NOVEL PROPELLANT CONTAINING PREPARATIONS FOR TIOTROPIUM

Abstract

The present invention relates to a novel propellant-gas-containing medicament composition based on tiotropium 1, processes for the preparation thereof and the use of such medicament compositions in the treatment of respiratory complaints.

Claims

1. An inhaler containing a pharmaceutical aerosol formulation consisting of: (i) the propellant gas HFA 134a; (ii) 0.005-0.03% by weight of tiotropium bromide; (iii) a mixture of the two cosolvents ethanol and water, the ethanol content being between 15-40% by weight and the water content being between 0.5-2.5%; and (iv) citric acid in a concentration between 0.005-0.1% by weight, wherein a single actuation from the inhaler has the following delivery characteristics: (a) a nominal dose between 5.5 μg and 6.5 μg; (b) a delivered dose between 4.5-5.6 μg; (c) a pulmonary dose (Fine Particle Dose) between 2-3 μg; and (d) a mean aerodynamic particle size between 2.5-3.5 μm.

2. An inhaler according to claim 1 wherein an inhaled dose is administered to a patient from a spray jet where the dose flows out of the metering chamber by actuation of the inhaler to expel it from a nozzle, an aerosol thus formed having the following delivery characteristics: (a) a nominal dose between 5.5 μg and 6.5 μg; (b) a delivered dose between 4.5-5.6 μg; (c) a pulmonary dose between 2-3 μg; and (d) a mean aerodynamic particle size between 2.5-3.5 μm.

3. An inhaler according to claim 2, wherein the bore diameter of the spray head used has a diameter of between 0.2-0.3 mm.

4. An inhaler according to claim 3, wherein the metering chamber has a volume of between 25 μl and 100 μl.

5. An inhaler according to claim 3, wherein the metering chamber has a volume of 50 μl.

6. An inhaler according to claim 4, wherein the sealing rings in a valve head are ethylene-propylene-diene monomer (EPDM).

7. A method for treating inflammatory or obstructive respiratory complaints in a patient, the method comprising administering to the patient the active substance tiotropium bromide with the inhaler according to claim 1.

8. A method for treating inflammatory or obstructive respiratory complaints in a patient, the method comprising administering to the patient the active substance tiotropium bromide with the inhaler according to claim 2.

9. An inhaler containing a pharmaceutical aerosol formulation consisting of: (i) a propellant gas HFA 134a; (ii) 0.005-0.03% by weight of tiotropium bromide; (iii) a mixture of co-solvents ethanol and water, the ethanol content being between 15-40% by weight and the water content being between 0.5-2.5% by weight; and (iv) an acid, the acid being an inorganic acid in a concentration that corresponds to a quantity of H+ions that can be obtained by the addition of a 1-3% by weight proportion of a 0.01 normal acid, wherein a single actuation from the inhaler has the following delivery characteristics: (a) a nominal dose between 5.5 μg and 6.5 μg; (b) a delivered dose between 4.5-5.6 μg; (c) a pulmonary dose (Fine Particle Dose) between 2-3 μg; and (d) a mean aerodynamic particle size between 2.5-3.5 μm.

10. An inhaler according to claim 9 wherein an inhaled dose is administered to a patient from a spray jet where the dose flows out of the metering chamber by actuation of the inhaler to expel it from a nozzle, an aerosol thus formed having the following delivery characteristics: (a) a nominal dose between 5.5 μg and 6.5 μg; (b) a delivered dose between 4.5-5.6 μg; (c) a pulmonary dose (Fine Particle Dose) between 2-3 μg; and (d) a mean aerodynamic particle size between 2.5-3.5 μm.

11. An inhaler according to claim 10, wherein the bore diameter of the spray head used has a diameter of between 0.2-0.3 mm.

12. An inhaler according to claim 11, wherein the metering chamber has a volume of between 25 μl and 100 μl.

13. An inhaler according to claim 11, wherein the metering chamber has a volume of 50 μl.

14. An inhaler according to claim 12, wherein the sealing rings in a valve head are ethylene-propylene-diene monomer (EPDM).

15. An inhaler according to claim 11, wherein the inorganic acid is aqueous hydrochloric acid.

16. An inhaler according to claim 11, wherein the inorganic acid is aqueous sulfuric acid.

17. A method for treating inflammatory or obstructive respiratory complaints in a patient, the method comprising administering to the patient the active substance tiotropium bromide with the inhaler according to claim 9.

18. A method for treating inflammatory or obstructive respiratory complaints in a patient, the method comprising administering to the patient the active substance tiotropium bromide with the inhaler according to claim 10.

