MXPA06004873A - Novel tiotropium salts, methods for the production thereof, and pharmaceutical formulations containing the same - Google Patents

Abstract

The invention relates to novel tiotropium salts, methods for the production thereof, pharmaceutical formulations containing the same, and the use thereof for producing a medicament that is used for the treatment of respiratory diseases, especially COPD (chronic obstructive pulmonary disease) and asthma.

Description

NEW TIOTROPY SALTS, PROCEDURES FOR THEIR PREPARATION, AS WELL AS MEDICINAL FORMULATIONS THAT CONTAIN THEM The invention relates to new tiotropium salts, to processes for their preparation, to medicated formulations containing them, as well as to their use to prepare a medicament for the treatment of diseases of the respiratory tract, especially for the treatment of COPD. (chronic obstructive pulmonary disease) and asthma.

BACKGROUND OF THE INVENTION Tiotropium bromide is known from the European patent application EP 418 716 A1 and has the following chemical structure: Tiotropium bromide represents a highly effective long-acting anticholinergic, which can be used for the therapy of respiratory diseases, in special COPD (chronic obstructive pulmonary disease) and asthma. By the term tiotropium is meant the free ammonium cation. Until now, other salts of tiotropium than bromide have not been explicitly described in the state of the art. By means of the methodology described in EP 418 716 (compare scheme 1), it should also be possible to access the halides, as well as the alkyl and aryl sulfonates of tiotropium analogously. However, through this methodology, other salts of tiotropium can not be obtained. It is the object of the present invention to provide new tiotropium salts, as well as an alternative synthesis process for their preparation, which allows the synthesis of new tiotropium salts by means of a simple methodology, of universal and careful use.

Detailed Description of the Invention The problem mentioned at the beginning is solved by means of the method according to the invention, described below. The invention relates to a process for preparing new tiotropium salts of formula 1 wherein X ~ means an anion, characterized in that a salt of tiotropium of formula 2 is reacted wherein Y- means a • anion other than X ", selected from the group of halides, with an AgX salt, in which X can have the meanings indicated above, in a solvent appropriate. In the process according to the invention, AgX silver salts are used as the source for the anions X ~. In principle, the process is suitable for preparing all the compounds of formula 1, whose anion X "forms soluble silver salts with silver, The process according to the invention is preferably carried out in a polar solvent. solvents, in which the AgX silver salts are soluble, whereas, on the contrary, the resulting AgY silver salts are insoluble Preferred solvents are polar aprotic solvents selected from the group of amides such as, for example, dimethylformamide and N -methyl-pyrrolidinone, of the ethers such as, for example, tetrahydrofuran, dioxane, dimethyl ether and nitriles such as, for example, acetonitrile, Particularly preferred are dimethylformamide, N-methyl-pyrrolidinone, tetrahydrofuran, dioxane as solvents. , dimethyl ether or acetonitrile, with acetonitrile being preferred according to the invention. According to the invention, based on the starting compound 2 used, stoichiometric amounts of the AgX silver salt are required. But, possibly, the silver salt can also be used in excess (for example, 1.1 equivalents referred to 2).

The reaction according to the invention is preferably carried out by incorporation of the compound of the formula 2, as well as the silver salt AgX in one of the aforementioned solvents and by reaction at a temperature of at least 0 ° C up to at most the boiling temperature of the solvent used. However, the reaction is preferably carried out at less than 100 ° C, with special preference at less than 80 ° C., more preferably less than 60 ° C. With particular preference, the reaction according to the invention is carried out at a temperature in the range of 10-40 ° C, preferably at about 20-30 ° C. Compared to the reaction at higher temperatures, temperatures in the range of about 10-40 ° C can lead to longer reaction times. However, according to the invention, reaction temperatures in the range of about 10-40 ° C are preferred due to the careful reaction conditions. Preferred according to the invention is the process according to the invention, in which those compounds of the formula 2 are used as the starting material, in which Y- represents a halogenide other than X ", selected from the group consisting of fluoride, chloride, bromide and iodide, where chloride, bromide and iodide, preferably bromide and iodide, are especially important according to the invention.

With special preference, by means of the aforementioned process, those salts 1 are obtained, in which X "is an anion selected from the group consisting of fluoride, chloride, bromide, iodide, C 1 -C 4 alkyl sulfate, sulfate, hydrogen- sulfate, phosphate, hydrogen-phosphate, dihydrogen-phosphate, nitrate, maleate, acetate, trifluoroacetate, citrate, fumarate, tartrate, oxalate, succinate, saccharate and benzoate, or alkyl C? -C-sulfonate, which may optionally be mono-, di- or tri-substituted with fluorine in the alkyl radical, or phenylsulfonate, in which the phenylsulfonate may optionally be mono- or poly-substituted in the phenyl ring with C 1 -C 4 alkyl, with particular preference also obtained by procedure mentioned above, those salts 1, in which X ~ is an anion selected from the group consisting of methyl sulfate, ethyl sulfate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, nitrate, maleate , acetate, trifluoroacetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, methanesulfonate, ethanesulfonate, saccharate, fluoromethanesulfonate, difluoromethanesulfonate, trifluoromethanesulfonate, phenylsulfonate and toluenesulfonate. According to the invention, it is also preferably obtained by means of the aforementioned process those salts 1, in which X "is selected from nitrate, maleate, acetate, saccharate, trifluoroacetate, benzoate, methanesulfonate, trifluoromethanesulfonate and toluenesulfonate, where they are preferably obtained those salts 1. according to the process according to the invention, in which X- is selected from acetate, methanesulfonate, saccharate, toluenesulfonate, trifluoroacetate and benzoate, with special preference of methanesulfonate, saccharate, toluenesulfonate and benzoate. refers to the use of the compounds of formula 2, in which Y ~ may have the meanings indicated above, co or starting compound to prepare the compounds of formula 1. As Ci-Cio alkyl they are designated, provided that they are not indicate otherwise, branched and unbranched alkyl groups with 1 to 10 carbon atoms, preferably 1 to 4 atoms of carbon. By way of example, methyl, ethyl, propyl or butyl are mentioned. To designate methyl, ethyl, propyl or butyl groups, the abbreviations Me, Et, Prop or Bu are also optionally used. Unless otherwise described, the definitions of propyl and butyl cover all the imaginable isomeric forms of the corresponding radicals. In this manner, propyl encompasses, for example, n-propyl and iso-propyl, butyl embraces iso-butyl, sec. -butyl and tere. -butyl, etc. Unless otherwise indicated, the alkyl radicals may also be optionally substituted as long as they are components of other radicals (for example, alkylsulfonate), for example with one or more radicals selected from the group consisting of fluorine, chlorine, bromine, CF3, hydroxy or methoxy. Halogen is, within the scope of the present invention, fluorine, chlorine, bromine or iodine. The term C5-C10 aryl represents a system of aromatic rings with 6 to 10 carbon atoms. Preferred aryl radicals are phenyl or naphthyl. These may be optionally substituted, for example with one or more radicals selected from the group consisting of methyl, fluorine, chlorine, bromine, hydroxy, CF3 or methoxy. The preparation of the starting compounds of the formula 2 is carried out, for example, by analogy to the methodology described in EP-A-418716. This is represented in Scheme 1 below. 3 2 Scheme 1: Starting from ester of scopindithylene glycolic acid 3 the starting compounds 2 can be obtained by reaction with the Me-Y reagent. In the state of the art, only the synthesis of tiotropium bromide (according to Scheme 1) has been described so far explicitly. In both the compounds of the formula 2, in which Y "has a different meaning of bromide, are new and can be used as tiotropium bromide as starting compounds in the synthesis according to the invention to prepare the compounds of formula 1, the present invention also refers to the starting compounds of the formula 2 as those in which Y- can have all the meanings mentioned above with the exception of bromide, optionally in the form of their solvates or hydrates, by way of example, by means of this procedure the starting compounds of formula 2 which The following are also not yet described in the state of the art, also preferred according to the invention: scopinyester-di-2-thienyl glycolic acid methoiodide (tiotropium iodide). Whenever this new compound can be used in the process according to the invention as a starting compound, the present invention is also directed with particular preference to the tiotropium iodide mentioned above as such, optionally in the form of its solvates or hydrates. The following examples serve to provide a further explanation of the present invention, without, however, limiting the scope of the invention to the illustrative embodiments set forth below.

