MXPA05006383A

MXPA05006383A - Tiotropium containing hfc solution formulations.

Info

Publication number: MXPA05006383A
Application number: MXPA05006383A
Authority: MX
Inventors: Schmidt Friedrich
Original assignee: Boehringer Ingelheim Pharma
Priority date: 2002-12-16
Filing date: 2003-12-04
Publication date: 2005-08-29
Also published as: WO2004054580A1; CA2510043A1; ZA200503546B; PL375868A1; CN1726038A; KR20050085650A; IL169178A0; JP2006510680A; RU2005122444A; EP1575588A1; BR0317340A; AU2003303029A1

Abstract

This invention relates to tiotropium containing stable pharmaceutical solution formulations suitable for aerosol administration. More particularly, this invention relates to tiotropium containing stable pharmaceutical solution formulations suitable for aerosol administration wherein either an inorganic acid or an organic acid is added to the aerosol solution formulation which contains a tiotropium salt, preferably tiotropium bromide in solution with an environmentally safe hydrofluorocarbon (HFC) as a propellant, together with an organic compound as a cosolvent. The acid provides stability against degradation or decomposition of the medicament resulting largely from interaction of the medicament with the cosolvent and/or water present in the solution formulation.

Description

FORMULATIONS OF HYDROFLUOROCARBURO SOLUTIONS CONTAINING TIOTROPIO FIELD OF THE INVENTION This invention relates to formulations of stable pharmaceutical solutions containing tiotropium, suitable for aerosol administration. More particularly, this invention relates to formulations of stable pharmaceutical solutions containing tiotropium suitable for aerosol administration in which an inorganic acid or an organic acid is added to the formulation of the aerosol solution containing a salt of tiotropium, preferably bromide of tiotropium in solution with a hydrofluorocarbon (HFC) safe for the environment as a propellant, together with an organic compound as a cosolvent. The acid provides stability against the degradation or decomposition of the medicament that occurs to a large extent due to the interaction of the medicament with the cosolvent and / or with the water present in the formulation of the solution. BACKGROUND OF THE INVENTION Tiotropium bromide is known from the European patent application EP 418 716 A1 and has the following structure REF.:163845 chemistry: Tiotropium bromide is a highly effective anticholinergic with long-lasting activity that can be used to treat respiratory ailments, particularly COPD (chronic obstructive pulmonary disease) and asthma. The term tiotropium refers to the free ammonium cation. To treat the aforementioned complaints, it is useful to administer the active substance by inhalation. In addition to the administration of broncholitically active compounds in the form of inhalable powders containing the active substance, the administration of tiotropium bromide can also be carried out in the form of formulations of aerosol solutions containing hydrofluorocarbons. The administration of aerosolized medication formulations through metered dose inhalers (MDIs) is widely used in therapeutics, such as in the treatment of obstructive airway diseases and asthma. Compared with oral administration, inhalation provides a faster onset of action while minimizing systemic side effects. Aerosol formulations can be administered by inhalation through the mouth or topically by application to the nasal mucosa. Formulations for aerosol administration by means of MDI can be solutions or suspensions. The formulations in solution offer the advantage of being of a homogeneous nature with the drug and excipient completely dissolved in the propellant vehicle. The solution formulations also avoid the physical stability problems associated with suspension formulations and thus ensure a more consistent uniform dosage administration while also eliminating the need for surfactants. The administration of formulations of aerosol solutions by means of the MDI depends on the propulsive force of the propellant system used in its manufacture. Traditionally, the propellant comprises a mixture of chlorofluorocarbons (CFCs) to provide the desired solubility, vapor pressure, and stability of the formulation. However, since in recent years it has been established that CFCs are harmful to the environment as they contribute to the reduction of the earth's ozone layer, it is desirable to replace CFC propellants in aerosol formulations. harmful to the environment by hydrofluorocarbon (HFC) propellants or other non-chlorinated propellants safe for the environment. For example, U.S. Patent No. 4,174,295 describes the use of propellant systems consisting of combinations of HFCs, which may also contain a saturated hydrocarbon component, suitable for application in the field of household products, such as lacquers. for hair, anti-perspiration products, perfumes, deodorants, paints, insecticides and the like. It is known in the art that certain HFCs have properties suitable for use as propellants for the administration of aerosolized drugs. For example, published European patent application No. 0 372 777 (EPO89312270.5) describes the use of 1,1,1,2-tetrafluoroethane (HFC-134 '(a)) in combination with at least one "adjuvant" (a compound having a higher polarity than HFC-134 (a)) and a surfactant to prepare suspension and solution drug formulations suitable for administration by the aerosol route. Also, published PCT patent application No. W091 / 11496 (PCT / EP91 / 00178) describes the use of 1,1,1,2,3,3,3-heptafluoropropane (HFC-227), optionally mixed with other components propellants, for use in the preparation of aerosol suspension medication formulations.