Description

BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWING

[0062] FIG. 1: Inhaler containing medicinal solution, where (a) depicts a cartridge containing a propellant gas-containing solution, and (b) depicts a nozzle characterized by a bore diameter.

[0063] FIG. 2: An expanded view of the Inhaler containing medicinal solution, where (c) depicts the metering chamber of the cartridge.

DESCRIPTION OF THE INVENTION

[0064] The present invention relates to a novel propellant-gas-containing medicament composition based on tiotropium 1, processes for the preparation thereof and the use of such medicament compositions in the treatment of respiratory diseases.

[0065] Surprisingly, an unexpected, beneficial therapeutic effect can be demonstrated, particularly taking account of a reduced rate of side effects in the treatment of inflammatory or obstructive respiratory diseases and/or asthma, if tiotropium bromide is used as a solution-type metered dose aerosol in a specific dosage. On the basis of this special dosage, the tiotropium-containing medicament compositions according to the invention can also be used in particular as a monotherapy, while the activity/side effect profile is optimised by the particular dosage to be used. Medicament formulations of this kind are characterised according to the invention by an improved pharmaceutical stability (chemical and physical), particularly also by an optimum stability while at the same time keeping the above dosage requirements over time.

[0066] Within the scope of the present patent application, the term tiotropium 1 denotes salts. In the above-mentioned salts the tiotropium cation represents the pharmacologically active ingredient. Within the scope of the present patent application an explicit reference to the above cations is indicated by the use of the number 1′. By the salts 1 which may be used within the scope of the present invention are meant the compounds which contain, in addition to tiotropium, as counter-ion (anion), chloride, bromide, iodide, sulphate, methanesulphonate or para-toluenesulphonate. Within the scope of the present invention, the methanesulphonate, chloride, bromide and iodide are preferred of all the salts 1, the methanesulphonate and bromide being of particular importance. Of outstanding importance according to the invention are salts 1 selected from among tiotropium bromide, tiotropium chloride and tiotropium methanesulphonate. Tiotropium bromide is particularly preferred.

[0067] The substance 1 is administered by producing an inhalable aerosol, by spraying a pressurised active substance solution. Inhalable aerosols of this kind contain a propellant gas to produce the inhalable aerosol. The propellant gases that can be used to prepare inhalable aerosols are known from the prior art. The propellant-gas-containing inhalable aerosols according to the invention contain the propellant gas HFA 134a. In another embodiment, the propellant-gas-containing inhalable aerosols according to the invention may contain, in addition to the propellant gas HFA 134a, other propellant gases which are selected for example from among the hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellant gases may be used in addition to the propellant gas HFA 134a on their own or in mixtures together with the propellant gas HFA 134a.

[0068] Particularly preferred according to the invention are propellant-gas-containing inhalable aerosols which contain only HFA134a as propellant gas. The propellant-gas-containing inhalable aerosols according to the invention may also contain other ingredients such as cosolvents, stabilisers, surfactants, antioxidants, lubricants and preservatives. All these other ingredients are known in the art.

[0069] The formulations according to the invention for preparing propellant-gas-containing inhalable aerosols contain means for adjusting the pH. The propellant-gas-containing inhalable aerosols according to the invention have a pH of 6-8, preferably 6.5-7.5. The pH of the propellant-gas-containing inhalable aerosols corresponds according to the invention to the pH that can be obtained by conversion from the measured value. The measured value used for the conversion corresponds to the value that can be measured by a pH electrode directly in the solution of the active substance in the cosolvent(s), preferably in the solution of active substance and ethanol and water. The propellant-gas-containing inhalable aerosols according to the invention contain an acid, preferably selected from among inorganic or organic acids.

[0070] Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which already form an acid addition salt with the active substance. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH. In another embodiment according to the invention citric acid is particularly preferably used. Preferably, propellant-gas-containing inhalable aerosols contain citric acid in an amount of 0.005-0.1%, particularly preferably in an amount of 0.05-0.1%, particularly preferably 0.04-0.09%, most particularly preferably 0.03-0.08%, also particularly preferably 0.02-0.05%.

[0071] In another preferred embodiment the propellant-gas-containing inhalable aerosols according to the invention contain an inorganic acid in a concentration that corresponds to a quantity of H.sup.+-ions which can be obtained by adding a 1-3% proportion of a 0.01 normal acid, preferably an inorganic acid in a concentration that corresponds to a quantity of H.sup.+-ions which can be obtained by adding a 1.5-2.5% proportion of a 0.01 normal acid.