A. I. Starting materials A. 1.1. Tiotropium bromide: Tiotropium bromide can be obtained, for example, according to the procedure described in the European patent application EP 418 716.

A. 1.2. Tiotropium iodide: 124.57 g of di- (2-thienyl) glycolic acid escopinic ester are dissolved in 650 ml of dichloromethane and 1300 ml of acetonitrile by heating slightly. After cooling to room temperature, 51.52 g of methyl iodide are added. Once After completion of the reaction at room temperature, the crystals produced are separated and washed with cold acetonitrile. The mother liquors are concentrated and left to rest. The product that crystallizes in the mother liquor is isolated and recrystallized together with the first fraction of crystals in methanol. Yield: 111.33 g of white crystals; melting point: 202-203 ° C (with decomposition) A. II. EXAMPLES OF SYNTHESIS ACCORDING TO THE INVENTION Example 1: Tiotropium Benzoate 4.00 g of tiotropium bromide and 1958 g of silver benzoate are suspended in 100 ml of acetonitrile and stirred for 2 h at room temperature. Celite is added, stirred for another 30 minutes, filtered and evaporated in vacuo to a residual volume of about 30 ml. In this case, the product crystallizes. Filtration and drying at 40 ° C provide 3.61 g of the title compound. Melting point: 169 ° C; the structure and stoichiotry of the product were confirmed by spectroscopy.

Example 2: Tiotropium saccharide By analogy to the prescription according to Example 1, the title compound was obtained, starting from tiotropium bromide, by means of silver saccharate. Melting point 192 ° C (from acetonitrile); the structure and Stoichiometry of the product was confirmed by spectroscopy.

Example 3: Tiotropium paratoluensulfonate By analogy to the prescription according to Example 1, the title compound was obtained, starting from tiotropium bromide, by means of silver toluensulfonate. Melting point 153 ° C (from acetonitrile / diethyl ether); the structure and stoichiometry of the product were confirmed by spectroscopy.

Example 4: Tiotropium methanesulfonate By analogy to the prescription according to Example 1, the title compound was obtained, starting from tiotropium bromide, by means of silver methanesulfonate. Melting point 231 ° C (from methanol); the structure and stoichiometry of the product were confirmed by spectroscopy. In an analogous manner, the obtained products 1 are obtained, starting from tiotropium iodide.

A. III. Characterization of the examples of synthesis according to the invention The compounds obtained according to the above procedure were further characterized with the aid of X-ray powder diffraction. To record the following X-ray powder diagrams mentioned, the following was produced way. X-ray powder diagrams were recorded in the framework of the present invention by means of a Bruker D8 Advanced equipment with a DSL detector (= place-sensitive detector) • 5 (CuKa radiation,? = 1.5418 A, 30 kV, 40 mA).

Example 1: Tiotropium Benzoate The tiotropium benzoate obtained according to the above methodology is highly crystalline and is obtained in the anhydrous form. Further testing was carried out with the aid of X-ray powder diffraction. The X-ray powder diagram obtained for the anhydrous tiotropium benzoate is depicted in Figure 1. Table 1 below shows the characteristic peaks and the normed intensities.

Table 1 0 - 5 10 15 0 5 / * / * / In the previous table, the value? 2? [°] "represents the diffraction angle in degrees and the value dhi [Á]" represents the spacing in the reticular plane determined in Á. The tiotropium benzoate obtained according to the synthesis process according to the invention is highly crystalline and, therefore, is especially suitable for preparing, for example, drug formulations which must be applied by inhalation, such as powders for inhalation or, for example , also aerosol formulations with propellant gas content. Accordingly, the present invention also relates to tiotropium benzoate as such, especially to crystalline tiotropium benzoate, optionally in the form of its hydrates or solvates. In this case, a crystalline tiotropium benzoate is particularly preferred, which is characterized in that, for example, in the X-ray powder diagram it has the characteristic values d = 10.38 A; 5.41 A; 5.05 A and 4.9 Á.

The tiotropium benzoate obtainable according to the above process can be converted directly into its corresponding hydrate by directed action of moisture (ie water vapor, or the like). Accordingly, the present invention also relates to the aforementioned tiotropium benzoate in the form of its hydrate.

Example 2: Tiotropium saccarate The tiotropium saccharate obtained according to the above methodology is highly crystalline and is obtained in anhydrous form. Further testing was carried out with the aid of X-ray powder diffraction. The X-ray powder diagram obtained for the anhydrous tiotropium saccharate is shown in Figure 2. 5 The following Table 2 lists the characteristic peaks and the regulated intensities. .