US-A-2 868 641 and US-A-3 282 781 describe aerosol compositions comprising a medicament (epinephrine or isoproterenol HC1), a cosolvent, a propellant and ascorbic acid as an anti-oxidant. European patent EP 673 240 Bl proposes the addition of acids to medicinal formulations for aerosol in order to provide stabilization of the medicament. DESCRIPTION OF THE INVENTION The term "formulation of an aerosol solution" means a pharmaceutical formulation of a medicament suitable for aerosol administration in which the medicament and the excipients are completely dissolved.

The term "formulation of a stabilized aerosol solution" means a formulation of an aerosol solution that exhibits substantial chemical stability over time. The present invention provides formulations of stabilized-aerosol solutions comprising a tiotropium salt, a HFC propellant, a cosolvent, and an inorganic or organic acid, characterized in that the concentration of the acid is in a range corresponding to a range of pH 2.5 - 4.5 in aqueous solution. In the preferred aerosol solution formulations according to the invention, the concentration of the acid is in a range corresponding to a pH range of 3.0-4.3, more preferred 3.5-4.0, in aqueous solution. A small amount of water (up to about 5%, preferably up to about 3% by weight) may also be present in the propellant / co-solvent system. The formulation of an aerosol solution according to the invention preferably contains from 0.00008 to 0.4%, preferably from 0.0004 to 0.16%, more preferably from 0.0008 to 0.08% tiotropium. By tiotropium is meant the free ammonium cation. In the tiotropium salt present in the formulation according to the invention, the counterion (anion) may be chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate. Of these anions, bromide is preferred. If the preferred salt of tiotropium, tiotropium bromide, is used, the amounts mentioned above correspond to 0.000096 to 0.48% tiotropium bromide, preferably from 0.00048 to 0.192 ¾, more preferably from 0.00096 to 0.096% of tiotropium bromide. Tiotropium bromide can be obtained in different crystalline modifications, depending on the choice of reaction conditions and solvents. Most preferred according to the invention are those formulations, which contain tiotropium in the form of the tiotropium bromide monohydrate as described in WO 02/30928. This tiotropium bromide monohydrate is characterized by an endothermic peak at 230 + 5 ° C determined by DSC. Accordingly, the aerosol solution formulations according to the invention preferably contain 0.0001 to 0.5% tiotropium bromide monohydrate, preferably 0.0005 to 0.2%, more preferably 0.001 to 0.1% tiotropium bromide. monohydrate. Suitable HFC propellants are those which, when mixed with the cosolvent (s), form a homogeneous propellant system in which a therapeutically effective amount of the drug can be dissolved. The HFC propellant must be toxicologically safe and must have a vapor pressure that is adequate to allow the medication to be administered by means of a pressurized MDI. Additionally, the HFC propellant must be compatible with the components of the MDI device (such as containers, valves, and seals, etc.) used to administer the medication. Preferred HFC propellants are 1,1,1,2-tetrafluoroethane (HFC-134 (a)) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227). HFC-13 (a) is particularly preferred. Other examples of HFC propellants are HFC-32 (difluoromethane), HFC-143 (a) (1,1,1-trifluoroethane), HFC-134 (1, 1, 2,2-tetrafluoroethane), and HFC-152a (1 , 1-difluoroethane). It should be clear to those skilled in the art that non-halogenated hydrocarbon propellants can be used in the present invention in place of the HFC propellants. Examples of non-halogenated hydrocarbons are saturated hydrocarbons, including propane, n-butane, and isobutane, and ethers, including diethyl ether. It should also be clear to those skilled in the art that, although the use of a single HFC propellant is preferred, a mixture of two or more HFC propellants, or a mixture of at least one HFC propellant and one or more non-HFC propellants may be employed. CFC, in the formulation of an aerosol solution of the present invention. An HFC / co-solvent, substantially non-aqueous propellant system is preferred. The water may be present in small amounts as an impurity in the HFC / cosolvent propellant system, it may be introduced during the manufacturing process or it may permeate the system through the valve or closures or seals of the valve / container. If desired, small amounts of water (up to about 5%, preferably up to about 2% by weight) can be added to the HFC / propellant system, for example, to aid in manufacturing. The acid of the formulations according to the invention may be any inorganic or mineral acid, for example, hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid, or the like .. Among the acids mentioned, hydrochloric acid is of particular interest. Acid can also be selected from the group of acids known to those skilled