[0072] In another preferred embodiment the propellant-gas-containing inhalable aerosols according to the invention contain hydrochloric acid and/or hydrobromic acid, preferably hydrochloric acid, as the inorganic acid.

[0073] In another preferred embodiment the propellant-gas-containing inhalable aerosols according to the invention contain sulphuric acid as the inorganic acid.

[0074] In another preferred embodiment the propellant-gas-containing inhalable aerosols according to the invention contain an organic acid selected from among ascorbic acid, fumaric acid and citric acid.

[0075] In another preferred embodiment the propellant-gas-containing inhalable aerosols according to the invention contain ascorbic acid as the inorganic acid.

[0076] The proportion of dissolved pharmaceutically active substance 1 in the finished preparation (based on a metering chamber of 50 μl) is 0.005-0.05% according to the invention. Preferably, the formulations according to the invention for preparing propellant-gas-containing inhalable aerosols contain 0.005-0.03% of the dissolved active substance 1. Also preferably, the formulations according to the invention for preparing propellant-gas-containing inhalable aerosols contain 0.008-0.045% of the dissolved active substance 1. Also preferably, the formulations according to the invention for preparing propellant-gas-containing inhalable aerosols contain 0.01-0.04% of the dissolved active substance 1. Also preferably, the formulations according to the invention for preparing propellant-gas-containing inhalable aerosols contain 0.01-0.02% of the dissolved active substance 1. Also preferably, the formulations according to the invention for preparing propellant-gas-containing inhalable aerosols contain 0.02% of the dissolved active substance 1.

[0077] The overall composition according to the invention of the propellant-gas-containing inhalable aerosols is obtained from the percentage of dissolved active substance (% by weight) plus the percentage of cosolvents (% by weight), plus the percentage of acid (% by weight), the remainder up to 100% being made up by the propellant gas. If the inhalable aerosols according to the invention contain other ingredients such as stabilisers, surfactants, antioxidants, lubricants and preservatives, these are present in an amount of less than 2% (% by weight), preferably less than 1%, while the amount of propellant gas is reduced accordingly by the presence of these additional components. In one particular embodiment, the inhalable aerosols according to the invention contain only active substance, cosolvents, acid and propellant gas.

[0078] The medicament formulations according to the invention are administered as single doses by means of a spray jet, in which a dose flows out of the metering chamber by actuation of the inhaler by expulsion from the nozzle. The metering chamber has a capacity of between 25 μl and 100 μl, preferably 50 μl. According to the invention the details of the composition of the medicament formulation (proportion of the acid in % by weight and proportion of the dissolved active substance 1 in % by weight) for determining the dose are based on a metering chamber with a volume of 50 μl, unless stated otherwise. By suitable calculation adjustments (e.g. doubling, halving) the skilled man can also obtain the corresponding concentrations for the proportions of acid and active substance for a metering chamber of for example 25 μl and 100 μl and these are encompassed by the invention.

[0079] As another embodiment according to the invention the metering is carried out by 2 spray jets immediately following one another, preferably within less than 10 minutes, so that the overall dose corresponds to the administration of 2 partial doses of 1 spray jet. In this embodiment of the invention the nominal dose and the further dosage details according to the invention that can be derived from it relate to the total amount administered in the two spray jets.

[0080] This metering is particularly suitable for treating a medium- or high-grade COPD.

[0081] Medicament formulations according to the invention which are administered as single doses, the metering chamber having a volume of 25 μl, preferably contain the dissolved medicament 1 in an amount of 0.01-0.1%, particularly preferably in an amount of 0.01-0.09%, particularly preferably in an amount of 0.016-0.09%, particularly preferably in an amount of 0.02-0.08%, particularly preferably in an amount of 0.02-0.04%, particularly preferably in an amount of 0.04%. Medicament formulations according to the invention which are administered as single doses, the metering chamber having a volume of 50 μl, preferably contain the dissolved medicament 1 in an amount of 0.005-0.05%, particularly preferably in an amount of 0.005-0.045%, particularly preferably in an amount of 0.008-0.04%, particularly preferably in an amount of 0.01-0.02%, particularly preferably in an amount of 0.012%, particularly preferably in an amount of 0.02%.

[0082] Medicament formulations according to the invention which are administered as single doses, the metering chamber having a volume of 100 μl, preferably contain the dissolved medicament 1 in an amount of 0.0025-0.025%, particularly preferably in an amount of 0.0025-0.0225%, particularly preferably in an amount of 0.004-0.02%, particularly preferably in an amount of 0.005-0.02%, particularly preferably in an amount of 0.005-0.01%, particularly preferably in an amount of 0.01%.