Table 2: 0 15 20 25 In the previous table, the value "2? [°]" represents the angle of diffraction in degrees and the value "dhi [Á]" represents the spacing in the reticular plane determined in Á. The tiotropium saccharate obtained according to the synthesis process according to the invention is highly crystalline and, therefore, is especially suitable for preparing, for example, drug formulations which must be applied by inhalation, such as powders for inhalation or, for example , also aerosol formulations with propellant gas content. Accordingly, the present invention also relates to tiotropium saccharate as such, especially crystalline tiotropium saccharate, optionally in the form of its hydrates or solvates. In this case, the anhydrous crystalline tiotropium saccharate according to the invention is especially preferred, which is characterized in that, for example, in the X-ray powder diagram it has the characteristic values d = 14.42 A; 5.61 A; 4.79 A and 3.59 Á.

Example 3: Tiotropium paratoluensulfonate The tiotropium toluenesulfonate obtained according to the above methodology is highly crystalline and is obtained in anhydrous form. Further testing was carried out with the aid of X-ray powder diffraction. The X-ray powder diagram obtained for anhydrous tiotropium toluene sulfonate is shown in Figure 3. Table 3 lists characteristic peaks and regulated intensities.

Table 3: In the previous table, the value N2? [°] "represents the diffraction angle in degrees and the value Ndhk? [Á]" represents the spacing in the reticular plane determined in Á. Tiotropium toluenesulfonate obtained according to the synthesis process according to the invention is highly crystalline and, therefore, is especially suitable for preparing, for example, drug formulations which must be applied by inhalation, such as powders for inhalation or, for example , also aerosol formulations with propellant gas content. Accordingly, the present invention also relates to tiotropium toluene sulfonate as such, especially to crystalline tiotropium toluene sulfonate, optionally in the form of its hydrates or solvates. In this case, the anhydrous crystalline tiotropium toluene sulfonate according to the invention is especially preferred, which is characterized in that it has, for example, the characteristic values d = 15.73 A in the X-ray powder diagram; 5.42 Á and 4.59 A.

Example 4: Tiotropium methanesulfonate The tiotropium methanesulfonate obtained according to the above methodology is highly crystalline and is obtained in anhydrous form. Further testing was carried out with the aid of X-ray powder diffraction. The X-ray powder diagram obtained for the anhydrous tiotropium methanesulfonate is depicted in Figure 4. Table 4 below lists the characteristic peaks and the regulated intensities.

Table 4: In the above table, the value "2? [°]" represents the diffraction angle in degrees and the value ?? dhk? [Á] "represents the spacing in the reticular plane determined in A. The tiotropium methanesulfonate obtained according to the synthesis process according to the invention is highly crystalline and, therefore, is especially suitable for preparing, for example, drug formulations which they must be applied by inhalation, such as powders for inhalation or, for example, also aerosol formulations with propellant gas content Accordingly, the present invention also relates to tiotropium methanesulfonate as such, especially to crystalline tiotropium methanesulfonate. , optionally in the form of their hydrates or solvates In this case, the anhydrous crystalline tiotropium methanesulfonate according to the invention is especially preferred, which is characterized in that in the X-ray powder diagram it has, for example, the characteristic values d = 7.32 Á; 5.34 Á; 4.93 A; 4.55 A and 4.19 Á.

B. Drug formulations The present invention also relates to new medicament formulations, which contain the above-mentioned new tiotropium salts: tiotropium benzoate, tiotropium saccharate, tiotropium toluensulphonate or tiotropium methanesulfonate. The name salt of tiotropium in the part of the description given below should be understood as referring to the four new tiotropium salts mentioned above, unless one or more of the mentioned salts is explicitly mentioned. The new tiotropium salts are preferably applied by inhalation. Here come into consideration powdered formulations which are applied by inhalation, aerosol formulations containing propellant gases or solutions for inhalation which do not contain propellant gases.

B .1. Powders for inhalation The present invention also relates to inhalation powders containing 0.001 to 3% tiotropium in the form of one of the new tiotropium salts according to the invention mixed with a physiologically safe adjuvant. By tiotropium it should be understood, in this case, the ammonium cation. According to the invention, powders for inhalation containing 0.01 to 2% tiotropium are preferred. Especially preferred inhalation powders contain tiotropium in a amount from about 0.03 to 1%, preferably from 0.05 to 0.6%, with special preference from 0.06 to 0.3%. Finally, according to the invention, powders for inhalation containing approximately 0.08 to 0.22% of - 5 tiotropium. The portions of tiotropium mentioned above are referred to the amount of tiotropium cation contained. The absolute amount of the new tiotropium salts that results from this amount, which will be used in the formulations , can be calculated by the expert without great difficulties. The adjuvants, which are used in the sense of the present invention, are prepared by means of grinding and / or screening according to customary methods, known in the art. state of the art. In the case of the adjuvants that are used according to the invention, it is also possible to use mixtures of adjuvants, which are obtained by mixing fractions of adjuvants of different average particle size. 0 As physiologically safe adjuvants, which can be used to prepare the powders for inhalation in the framework of the "inhalants" according to the invention, there can be mentioned, for example, the monosaccharides (for example, glucose, fructose, arabinose), disaccharides (for example, lactose, saccharose, maltose, trehalose), oligosaccharides and polysaccharides (e.g., dextran, dextrin, maltodextrin, starch, cellulose), polyalcohols (e.g., sorbitol, mannitol, xylitol), cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin, β-cyclodextrin, methyl-β - cyclodextrin, hydroxypropyl-β-cyclodextrin), amino acids (eg, arginine hydrochloride) or also salts (eg, sodium chloride, calcium carbonate), or mixtures thereof. Preferably, monosaccharides or disaccharides are used, with lactose or glucose being preferred, especially, but not exclusively, in the form of their hydrates. According to the invention, lactose, most preferably lactose monohydrate, is especially preferred as a coadjuvant. The adjuvants have, within the framework of the inhalation powders according to the present invention, a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, with particular preference between 15 and 80 μm. It may be convenient, if appropriate, to add to the aforementioned coadjuvants fractions of finer coadjuvants with an average particle size of 1 to 9 μm. The determination of the average particle size can be carried out according to methods known in the state of the art (see, for example, WO 02/30389, Sections A and C). The finer coadjuvants mentioned in the last term are also selected from the group of aforementioned coadjuvants which can be used. Finally, for the preparation of powders for inhalation according to the invention is added to the adjuvant mixture micronized tiotropium salt, which is preferably characterized by an average particle size of 0.5 to 10 μm, particularly preferably 1 to 5 μm. The determination of the average particle size can be carried out according to methods known in the state of the art (see, for example, WO 02/30389, section B).