in the art as organic acids, which are considered in most cases as weak acids in relation to inorganic acids. Representative of this group and preferred in this invention are the Ascorbic acid, citric acid, lactic acid, malic acid, benzoic acid and tartaric acid According to this invention, citric acid and ascorbic acid are the most preferred organic acids The formulations according to the invention can be prepared analogously to the methods known in the art. If desired, pharmaceutically acceptable excipients may be included. is in the aerosol solution formulations of the present invention. For example, a soluble surfactant may be added in order to improve the operation of the valve systems employed in the DI devices used for the aerosol administration of the formulations. Examples of preferred surfactants are sorbitan trioleate, lecithin, and isopropyl myristate. Other suitable lubricants are well known in the art (see, for example, published European patent application No. 0372777 (EPO 893122705)). Other excipients are: (a) antioxidants, for example ascorbic acid and tocopherol; (b) taste masking agents, for example, menthol, sweeteners, and artificial or natural flavors; and (c) pressure modifying agents, for example, n-pentane, iso-pentane, neo-pentane, and n-hexane. Examples of cosolvents applicable in the formulations according to the invention are: alcohols, for example, ethyl alcohol, isopropyl alcohol, and benzyl alcohol; glycols for example, propylene glycol, polyethylene glycols, polypropylene glycols, glycol ethers, and oxyethylene and oxypropylene block copolymers and other substances, for example, glycerol, polyoxyethylene alcohols, polyoxyethylene fatty acid esters, and glycofurols (for example glycofurol 75). Examples of cosolvents that may be inert to the interaction with the drug (s) are the hydrocarbons, for example, n-propane, n-butane, isobutane, n-pentane, iso-pentane, neo-pentane, and n-hexane; and ethers, for example, diethyl ether. A preferred cosolvent according to this invention is ethyl alcohol (ethanol). The amount of co-solvent is preferably in the range of 5-50 ¾ (w / w) of the total composition. More preferably, the amount of cosolvent in the formulation according to the invention is in the range of 10 -40% (w / w), preferably in the range of 15-30%. As mentioned hereinabove, the formulations according to the invention may contain a small amount of water. A preferred embodiment of the invention corresponds to formulations containing water in an amount of up to 5% (w / w), preferably up to 3% (w / w). Another preferred embodiment of the invention relates to formulations that do not contain water. In these water-free formulations the amount of cosolvent is preferably in the range of about 20-50% (w / w), more preferably in the range of about 30-40% (w / w) · Especially in these free formulations. Water, the anhydrous form of tiotropium bromide obtainable from the tiotropium bromide monohydrate mentioned hereinbefore can be used. The anhydrous form is obtained from the crystalline tiotropium monohydrate bromide described in WO 02/30928 by carefully drying at more than 50 ° C, preferably at 60-100 ° C, most preferably at 70-100 ° C, under pressure reduced, preferably in a high vacuum for a period of 15 minutes to 24 hours, preferably 20 minutes to 12 hours, most preferably 30 minutes to 6 hours. The term "reduced pressure" most preferably refers to a pressure of up to 5 x 103 Pa, preferably 1 x 103 Pa, most preferably 5 x 102 Pa.

Most preferably, the dehydration mentioned above to form the anhydrate is carried out at about 1 x 102 Pa or less. As an alternative to the high pressure drying step described above, the anhydrous form can also be prepared by storing the crystalline tiotropium bromide monohydrate on a desiccating agent, preferably on desiccated silica gel, at room temperature for a period of time. 12 to 96 hours, preferably 18 to 72 hours, most preferably at least 24 hours. The anhydrous form obtained in this way should be stored more or less dry, depending on the particle size, to preserve its anhydrous state. In the case of thick crystals of anhydrous tiotropium bromide, which can be prepared for example as described above, storage at < 75% h.r. (relative humidity) is sufficient to maintain the anhydrous state. In the micronized state, this is when the material has a much larger surface area, the water can be absorbed even at lower moisture levels. In order to maintain the anhydrous form in the micronized state, it is therefore advisable to store the anhydrous form of tiotropium bromide on dried silica gel. The anhydrous form of tiotropium bromide was subjected to X-ray analysis which revealed that crystalline anhydrous tiotropium bromide is characterized by elementary cells a = 10.4336 (2) A, b = 11.3297 (3) A, c = 17.6332 (4) Á ya = 90 °, ß = 105,158 (2) ° y? = 90 ° (cell volume = 2011,89 (8) Á3). The crystal structure of the anhydrous form of tiotropium bromide can be described as a layered structure.