[0083] In another particularly preferred form, medicament formulations according to the invention contain only the active substance 1 as sole component as a pharmacologically active ingredient (active substance) for treating inflammatory or obstructive respiratory diseases.

[0084] The percentages given within the scope of the present invention are always percent by weight. If proportions by mass of tiotropium are expressed as percent by weight, the corresponding values for the crystalline tiotropium bromide monohydrate that is preferably used within the scope of the production according to the present invention can be obtained by multiplication by the conversion factor 1.2495 based on the molecular mass of the tiotropium bromide.

[0085] The formulations for preparing propellant-gas-containing inhalable aerosols contain cosolvents, according to the invention. Preferably, according to the invention, the formulations contain a mixture of water and ethanol as cosolvents. Preferably, also, the formulations contain an amount of water of 0.5-2.5% and 15-40% ethanol. Particularly preferably the formulations contain a proportion of water of 0.5-2% and 15-40% ethanol. Preferably, moreover, the formulations contain a proportion of water of 1-2% and 15-35% ethanol. More preferably the formulations contain a proportion of water of 1-2% and 20-30% ethanol.

[0086] According to the invention these quantities of water are preferably added to the propellant gases or the solutions of the active substance 1 and the cosolvents if the propellant gas, propellant gas mixture or formulation does not contain any other water (free water). Technically, the water may be mixed with the propellant gas even before the medicament formulation is prepared, or first the medicament formulation is prepared with anhydrous propellant gas or propellant gas mixture and then the corresponding amount of water is added.

[0087] In some cases, the term medicament formulation is used within the scope of the present invention instead of the term solution formulation. The two terms are to be regarded as equivalent within the scope of the present invention.

[0088] The propellant-containing inhalable aerosols or solution formulations according to the invention may also contain other constituents such as surface-active agents (surfactants), adjuvants, antioxidants or flavourings.

[0089] The surface-active agents (surfactants) optionally present in the solutions 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, propyleneglycol, polyethyleneglycol, Brij, ethyl oleate, glyceryl trioleate, glyceryl monolaurate, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, oleyl oleate, sterylalcohol, cetylpyridinium chloride, block polymers, natural oil, ethanol and isopropanol.

[0090] If the solutions according to the invention contain surfactants these are preferably used in an amount of 0.0005-1%, particularly preferably 0.005-0.5%. In another preferred embodiment the solutions according to the invention do not contain any surface-active agents (surfactants).

[0091] The antioxidants optionally contained in the solutions according to the invention are preferably selected from the group consisting of ascorbic acid, citric acid, sodium edetate, editic acid, tocopherols, butylhydroxytoluene, butylhydroxyanisole and ascorbylpalmitate, while tocopherols, butylhydroxytoluene, butylhydroxyanisole or ascorbylpalmitate are preferably used.

[0092] The flavourings optionally contained in the solutions according to the invention are preferably selected from the group consisting of peppermint, saccharine, Dentomint®, aspartame and ethereal oils (for example cinnamon, aniseed, menthol, camphor), peppermint or Dentomint® being particularly preferred.

[0093] The solutions according to the invention may be prepared using methods known in the art. For this, the constituents of the formulation are mixed with the propellant gas or gases (optionally at low temperatures) and filled into suitable containers.

[0094] Surprisingly it has been found that the problem of the invention is solved by the preparation of a medicament for treating inflammatory or obstructive respiratory complaints in the form of a medicament formulation, the medicament formulation containing as active substance exclusively 1 in dissolved form, characterised in that the medicament formulation contains the propellant gas HFA 134a

[0095] and as other ingredients 0.005-0.03% of the active substance 1, a mixture of the two cosolvents ethanol and water, the ethanol content being between 15-40% and the water content being between 0.5-2.5%, and an acid, which is present in an amount such that the pH is between 6 and 8.

[0096] In one particular embodiment the problem of the invention is solved by a medicament formulation for the treatment of inflammatory or obstructive respiratory complaints, the medicament formulation containing as active substance exclusively 1 in dissolved form, and is characterised in that the medicament formulation contains the propellant gas HFA 134a, and as other ingredients 0.005-0.03% of the active substance 1, a mixture of the two cosolvents ethanol and water, the ethanol content being between 15-40% and the water content being between 0.5-2.5%, and an organic acid in a concentration of between 0.005-0.1%, preferably between 0.008-0.09%, more preferably between 0.01-0.08, more preferably between 0.02-0.06, and more preferably between 0.02-0.05%.