Procedures for grinding and micronising active principles are known in the state of the art. If a specifically prepared mixture of adjuvants is not used as a coadjuvant, those adjuvants having an average particle size of 10-50 μm and a portion of 10% fine particles of 0.5 to 6 μm are particularly preferably used. In this case, the mean particle size is understood, in the sense applied herein, to be 50% of the volume distribution measured with a laser diffractometer according to the dry dispersion method (see, for example, WO 02). / 30389, sections A and C). Analogously, on the part of fine particles of 10% is here understood the value of 10% of the volume distribution measured with a laser diffractometer. In other words, in the sense of the present invention, the value of the fine particle portion of 10% represents the particle size, below which is 10% of the amount of particles (referred to in FIG. volume distribution). In the case of the percentage data mentioned in the framework of the present invention, it is always percentages by weight, unless specifically indicated otherwise. In especially preferred inhalable powders, the adjuvant is characterized by an average particle size of 12 to 35 μm, with particular preference of 13 to 30 μm. Especially preferred are also those powders for inhalation in which the part of fine particles of 10% is from about 1 to 4 μm, preferably from about 1.5 to 3 μm. The powders for inhalation according to the invention are characterized according to the object of the present invention by a great homogeneity in the sense of the accuracy of the individual dosage. This is in a range of < 8%, preferably < 6%, with special preference < 4%. After weighing the starting materials, the preparation of the powders for inhalation is carried out from the adjuvants and the active principle, using procedures known in the state of the art. Reference is here made, for example, to the disclosure of WO 02/30390. The powders for inhalation according to the invention can be obtained, for example, according to the mode of proceed described below. In the preparation processes described below, the mentioned components are used in the proportions by weight, as described in the compositions described above of the powders for inhalation. First, the adjuvant and the active ingredient are incorporated in a suitable mixing vessel. The active principle used has an average particle size of 0.5 to 10 μm, preferably 1 to 6 μm, particularly preferably 2 to 5 μm. The addition of the active principle and the adjuvant is preferably carried out by means of a screen or a screen granulator with a mesh size of 0.1 to 2 mm, more preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm. Preferably the adjuvant and then the active ingredient are incorporated into the mixing vessel. Preferably, the addition of both components in this mixing process is done in portions. It is especially preferred to screen both components alternately, in layers. The process of mixing the adjuvant with the active principle can be carried out already during the addition of both components. However, preferably, the mixing is carried out only after the screening of layers of both components. The present invention also relates to the use of the powders for inhalation according to the invention for the preparation of a medication for the treatment of diseases of the respiratory tract, especially for the treatment of COPD (chronic obstructive pulmonary disease) and / or asthma. The powders for inhalation according to the invention can be applied, for example, by means of inhalers, which dose a single dose of a reserve by means of a dosing chamber (for example, according to US 4570630A) or through other devices (for example, according to DE 36 25 685 A). Preferably, the powders for inhalation according to the invention are filled into capsules (the so-called "inhalants"), which are used in inhalers as described, for example, in WO 94/28958. The capsules containing the powder for inhalation according to the invention are applied, with special preference, with an inhaler as shown in Figure 5. This inhaler is characterized by a housing 1, which contains two windows 2, a cover 3, in which there are openings for the entry of air and which is provided with a screen 5 fixed through a screen housing 4, an inhalation chamber 6 attached to the cover 3, in which a push-button 9 is provided which moves towards a spring 8 provided with two beveled needles 7, a nozzle 12 joined through a shaft 10 in a folding manner with the housing 1, the cover 3 and a cover 11, as well as holes allowing air 13 to pass to adjust the resistance to current. The present invention also relates to the use of the powders for inhalation according to the invention for the preparation of a medicament for the treatment of diseases of the respiratory tract, especially for the treatment of COPD and / or asthma, characterized in that the inhaler shown in Figure 5, described above, is used. In order to use the powders for inhalation according to the invention by means of capsules containing the powder, those capsules are preferably used whose material is selected from the group of synthetic materials, with special preference selected from the group consisting of polyethylene, polycarbonate, polyester, polypropylene and poly (ethylene terephthalate). Polyethylene, polycarbonate or poly (ethylene terephthalate) are especially preferred as plastic materials. If polyethylene is used as one of the preferred capsule materials especially according to the invention, polyethylene is preferably used with a density between 900 and 1000 kg / m3, preferably 940-980 kg / m3, with special preference of about 960 - 970 kg / m3 (high density polyethylene). The synthetic materials in the sense of the invention can be processed in various ways by means of of the process known in the state of the art. In the sense of the invention, the processing of plastic materials with the technique of injection casting is preferred. The injection molding technique is especially preferred regardless of the use of release agents. This method of preparation is well defined and is characterized in that it can be especially well reproduced. Another aspect of the present invention relates to the aforementioned capsules, which contain the powder for inhalation according to the invention mentioned above. These capsules may contain about 1 to 20 mg, preferably about 3 to 15 mg, with particular preference about 4 to 12 mg of powder for inhalation. Preferred formulations according to the invention contain 4 to 6 mg of powder for inhalation. Equally relevant according to the invention are the inhalation capsules containing the formulations according to the invention in an amount of 8 to 12 mg. In addition, the present invention relates to an inhalation kit, comprising one or more of the capsules described above, characterized by a powder content for inhalation according to the invention in combination with the inhaler according to Figure 5. The present invention It also refers to the use of the capsules mentioned above, characterized by a powder content for inhalation according to the invention, for the preparation of a medicament for the treatment of diseases of the respiratory tract, especially for the treatment of COPD and / or asthma. The preparation of filled capsules, which contain the powders for inhalation according to the invention, is carried out according to methods known in the state of the art by filling the empty capsules with the powders for inhalation according to the invention.

B.l.l. Examples of powders for inhalation according to the invention The following examples serve for a further explanation of the present invention, but without limiting the scope of the invention to the following illustrative embodiments.

B.1.1.1. Starting materials Active principle The new crystalline tiotropium salts according to the invention are used to prepare the inhalable powders according to the invention. The micronization of these active principles is carried out by analogy to the processes known in the state of the art (see, for example, WO 03/078429 Al).

Coadjuvant: In the following examples, lactose monohydrate is used as an adjuvant. This can be purchased, for example, from the company Borculo Domo Ingredients, Borculo / NL under the product name Lactochem Extra Fine Powder. The specifications according to the invention for the particle size are satisfied by the quality of this lactose.