Bromide ions are located between the layers of tiotropium. Additional details on the determination of the crystalline structure of said anhydrous form are given in the experimental part of this patent application. Accordingly, another preferred embodiment of the invention relates to a formulation of a stabilized aerosol solution comprising anhydrous tiotropium bromide characterized by the aforementioned parameters, a HFC propellant, a cosolvent, and an inorganic or organic acid, characterized by The concentration of the acid is in a range that corresponds to a pH range of 2.5 - 4.5 in aqueous solution and further characterized in that the formulation is free of water. The formulations according to the invention can be administered with inhalers known in the art (metered dose inhalers = MDIs). In another aspect, the invention relates to the use of a formulation of an aerosol solution as described hereinabove, for the manufacture of a medicament for the treatment of respiratory ailments, particularly GOPD (chronic obstructive pulmonary disease) and asthma. In still another aspect, the invention relates to a method for the treatment of respiratory ailments, such as in particular COPD (chronic obstructive pulmonary disease) or asthma, characterized by the administration of a formulation of an aerosol solution as described earlier in this specification. The following examples serve to further illustrate the present invention without restricting its scope to the embodiments provided below by way of example. I. And formulation materials TO) B) Component Concentration [% w / w] Tiotropium bromide mo-0.02 no hydrate Ethanol abs. (USP) 20, 0 aqueous HC1 0.01 mol / 1 2.0 (USP) HFC-134a 77, 98 C) Component Concentration [% w / w] Tiotropium bromide mo-01, nohydrate Ethanol abs. (USP) 15, 0 Water (purified, USP) 2.0 Citric acid (USP) 0.004 HFC-227 82, 986 D) AND) The mentioned formulations can be prepared by conventional methods known in the art. II. Preparation of crystalline anhydrous tiotropium bromide: The anhydrous form is produced from crystalline tiotropium bromide monohydrate (obtainable as described in WO 02/30928) by careful drying at 80-100 ° C under reduced pressure, preferably under a high vacuum (at about 1 x 102 Pa or less) for a period of at least 30 minutes. Alternatively to the drying step at 80-100 ° C under vacuum, the anhydrous form can also be prepared by storing on dried silica gel, at room temperature for a period of at least 24 hours. III. Characterization of crystalline anhydrous tiotropium bromide As described hereinabove, crystalline anhydrous tiotropium bromide according to the invention can be obtained from crystalline tiotropium bromide monohydrate The crystalline structure of anhydrous tiotropium bromide was determined From the high-resolution X-ray data in the powder (synchrotron radiation) using a real-space method with the so-called simulated banding procedure, a final Rietveld analysis was carried out to refine the structural parameters. contains the experimental data obtained for crystalline anhydrous tiotropium bromide.

Table 1: Experimental data referring to the analysis of the crystal structure of tiotropium bromide (anhydrous) formula Ci9H22N04S2Br temperature [° C] 25 molecular weight [g / mol] 472, 4 group of space P21 / ca [Á] 10, 4336 (2) b [Á] 11, 3297 (3) c [Á] 17, 6332 (4) ß [°] 105,158 (2) V [Á3] 2011, 89 (8) Z 4 calculated density [g cirf3] 1,56 2T (interval) [°] 2,0 - 20 interval [° 2T] 0 , 003 counting time / stage 3 [seconds] wavelength [Á] 0.7000 The crystal structure of the anhydrous form of tiotropium bromide can be described as a layered structure. Bromide ions are located between the layers of tiotropium. In order to clarify the structure of crystalline anhydrous tiotropium bromide, a high-resolution X-ray diagram was determined in the powder at room temperature in the National Synchrotron Source (Brookhaven National Laboratory, USA) at the X3B1 measuring station (? = 0,700 Á). For this experiment, a sample of crystalline tiotropium bromide monohydrate was placed in a 0.7 mm diameter quartz glass capillary. The water was removed by heating to 80 ° C in a stove under reduced pressure. The structural resolution was obtained by the so-called simulated banding procedure. For this, the DASH program produced by the Cambridge Crys tallographic Data Center (CCDC, Cambridge, United Kingdom) was used. Table 2 shows the atomic coordinates obtained for crystalline anhydrous tiotropium bromide.

