage container contains a water-soluble aerosol formulation according to the present invention.

The atomization process is started by pressing a start key lightly. The locking element then opens the drive element. The tensioned spring moves the piston into the cylinder of the pump housing. The liquid is sprayed from the nozzle of the atomizer in atomized form.

Further details of the structure are disclosed in PCT applications WO 97/12683 and WO 97/20590, which are incorporated herein by reference.

The components of this sprayer are made of materials suitable for their function. The housing and other parts of the sprayer-if functional, are preferably made of plastic, for example by injection molding. For medical use, physiologically acceptable materials are used.

FIGS. 1a/b, identical to FIGS. 6a/b of WO97/12687, show the use of Respimat^®The nebulizer may advantageously inhale the water-soluble spray preparation according to the invention.

FIG. 1a shows a longitudinal section of the atomizer with the spring tensioned, and FIG. 1b shows a longitudinal section of the atomizer with the spring relaxed.

The upper housing part (51) contains a pump housing (52) which is fitted at one end with a holder (53) for the atomizer nozzle. Wherein the holder has a nozzle body (54) and a filter (55). A hollow piston (57), fixed to the driving flange (56) of the locking pliers, projects partly in the cylinder of the pump housing. The hollow piston carries a valve body (58) at its distal end. The hollow piston is closed by a gasket (59). The interior of the upper portion of the housing has a stop (60) against which the drive flange can abut when the spring is relaxed. A stop (61) is located on the drive flange against which the drive flange can abut when the spring is tensioned. After the spring is tightened, the locking device (62) slides between a stop (61) in the upper part of the housing and a support body (63). An activation key (64) is coupled to the locking device. The upper part of the housing ends in an interface piece (65) and is closed by a movable protective cover (66).

A spring housing (67) with a compression spring (68) is rotatably mounted to the housing upper part by means of a fixing catch (69) and a rotational bearing. A lower housing portion (70) moves into the spring housing. The spring housing has a replaceable reservoir (71) inside for the atomized liquid (72). The reservoir is closed by a stopper (73) through which a hollow piston projects into the reservoir and the end of which is immersed in a liquid solution (the active substance solution is stored).

The shaft (74) of the mechanical calculator is mounted outside the spring housing. A drive pinion (75) is located at the end of the shaft facing the upper portion of the housing. A slider (76) is provided on the shaft.

The nebulizers described above are suitable for nebulizing the aerosol formulations of the invention to form aerosols suitable for inhalation.

If the above technique is used (Respimat)^®) The amount of aerosol of the formulation of the invention, which is discharged, should be at least 97%, preferably at least 98%, of the total operating (ejection) amount in the inhaler, and should correspond to a defined amount, which is within a tolerance range of not more than 25%, preferably 20%, of this amount. The defined amount delivered per ejection is preferably between 5 and 30 mg, more preferably between 5 and 20 mg of the formulation.

However, it is also possible to use inhalers other than those mentioned above to atomise the formulations of the present invention, for example Jet-Stream inhalers (Jet-Stream inhalers).

Examples

I. Synthesis example of tiotropium Bromide monohydrate

In a suitable reaction vessel 15.0 kg of tiotropium bromide are added to 25.7 kg of water. The mixture was heated to 80 to 90 ℃ and stirred at constant temperature until a clear solution was formed. Activated carbon (0.8 kg) was wetted with water and suspended in 4.4 kg of water, and the mixture was added to an aqueous solution containing tiotropium bromide and washed with 4.3 kg of water. The mixture thus obtained is stirred at 80 to 90 ℃ for at least 15 minutes and then filtered with hot filter paper into an apparatus preheated to a peripheral temperature of 70 ℃. The filter paper was washed with 8.6 kg of water. The contents of the apparatus are cooled to 20 to 25 ℃ at a rate of 3 to 5 ℃ per 20 minutes. The apparatus is further cooled to 10 to 15 ℃ using cold water and stirred for at least one more hour to complete the crystallization. The crystals were separated by suction filtration and drying, and the separated crystal slurry was washed with 9 liters of cold water (10 to 15 ℃ C.) and cold acetone (10 to 15 ℃ C.). The crystals obtained were dried at 25 ℃ for 2 hours in a stream of nitrogen. Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory).

Formulation examples

A 100ml pharmaceutical formulation comprising:

examples	Tiotropium based amount of tiotropium bromide	Amount of tiotropium bromide monohydrate	Amount of benzalkonium chloride	Amount of disodium ethylene diamine tetraacetate	pH value adjusted with HCl (1N)
						1	0.045g	---	10mg	10mg	2.9
2		0.057	10mg	10mg	2.9
						3	0.023g	---	10mg	10mg	2.9
4		0.028	10mg	10mg	2.9
						5	0.045g	---	10mg	10mg	2.8
6		0.057	10mg	10mg	2.8
						7	0.023g	---	10mg	10mg	2.8
8		0.028	10mg	10mg	2.8

9	0.045g	---	10mg	10mg	3.0
						10		0.057	10mg	10mg	3.0
11	0.023g	---	10mg	10mg	3.0
						12		0.028	10mg	10mg	3.0

The remaining component is purified water, or water with a temperature of 15 deg.C to 31 deg.C and a density of 1.00g/cm³Water for injection of

Also examples 13 to 24:

similar to examples 1 to 12, but 9 mg of disodium edetate were used.

Further examples 25 to 36:

similar to examples 1 to 12, but 11 mg of disodium edetate were used.

Also examples 37 to 48:

similar to examples 1 to 12, but using 9 mg of benzalkonium chloride.

Also examples 49 to 60:

analogously to examples 1 to 12, 11 mg of benzalkonium chloride were used.

In other embodiments, the amount of benzalkonium chloride is 8 or 12 mg.