B.1.1.2. Preparation of the powder formulations according to the invention: I) Equipment For preparing powders for inhalation, the following machines and devices can be used, for example: Container for mixing or mixing powders: Turbulamischer 2 L, type 2C; manufacturer Willy A. Bachofen AG, CH-4500 Basel.

Manual sieve: mesh width 0.135 mm The filling of the empty inhalation capsules can be done manually or mechanically by means of inhalation powders containing tiotropium. The following equipment can be used.

Encapsulating machine: MG2, type G100, manufacturer: MG2 S.r.l, 1-40065 Pian di Macina di Pianoro (BO), Italy Formulation example 1: Mixture of powder: 299.39 g of coadjuvant and 0.61 g of micronized tiotropium salt are used to prepare the powder mixture. In the 300 g of powders for inhalation obtained from it, the proportion in active principle referred to tiotropium is 0.16% in the case of tiotropium benzoate or tiotropium methanesulfonate, and 0.14% in the case of tiotropium saccharate or tiotropium toluene sulfonate. Through a manual sieve with a mesh width of 0.315 mm, approximately 40-45 g of coadjuvant are placed in a suitable mixing vessel. Then they are sieved alternately, layered, the tiotropium salt in portions of approximately 90-110 mg and coadjuvant in portions of approximately 40-45 g. The addition of the adjuvant and the active principle is carried out in 7 or 6 layers. The sieved components are then mixed (mixing: 900 revolutions). The final mixture is added two more times through a manual sieve and then mixed (mixing: 900 revolutions). According to the procedure described in Example 1, inhalable powders of this type can be obtained, which carry, after filling the corresponding capsules of synthetic material, for example to the following inhalation capsules: Formulation Example 2: Tiotropium Benzoate: 0.0113 mg Lactose Monohydrate: 5.4887 mg Polyethylene Capsules: 100.0 mg Total: 105.5 mg Formulation Example 3: Tiotropium saccharide: 0.0113 mg Lactose monohydrate: 5.4887 mg Polyethylene capsules: 100.0 mg Total: 105.5 mg Formulation Example 4: Tiotropium Saccharate: 0.0113 mg Lactose Monohydrate * ': 5.4887 mg Polyethylene Capsules: 100.0 mg Total: 105.5 mg *) Lactose contains 5% fine particles added specifically to micronized lactose monohydrate with an average particle size of approximately 4 μm.

Formulation Example 5: Tiotropium methanesulfonate: 0.0113 mg Lactose monohydrate: 5.4887 mg Polyethylene capsules: 100.0 mg Total: 105.5 mg Formulation Example 6: Totropium toluensulfonate: 0.0225 mg Lactose monohydrate: 5.4775 mg Polyethylene capsules: 100.0 mg Total: 105.5 mg Formulation Example 7: Tiotropium Benzoate: 0.0056 mg Lactose Monohydrate: 5.4944 mg Polyethylene Capsules: 100.0 mg Total: 105.5 mg Formulation Example 8: Tiotropium Methansulfonate: 0.0056 mg Lactose Monohydrate: 5.4944 mg Polyethylene Capsules: 100.0 mg Total: 105.5 mg Formulation Example 9: Tiotropium Methansulfonate: 0.0056 mg Lactose Monohydrate * ': 9.9944 mg Polyethylene Capsules: 100.0 mg Total: 110.0 mg *) Lactose contains 5%' fine particles added specifically to micronized lactose monohydrate with a particle size medium of approximately 4 μm.

Formulation Example 10: Tiotropium Toluenesulfonate: 0.0113 mg Lactose Monohydrate * 1: 9.9887 mg Polyethylene Capsules: 100.0 mg Total: 110.0 mg *) Lactose contains 5% fine particles added specifically to micronized lactose monohydrate with a medium particle size of approximately 4 μm.

Formulation Example 11: Tiotropium Toluenesulfonate: 0.0225 mg Lactose Monohydrate: 9.9775 mg Polyethylene Capsules: 100.0 mg Total: 110.0 mg B .2. Sprays for inhalation containing propellant gas The new tiotropium salts can also optionally be applied in the form of aerosols for inhalation containing propellant gas. For this, aerosol solution formulations or aerosol suspension formulations can be used.