Table 2: Coordinates Atom X and Z Uiso SI 1,0951 (8) 0, 3648 (8) 0, 8189 (5) 0.075 (9) SI 0,9143 (9) 0, 1374 (8) 0, 9856 (5 ) 0.075 (9) 0 0, 6852 (13) 0.2339 (6) 0, 7369 (6) 0.075 (9) 01 0.7389 (15) 0, 0898. (9) 0, 8234 (6) 0, 075 (9) 02 0.8211 (10) 0.3897 (17) 0, 8277 (7) 0, 075 (9) 03 0, 4975 (?) 0, 4816 (9) 0, 6011 (7) 0, 075 (9) N 0, 4025 (10) 0, 2781 (8) 0.5511 (5) 0.075 (9) C 0.7509 (8) 0.1885 (6) 0.8038 (5) 0.075 ( 9) Cl 0.8593 (7) 0.2788 (5) 0, 8495 (4) 0.075 (9) C2 0.9924 (9) 0.2533 (6) 0.8225 (6) 0.075 (9) C3 0, 888 (9) 0.2664 (7) 0, 9382 ¡4) 0.075 (9) C4 0.5848 (12) 0.1596 (8) 0.6753 [8) 0.075 (9) C5 0.454 (13) 0, 1929 (14) 0, 6809 (8) 0, 075 (9) C6 0, 6156 (13) 0.1810 (13) 0, 5973 (9) 0.075 (9) C7 0.5493 (11 ) 0.2881 (11) 0.5578 (6) 0.075 (9) C8 0.5869 (12) 0.3832 (11) 0.6092 (7) 0.075 (9) C9 0.4947 (13) 0 , 3902 (10) 0, 6575 (6) 0, 075 (9) CIO 0, 00 (10) 0.2998 (11) 0, 6332 (6) 0, 075 (9) CU 0, 3220 (13) 0 , 3670 (13) 0, 4935 (6) 0, 075 (9) C12 0, 3450 (19) 0, 164 3 (26) 0, 5211 (11) 0, 075 (9) C13 0, 9184 (16) 0.3808 (9) 0, 9920 (6) 0, 075 (9) C14 1, 0313 (16) 0, 1552 (15) 0.8011 (15) 0.075 (9) C15 0.9515 (17) 0.3374 (10) 0.0501 (6) 0.075 (9) C16 0.9756 (18) 0.2190 ( 11) 1, 0742 (5) 0, 075 (9) C17 1, 1483 (22) 0.1762 (18) 0.7718 (24) 0.075 (9) C18 1.1860 (16) 0.2800 ( 15) 0.7768 (19) 0.075 (9) BR 0, 4597 (4) 0.8200 (15) 0, 61902 (25) 0, 042 (9) In the previous table the values "üj_so" indicate the isotropic temperature factors. For example, in the structural analysis by X-rays in individual crystals this corresponds to the values u (eq). Table 3 shows the reflections (Indexes h, k, l) of the powder diagram obtained for crystalline anhydrous tiotropium bromide. Table 3: Experimental data referring to the analysis of the crystal structure of anhydrous tiotropium bromide N ° h k 1 2T obs. 2ß calc. 2T obs. 2 © caic 1 1 0 0 8,762 8,769 -0, 007 2 0 1 1 9,368 9,369 -0, 001 3 -1 0 2 11,730 11,725 0,005 4 0 1 2 12, 997 13,004 -0,007 5 -1 1 2 14,085 14,094 -0,009 6 1 0 2 15,271 15,275 -0, 004 7 0 0 3 15, 620 15, 616 0, 004 8 0 2 1 16,475 16, 475 0.0 9 1 1 2 17,165 17, 170 -0, 005 10 2 0 0 17,588 17,591 - 0.003 11 -1 2 1 18,009 18,035 -0, 026 12 1 2 1 19,336 19, 328 0, 008 13 -2 1 2 19,596 19, 600 -0, 004 14 -1 0 4 20, 17 20, 22 -0, 005 15 0 0 4 20,865 20,872 -0, 007 16 2 1 1 21,150 21,145 0,005 17 -2 1 3 21,759 21,754 0,005 0 2 3 22,167 22,160 0, 007 -1 2 3 22,289 22, 288 0,001 2 0 2 22,735 22, 724 0, 011 -2 2 1 23,163 23,159 0, 004 -2 0 4 23,567 23,575 -0, 008 2 1 2 24,081 24, 058 0, 023 1 or 4 24,746 24,739 0, 007 -1 3 1 25,220 25,221 -0, 001 1 2 3 25,359 25,365 -0,006 or 3 2 25,790 25,783 0.007 1 1 4 25,978 25, 975 0,003 or 2 4 26,183 26,179 0.004 -1 3 2 26,383 26,365 0,018 -1 1 5 26,555 26, 541 0,014 -3 1 2 27, 024 27,021 0,003 3 1 0 27, 688 27, 680 0,008 -3 1 3 28,221 28,215 0,006 3 O 1 28, 377 28,376 0,001 -3 0 4 29,246 29,243 0.003 3 1 1 29,459 29,471 -0, 012 -1 2 5 29, 906 29,900 0.006 -3 2 1 30,171 30,165 0,006 0 2 5 30, 626 30, 626 0.0 1 1 5 30,871 30,856 0.015 0 O 6 31,504 31,532 -0,028 2 1 4 31, 826 31,847 -0.021 -2 1 6 32, 888 32,888 0,0 45 1 4 1 33,605 33,615 -0, 010 46 3 0 3 34,379 34, 377 0, 002 47 1 0 6 35,021 35,018 0, 003 48 - -4 1 1 35,513 35, 503 0, 01 49 1 1 6 35,934 35, 930 0,004 50 -1 1 7 36,544 36,543 0, 001 51 -4 1 4 37,257 37,255 0, 002 52 -4 2 2 37, 933 37, 952 -0,019 53 4 1 1 38,258 38,264 -0,006 It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the one that results from the present description of the invention.