In other embodiments, the amount of disodium edetate is 8 or 12 mg.

In the examples, examples 1 to 4 are most preferable.

Claims (30)

1. A pharmaceutical formulation comprising

One or more tiotropium salts as active substance in a concentration of between 0.023 ± 0.001 g per 100ml of formulation and 0.045 ± 0.001 g per 100ml of formulation, based on tiotropium, wherein the one or more tiotropium salts are present in the pharmaceutical formulation in completely dissolved form

Water is the only solvent and the solvent is,

adjusting the pH value to between 2.8 and 3.05 with an acid,

benzalkonium chloride as a pharmacologically acceptable preservative,

ethylenediaminetetraacetic acid or a pharmacologically acceptable salt thereof as a pharmacologically acceptable complexing agent in an amount of from 5 mg to 20 mg per 100ml of the preparation.

2. Pharmaceutical preparation according to claim 1, characterized in that the tiotropium salt is a salt with hydrobromic acid, hydrochloric acid, hydroiodic acid, monomethyl sulfate, methanesulfonic acid and/or p-toluenesulfonic acid.

3. Pharmaceutical formulation according to claim 1, characterized in that the active substance is tiotropium bromide.

4. Pharmaceutical formulation according to claim 1, characterized in that the active substance is tiotropium bromide monohydrate.

5. Pharmaceutical preparation according to claim 1, characterized in that disodium edetate is used as complexing agent.

6. Pharmaceutical preparation according to claim 4, characterized in that disodium ethylenediaminetetraacetate is used as complexing agent.

7. Pharmaceutical preparation according to claim 6, characterized in that the disodium edetate is present in an amount comprised between 8 mg per 100ml of preparation and 12 mg per 100ml of preparation.

8. Pharmaceutical preparation according to one of claims 1 to 7, characterized in that the pH value is between 2.8 and 3.0.

9. Pharmaceutical preparation according to one of claims 1 to 7, characterized in that the pH value is 2.9.

10. Pharmaceutical formulation according to one of claims 1 to 7, characterized in that the pH is adjusted with a mineral acid.

11. Pharmaceutical formulation according to claim 10, characterized in that the mineral acid is hydrochloric acid.

12. Pharmaceutical formulation according to one of claims 1 to 7, characterized in that it does not comprise any other excipients and additives than water, tiotropium salts, benzalkonium chloride, disodium ethylenediaminetetraacetate, hydrochloric acid and optionally sodium chloride.

13. Pharmaceutical preparation according to claim 12, characterized in that a 100ml preparation is prepared by adding 0.057 g of tiotropium bromide monohydrate, 10 mg of anhydrous benzalkonium chloride, 10 mg of disodium edetate dissolved in 100ml of water and adjusting the pH to 2.9 with 1N hydrochloric acid.

14. Pharmaceutical preparation according to claim 12, characterized in that a 100ml preparation is prepared by dissolving 0.028 g tiotropium bromide monohydrate, 10 mg benzalkonium chloride anhydrous, 10 mg disodium edetate in water added to 100ml and adjusting the pH to 2.9 with 1N hydrochloric acid.

15. Pharmaceutical formulation according to claim 12, characterized in that 0.045 g, based on the amount of tiotropium, of tiotropium salt, 10 mg of anhydrous benzalkonium chloride, 10 mg of disodium edetate are dissolved in water added to 100ml and the pH is adjusted to 2.9 with 1N-hydrogen chloric acid to prepare a 100ml formulation.

16. Pharmaceutical preparation according to claim 12, characterized in that 0.023 g, based on the amount of tiotropium, of tiotropium salt, 10 mg of anhydrous benzalkonium chloride, 10 mg of disodium ethylenediaminetetraacetate are dissolved in water added to 100ml and the pH is adjusted to 2.9 with 1N hydrochloric acid to prepare a 100ml preparation.

17. Pharmaceutical formulation according to one of claims 1 to 7 for use as a medicament for administration by inhalation.

18. A pharmaceutical formulation according to claim 13 for use as a medicament for administration by inhalation.

19. A pharmaceutical formulation according to claim 14 for use as a medicament for administration by inhalation.

20. A pharmaceutical formulation according to claim 15 for use as a medicament for administration by inhalation.

21. A pharmaceutical formulation according to claim 16 for use as a medicament for administration by inhalation.

22. Use of a pharmaceutical formulation according to one of claims 1 to 21 for aerosolization in an inhaler for aerosolizing a defined amount of the pharmaceutical formulation into an inhalable aerosol at a pressure of 100 to 600 bar through a nozzle having at least one nozzle opening of 2 to 10 microns deep and 5 to 15 microns wide.

23. Use according to claim 22, characterised in that the nozzle openings are at least two nozzle openings, the directions of which are mutually inclined at an angle of 20 to 160 degrees.

24. Use according to claim 23, characterized in that the defined amount is 10 to 50 μ l.

25. Use according to claim 23, characterized in that the inhaler is 9 to 15cm long and 2 to 4cm wide.

26. Use according to claims 22 to 25, characterized in that at least 97% of all activations of the inhaler release an amount of formulation in the range of 5 to 30 mg with a tolerance deviation in the range of 25%.

27. Use according to claim 26, characterised in that at least 97% of all activations of the inhaler release an amount of formulation in the range of 5 to 30 mg with a tolerance deviation in the range of 20%.

28. Use according to claim 27, characterised in that the release is achieved in at least 98% of all activations of the inhaler.

29. Use of a pharmaceutical formulation according to one of claims 1 to 21 for the preparation of a medicament for the treatment of asthma and/or COPD.

30. A process for the preparation of a pharmaceutical formulation according to one of claims 1 to 21 by mixing the individual components.