B .2.1. Formulations in solution for aerosol The term "solution formulation for aerosol" refers in this case to pharmaceutical formulations, in which the tiotropium salt, as well as also the adjuvants that are used eventually, are completely dissolved. The present invention provides the new aerosol formulations containing the tiotropium salts, which, in addition to one of the aforementioned tiotropium salts, contain a propellant agent HFA, a cosolvent and an inorganic or organic acid, and which are characterized, moreover, because the concentration of the acid is measured such that, in aqueous solution, it corresponds to a pH that varies in the range of 2.5 - 4.5. The aforementioned aerosol solution formulations are characterized by particularly high stability. Preferred aerosol solution formulations are characterized in that the acid concentration is measured such that, in aqueous solution, it corresponds to a pH that varies in the range of 3.0 - 4.3, with special preference of 3.5 - 4.0. The aerosol solution formulations according to the invention may also optionally contain • 5 small amount of water (preferably up to 5%, more preferably up to 3%, more preferably still up to 2%). The aerosol solution formulations according to the invention preferably contain such an amount of the new tiotropium salt that the cation portion of the tiotropium content is between 0.00008 and 0.4%, preferably between 0.0004 and 0.16%, with special preference between 0.0008 and 0.08%. As HFA propellants, in the context of aerosol solution formulations, those suitable for which form a homogenous propellant formulation with the co-solvents used, in which a therapeutically active amount of the tiotropium salt can be dissolved. According to the invention, propellants selected from the group consisting of 1,1,1,2- or tetrafluoroethane (HFA-134 (a)), 1,1,1,2,3,3 are preferred as the propellant HFA. , 3, - heptafluoropropane (HFA-227), HFA-32 (difluoromethane), HFA-143 (a) (1,1,1-trifluoroethane), HFA-134 (1,1,2,2-tetrafluoroethane) and HFA -152a (1,1-difluoroethane). Especially preferred according to the invention are HFA-134 (a) and HFA-227, 5 being HFA-134 (a) especially relevant according to the invention. In addition to the aforementioned HFA propellants, non-halogenated propellant gases can also be used alone or mixed with one or more of the aforementioned HFA propellants. Examples of non-halogenated propellants are saturated hydrocarbons such as, for example, n-propane, n-butane or isobutanes, or also ethers, such as, for example, diethyl ether. As acids, organic or inorganic acids can be used according to the invention. The inorganic acids are selected within the framework of the present invention from the group consisting of hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid, the use of hydrochloric acid or sulfuric acid, especially hydrochloric acid, being preferred according to the invention. The organic acids are selected within the framework of the present invention, for example from the group consisting of ascorbic acid, citric acid, lactic acid, maleic acid, benzoic acid or tartaric acid, with ascorbic acid and citric acid being preferred according to the invention. The aerosol solution formulations according to the invention can be obtained analogously to the processes known in the state of the art. Eventually, pharmaceutically acceptable adjuvants may be contained in the aerosol solution formulations according to the invention. By For example, surfactants and soluble lubricants can be used. As an example of such surfactants and soluble lubricants may be mentioned sorbitan trioleate, lecithin or also isopropyl myristate. As adjuvants may also be included antioxidants (for example, ascorbic acid or tocopherol), taste masking agents (for example, menthol, sweeteners and artificial or natural flavors). Examples of cosolvents that can be used according to the invention are alcohols (for example, ethanol, isopropanol and benzyl alcohol), glycols (for example, propylene glycol, polyethylene glycols, polypropylene glycol, glycol ether, oxyethylene and oxypropylene block copolymers) or else other substances such as, for example, glycerol, polyoxyethylene alcohols, esters of polyoxyethylene fatty acids and glycofurols (such as, for example, Glykofurol 75.) A preferred cosolvent according to the invention is ethanol. can be used in the formulations according to the invention is preferably in the range of 5-50%, preferably 10-40%, with special preference of 15-30%, based on the total formulation. In contrast, the percentage data within the framework of the present invention should understood as percentages by weight. The formulations according to the invention may contain, as mentioned above, small amounts of water. A preferred aspect of the present invention relates to formulations in which the water part is up to 5%, with special preference up to 3%, more preferably up to 2%. Another aspect of the present invention relates to aerosol solution formulations, that do not contain water. In these formulations, the amount of cosolvent is preferably in the range of 20-50%, preferably in the range of 30-40%. The formulations according to the invention can be applied by means of inhalers known in the state of the art (pMDIs = "pressurized metered dose inhalers"). The present invention also relates to the use of the aforementioned aerosol solution formulations, characterized by a content in the new tiotropium salt according to the invention for the preparation of a medicament for the treatment of diseases of the respiratory tract , especially for the treatment of COPD and / or asthma. The following examples serve to explain the present invention in more detail, but without limiting the scope of the invention to the following illustrative embodiments.

B.2.1.1 Examples of solution formulations for aerosol Formulation example 12: Formulation example 13: Formulation example 14: Formulation example 15: Formulation example 16: Formulation example 17: Formulation example 18; Formulation example 19: Formulation example 20: Formulation example 21: B .2.2. Aerosol suspension formulations The present invention also relates to suspensions of the new tiotropium salts according to the invention in the propellant gases HFA 227 and / or HFA 134a, optionally in mixture with one or more other propellant gases, preferably selected from the group consisting of propane, butane, pentane, dimethyl ether, CHC1F2, CH2F2, CF3CH3, isobutane, isopentane and neopentane. Preferred according to the invention are those suspensions which contain as a propellant gas only HFA 227, a mixture of HFA 227 and HFA 134a or only HFA 134a. If a mixture of the propellant gases HFA 227 and HFA 134a is used in the suspension formulations according to the invention, the weight ratios, in which these two propellant gas components can be used, can be varied freely. If in the suspension formulations according to the invention, in addition to the propellant gases HFA 227 and / or HFA 134a, one or more other propellant gases are used, selected from the group consisting of propane, butane, pentane, dimethyl ether, CHC1F2, CH2F2, CF3CH3, isobutane, isopentane and neopentane, the part of this other propellant gas component is preferably less than 50%, preferably less than 40%, especially preferably less than 30%. The suspensions according to the invention preferably contain such a quantity of new tiotropium salt, that the tiotropium cation part ranges between 0.001 and 0.8%, preferably according to the invention between 0.08 and 0.5%, with special preference between 0.2 and 0.4%.

In the case of the percentage data mentioned in the framework of the present invention, it is always a percentage by weight, unless otherwise indicated. The term suspension formulation is also used in the context of the present invention, instead of the term suspension. Both terms should be considered equivalent in the context of the present invention. The aerosols for inhalation or suspension formulations containing propellant gas according to the invention may also contain other components, such as surfactants (surfactants), adjuvants, antioxidants or flavors. Surfactants (surfactants) optionally contained in the suspensions according to the invention are preferably selected from the group consisting of polysorbate 20, polysorbate 80, Myvacet 9-45, Myvacet 9-08, isopropyl myristate, oleic acid, propylene glycol, polyethylene glycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol. Of the aforementioned suspension coadjuvants, polysorbate 20, polysorbate 80, Myvacet 9-45, Myvacet 9-08 or myristate Isopropyl. Myvacet 9-45 or isopropyl myristate are particularly preferred. As long as surfactants are present in the suspensions according to the invention, they are preferably used in a proportion of 0.0005-1%, with special preference of 0.005-0.5%. The adjuvants optionally contained in the suspensions according to the invention are preferably selected from the group consisting of alanine, albumin, ascorbic acid, aspartame, betaine, cysteine, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid and citric acid. With special preferenceIn this case, ascorbic acid, phosphoric acid, hydrochloric acid or citric acid are used, with special preference hydrochloric acid or citric acid. Provided that adjuvants are present in the suspensions according to the invention, they are preferably used in a proportion of 0.0001-1.0%, preferably 0.0005-0.1%, more preferably 0.001-0.01%, being especially significant according to the invention a proportion of 0.001-0.005%. The antioxidants optionally contained in the suspensions according to the invention are preferably selected from the group consisting of ascorbic acid, citric acid, sodium edetate, edetic acid, tocopherols, butylhydroxytoluene, butylhydroxyanisole and palmitate of ascorbyl, preferably using tocopherols, butylated hydroxytoluene, butylhydroxyanisole or ascorbyl palmitate. The flavorings optionally contained in the suspensions according to the invention are preferably selected from the group consisting of peppermint, saccharin, Dentomint, aspartame and essential oils (for example cinnamon, anise, menthol, camphor), with particular preference being, for example, peppermint or Dentomint®. As for the application by inhalation, it is necessary to make available the active principles in the form of fine particles. The new tiotropium salts according to the invention are ground (micronized) for this purpose or obtained in the form of fine particles by other technical processes, in principle known in the state of the art (for example precipitation, drying by spray). The processes for the micronization of active ingredients are known in the state of the art. Preferably, after the micronization, the active principle has an average particle size of 0.5 to 10 μm, preferably 1 to 6 μm, with particular preference of 1.5 to 5 μm. Preferably, at least 50%, preferably at least 60%, with special preference at least 70% of the active ingredient particles have a particle size that is within the size ranges previously mentioned. With particular preference, at least 80%, most preferably at least 90% of the active ingredient particles are within their particle size within the aforementioned ranges. Another aspect of the present invention relates to suspensions that only contain one of the two active principles according to the invention without other additives. To prepare the suspensions according to the invention, use can be made of the processes known in the state of the art. To do this, the components of the formulation are mixed with the propellant gas or (if possible at low temperatures) and packaged in suitable containers. The suspensions containing propellant gas according to the invention, mentioned above, can be applied by means of inhalers known in the state of the art. (pMDIs = pressurized metered dose inhalers). Accordingly, another aspect of the present invention relates to medicaments in the form of suspensions described above in combination with one or more of these appropriate inhalers for administering these suspensions. In addition, the present invention relates to inhalers, characterized in that they contain suspensions with propellant gas content according to the invention, as described above. The present invention also relates to containers (cartridges), which can be used equipped with a appropriate valve in a suitable inhaler and containing one of the suspensions with propellant gas content mentioned above, according to the invention. Appropriate containers (cartridges) and methods for filling these cartridges with the suspensions containing the propellant gas are known from the state of the art. Due to the pharmaceutical efficacy of tiotropium, the present invention also relates to the use of suspensions according to the invention for preparing a medicament that can be applied by inhalation or nasally, preferably to prepare a medicament for treatment by inhalation or by Nasal route o diseases in which anticholinergics can produce a therapeutic benefit. With particular preference, the present invention also relates to suspensions according to the invention for preparing a medicament for the treatment by inhalation of diseases of the respiratory tract, preferably of asthma or COPD. The following examples serve to illustrate the present invention, without limiting it to its content.