Claims

REIVI DICACIONES Having described the invention as above, the content of the following claims is claimed as property:

1. A formulation of an aerosol solution comprising a tiotropium salt, an HFC propellant, a cosolvent, and an inorganic or organic acid, characterized in that the concentration of the acid is in a range that corresponds to a pH range of 2.5. - 4,5 in aqueous solution.

2. The formulation of an aerosol solution according to claim 1, characterized in that it contains 0.00008 to 0.4% tiotropium.

3. The formulation of an aerosol solution according to claim 1 or 2, characterized in that the counterion (anion) which forms together with the tiotropium the tiotropium salt can be chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate.

4. The formulation of an aerosol solution according to claims 1, 2 or 3, characterized in that the propellant. HFC is selected from HFC-134 (a), HFC-227, HFC-32, HFC-143 (a), HFC-134, HFC-152a and their mixtures.

5. The formulation of an aerosol solution according to claims 1, 2, 3 or 4, characterized in that the acid is selected from inorganic acids, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid.

6. The formulation of an aerosol solution according to claims 1, 2, 3 or 4, characterized in that the acid is selected from the organic acids, ascorbic acid, citric acid, lactic acid, malic acid, benzoic acid, and acid tartaric

7. The formulation of an aerosol solution according to one of claims 1 to 6, characterized in that it contains water in an amount of up to about 5%.

8. The formulation of an aerosol solution according to one of claims 1 to 7, characterized in that it contains as a cosolvent, alcohols, glycols, glycol ethers, oxyethylene and oxypropylene block copolymers, glycerol, polyoxyethylene alcohols, ethers of fatty acid and polyoxyethylene or glycofuroles.

9. The formulation of an aerosol solution according to one of claims 1 to 8, characterized in that the cosolvent is present in an amount in the range of 5-50% (w / w).

10. The formulation of an aerosol solution according to one of claims 1 to 6, 8 or 9, characterized in that it does not contain water.

11. The use of a formulation of an aerosol solution according to one of claims 1 to 10, for the manufacture of a medicament for the treatment of respiratory ailments. RESUME OF THE INVENTION The present invention relates to formulations in stable pharmaceutical solution containing tiotropium suitable for aerosol administration. More particularly, this invention relates to stable pharmaceutical solution formulations containing tiotropium suitable for aerosol administration wherein either an inorganic acid or an organic acid is added to the formulation in an aerosol solution which contains a salt of tiotropium, preferably tiotropium bromide in solution with an environmentally safe hydrofluorocarbon (HFC) as a propellant, together with an organic compound as a cosolvent. The acid provides stability against the degradation or decomposition of the drug largely resulting from the interaction of the medicament with the cosolvent and / or water present in the formulation in solution.