B.2.1.2 Examples of suspension formulations for aerosol Suspensions containing, in addition to active principle and propellant gas, other components: Formulation example 22: Formulation example 23: Formulation example 24: Formulation Example 25: Formulation example 26: Formulation example 27: Formulation example 28: Formulation example 29: Formulation example 30: Suspensions containing only active principle and propellant gas: Formulation Example 31: Formulation example 32 Formulation example 33: Formulation example 34: Formulation example 35: Formulation example 36: Formulation Example 37: Formulation example 38 B.3. Sprays for inhalation without propellant gas Eventually, the new tiotropium salts can also be applied in the form of aerosols for inhalation without propellant gas. To apply these aerosols for inhalation without propellant gas, the new tiotropium salts are made available in the form of drug solutions. In this case, the solvent can be exclusively water, or it is a mixture of water and ethanol. The relative proportion in ethanol relative to water is not restricted, but preferably the maximum limit is up to 70 volume percent, especially up to 60 volume percent and with special preference up to 30 volume percent. The other percentages in volume are completed with water. The preferred solvent is water without the addition of ethanol. The concentration of the new tiotropium salts according to the invention, referred to the proportion of tiotropium in the finished drug preparation, depends on the desired therapeutic effect. For most diseases that respond to tiotropium, the concentration of tiotropium varies between 0.0005 and 5% by weight, preferably between 0.001 and 3% by weight. The pH value of the formulation according to the invention ranges between 2.0 and 4.5, preferably between 2.5 and 3.5 and, more preferably, between 2.7 and 3.3 and with special preference between 2.7 and 3.2. Most preferred are the pH values with an upper limit of 3.1. The pH value is adjusted by the addition of pharmacologically tolerable acids. Examples of preferred inorganic acids in this respect are: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are: ascorbic acid, citric acid, malic acid, aric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others.

Preferred inorganic acids are hydrochloric acid, sulfuric acid. Acids that already form a salt by addition of acids with the active ingredient can also be used. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred, citric acid being most preferred. If appropriate, mixtures of the aforementioned acids can also be used, in particular in the case of acids which, in addition to their acidifying properties, also have other properties, for example as flavorings. or antioxidants such as, for example, citric acid or ascorbic acid. As inorganic acids, hydrochloric acid is expressly mentioned. Optionally, pharmacologically tolerable bases can also be used for precise titration of the pH value. Suitable bases are, for example, alkali metal hydroxides and alkali metal carbonates. The preferred alkaline ion is sodium. If bases of this type are used, it must be taken into account that also the resulting salts, which are then contained in the finished drug formulation, are pharmacologically acceptable with the aforementioned acid. According to the invention, the addition of edetic acid (EDTA) or one of its known salts, as a stabilizer or complexing agent, can be dispensed with in the present formulation. Another embodiment contains edetic acid and / or the aforementioned salts thereof. In a preferred embodiment of this type, the content relating to sodium edetate is less than 10 mg / 100 ml. In this case, a preferred range is between 5 mg / 100 ml and less than 10 mg / 100 ml or another between more than 0 and 5 mg / 100 ml. In another embodiment, the content in edetato Sodium is 10 to 30 mg / 100 ml, preferably at most 25 mg / 100 ml. In a preferred embodiment, this addition is dispensed with completely. What is already detailed for sodium edetate applies analogously to other comparable additives which have complexing properties and which can be used in their place, such as, for example, nitrilotriacetic acid and its salts. Preferably, "complex formers" are understood to be molecules which are able to form complex bonds in the context of the present invention. Preferably, cations, especially metal cations, must be complexed by means of these compounds. Other cosolvents and / or other adjuvants can be added to the formulation according to the invention in addition to ethanol. Preferred co-solvents are those containing hydroxyl groups or other polar groups, for example alcohols - especially isopropyl alcohol, glycols -, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters, provided that no longer the solvent or the suspending agent. By coadjuvants and additives it is understood in this context any pharmacologically tolerable and therapeutically convenient substance, which is not an active principle but which, together with the active principle, can be formulated in the pharmacologically appropriate solvent, in order to improve the qualitative properties of the formulation of active principles. Preferably, these substances do not produce a pharmacological effect or, in the context with the desired therapy, do not produce any noteworthy effect or at least any undesired pharmacological effect. Examples of adjuvants and additives include surface-active substances such as, for example, soy lecithin, oleic acid, sorbitan esters, such as sorbitan trioleate, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives. , which prolong the duration of the finished pharmacological formulation, flavors, vitamins and / or other additives known in the state of the art. The additives also include pharmacologically harmless salts, such as, for example, sodium chloride. Preferred adjuvants are antioxidants, such as, for example, ascorbic acid, provided that they are not already used to regulate the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins that appear in the human organism. Preservatives may be applied to protect the formulation of contamination with pathogenic germs. Suitable preservatives are those known from the prior art, in particular benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate, in the concentration known in the state of the art. Preferred formulations contain, in addition to the solvent, water and one of the new tiotropium salts, only benzalkonium chloride and sodium edetate. In another preferred embodiment sodium edetate is dispensed with. The solutions according to the invention are applied by means of Respimat® inhaler. Another more developed embodiment of this inhaler is described in WO 97/12687 and its Figure 6.

B.3.1. Examples of aerosols for inhalation without propellant gas The following examples serve to further illustrate the present invention, without restricting it to its content.

Formulation example 39: Formulation Example 40 Formulation Example 41 Formulation example 42

Claims (28)

1. CLAIMS 1. Procedure for preparing new tiotropium salts of formula 1 wherein X means an anion, characterized in that a salt of tiotropium of formula 2 is reacted where Y "means an anion other than X ~, selected from the group of halides, with an AgX salt, in which X can have the meanings indicated with prior, in an appropriate solvent.
2. 2. Process according to claim 1, characterized in that the solvent is selected from the group consisting of amides, ethers and nitriles.
3. 3. Process according to claim 1, characterized in that acetonitrile is used as the solvent. Method according to one of claims 1 to 3, characterized in that those compounds of the formula 2 are used as the starting material, in which Y ~ means a halogenide other than X ", selected from the group consisting of fluoride, chloride , bromide and iodide 5. Process according to one of claims 1 to 4, for preparing compounds of the formula 1, in which X "means an anion selected from the group consisting of fluoride, chloride, bromide, iodide, alkyl C ? -C-sulfate, sulfate, hydrogen sulfate, phosphate, hydrogen-phosphate, dihydrogen phosphate, nitrate, maleate, acetate, trifluoroacetate, citrate, fumarate, tartrate, oxalate, succinate, saccharate and benzoate, or C? -C4 alkyl? -sulfonate, which may optionally be mono-, di- or tri-substituted on the alkyl radical with fluorine, or phenylsulfonate, wherein the phenylsulfonate may optionally be mono- or poly-substituted on the phenyl ring with C? -C4 alkyl . 6. Use of the compounds of formula 2, in which Y- can have the meanings mentioned in claims 1 to 5, as a starting compound for preparing the compounds of the formula 1. 7. Starting compounds of the formula 2, in which Y "can have the meanings mentioned in the claims 1 to 5, with the exception of bromide, optionally in the form of their solvates or hydrates 8. Starting compounds of formula 2 according to claim 7, in which Y ~ means iodide, optionally in the form of their solvates or Hydrates 9. Compounds of the formula 1, in which X "can have the meanings mentioned in claims 1 to 5, with the exception of bromide, optionally in the form of their solvates or hydrates. Compounds of the formula 1 according to claim 9, in which X ~ is benzoate, saccharate, toluenesulfonate or methanesulfonate, optionally in the form of their solvates or hydrates. 11. Crystalline tiotropium benzoate, optionally in the form of its solvates or hydrates. 12. Crystalline tiotropium benzoate according to claim 11, characterized in that in the X-ray powder diagram it has, among others, the characteristic values d = 10.38 A; 5.41 Á; 5.05 A and 4.9 A. 13. Crystalline tiotropium saccarate, eventually in the form of its solvates or hydrates. 14. Crystalline tiotropium saccarate according to claim 13, characterized in that in the X-ray powder diagram it has, among others, the characteristic values d = 14.42 Á; 5.61 A; 4.79 A and 3.59 A. 15. Crystalline tiotropium toluensulfonate, optionally in the form of its solvates or hydrates. 16. Crystalline tiotropium toluensulfonate according to claim 15, characterized in that the X-ray powder diagram shows, among others, the characteristic values d = 15.73 A; 5.42 A and 4.59 Á. 17. Crystalline tiotropium methanesulfonate, optionally in the form of its solvates or hydrates. 18. Crystalline tiotropium methanesulfonate according to claim 17, characterized in that in the X-ray powder diagram it has, among others, the characteristic values d = 7.32 A; 5.34 A; 4.93 A; 4.55 A and 4.19 A. 19. Use of a tiotropium salt according to one of claims 9 to 18 to prepare a medicament for the treatment of diseases of the respiratory tract, especially for the treatment of COPD. (chronic obstructive pulmonary disease) and asthma. 20. Medicament, characterized in that it contains a tiotropium salt according to one of claims 9 to 18. 21. Medicament according to claim 20, characterized in that it exists as a form of administration suitable for inhalation. 22. Medicament according to claim 21, characterized in that it is a form of administration selected from the group of powders for inhalation, aerosols dosable with propellant gas and solutions or suspensions for inhalation without propellant gas. 23. Medicament according to claim 22, characterized in that it is a powder for inhaling, which contains, in addition to the tiotropium salt, one or more appropriate physiologically acceptable adjuvants selected from the group of monosaccharides, disaccharides, oligosaccharides and polysaccharides, polyalcohols, cyclodextrins, amino acids or also salts or mixtures of these adjuvants with each other. 24. Medicament according to claim 23, characterized in that the adjuvant is selected from the group consisting of glucose, fructose, arabinose, lactose, sucrose, maltose, trehalose, dextran, dextrin, maltodextrin, starch, cellulose, sorbitol, anita, xylitol, a-cyclodextrin, β-cyclodextrin, β-cyclodextrin, methyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, arginine hydrochloride, sodium chloride or calcium carbonate, or mixtures thereof. 25. Medication according to claim 23 or 24, characterized in that it contains between 0.01 and 2% tiotropium. 26. Capsules, characterized by a powder content for inhalation according to one of claims 23 to 25. 27. A drug according to claim 22, characterized in that it is an aerosol for inhalation with propellant gas, which contains the Tiotropium salt in dissolved or dispersed form. 28. Medicament according to claim 22, characterized in that it is a solution or suspension for inhalation without propellant gas which, as a solvent, contains water, ethanol or a mixture of water and ethanol.