[0097] In one particular embodiment the problem of the invention is solved by a medicament formulation for the treatment of inflammatory or obstructive respiratory complaints, the medicament formulation containing as active substance exclusively 1 in dissolved form, and is characterised in that the medicament formulation contains the propellant gas HFA 134a, and as other ingredients 0.005-0.03% of the active substance 1, a mixture of the two cosolvents ethanol and water, the ethanol content being between 15-40% and the water content being between 0.5-2.5%, and an inorganic acid in a concentration that corresponds to a quantity of H.sup.+-ions that can be obtained by the addition of a 1-3% proportion of a 0.01 normal acid, preferably an inorganic acid in a concentration that corresponds to a quantity of H.sup.+-ions that can be obtained by the addition of a 1.5-2.5% proportion of a 0.01 normal acid.

[0098] Corresponding amounts of inorganic acid that correspond to the inventive quantity of H.sup.+-ions can be obtained by the addition of 1-3% of a 0.01 normal acid or 0.1-0.3% of a 0.1 normal acid or by the addition of a corresponding amount that can be determined by conversion in a comparable manner. Corresponding amounts of inorganic acid that correspond to the quantity of H.sup.+-ions preferred according to the invention can be obtained by the addition of 1.5-2.5% of a 0.01 normal acid or 0.15-0.25% of a 0.1 normal acid or by the addition of a corresponding amount that can be determined by conversion in a comparable manner.

[0099] In one particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the medicament formulation contains as acid an organic acid, preferably citric acid in a concentration of between 0.005-0.1%, preferably between 0.008-0.09%, more preferably between 0.01-0.08, more preferably between 0.02-0.06, and more preferably between 0.02-0.05%.

[0100] In one particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the medicament formulation contains as acid an organic acid, preferably ascorbic acid in a concentration of between 0.005-0.1%, preferably between 0.008-0.09%, more preferably between 0.01-0.08, more preferably between 0.02-0.06, and more preferably between 0.02-0.05%.

[0101] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the medicament formulation contains as acid an inorganic acid in a concentration that corresponds to a quantity of H.sup.+-ions that can be obtained by the addition of a 1-3% proportion of a 0.01 normal acid, preferably an inorganic acid in a concentration that corresponds to a quantity of H.sup.+-ions that can be obtained by the addition of a 1.5-2.5% proportion of a 0.01 normal acid.

[0102] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the medicament formulation contains as acid aqueous hydrochloric acid in a concentration that corresponds to a quantity of H.sup.+-ions that can be obtained by the addition of a 1-3% proportion of a 0.01 normal acid, preferably an inorganic acid in a concentration that corresponds to a quantity of H.sup.+-ions that can be obtained by the addition of a 1.5-2.5% proportion of a 0.01 normal acid, preferably in that the medicament formulation contains a 1-3% proportion of a 0.01 molar hydrochloric acid, more preferably in that the medicament formulation contains a 1.5-2.5% proportion of a 0.01 molar hydrochloric acid.

[0103] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the medicament formulation contains as acid aqueous sulphuric acid in a concentration that corresponds to a quantity of H.sup.+-ions that can be obtained by the addition of a 1-3% proportion of a 0.01 normal acid, preferably an inorganic acid in a concentration that corresponds to a quantity of H.sup.+-ions that can be obtained by the addition of a 1.5-2.5% proportion of a 0.01 normal acid.

[0104] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the nominal dose of the single dosage is between 5.5 μg and 6.5 μg, the delivered dose is between 4.5-5.6 μg, and the pulmonary dose is between 2-3 μg and the mean aerodynamic particle size is between 2.5-3.5 μm.

[0105] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the nominal dose of the single dosage is between 5.5 μg and 6.5 μg, and the delivered dose is preferably between 4.7-5.4 μg, particularly preferably between 4.8-5.3 μg, more particularly preferably between 4.9-5.2 μg, and most particularly preferably between 5-5.1 μg.

[0106] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the nominal dose of the single dosage is between 5.5 μg and 6.5 μg, and the pulmonary dose is preferably between 2.0-3.0 μg, particularly preferably between 2.1-3.0 μg, most particularly preferably between 2.3-2.9 μg, and even more particularly preferably between 2.4-2.7 μg.

[0107] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the nominal dose of the single dosage is between 5.5 μg and 6.5 μg, and the mean aerodynamic particle size is preferably between 2.6-3.4 μm, more preferably between 2.7-3.3 μm.

[0108] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the dose is administered by the application of a single dose by a spray jet, in which a dose flows out of the metering chamber by actuation of the inhaler and is expelled from the nozzle and the resulting aerosol is characterised in that the nominal dose of the single dosage is between 5.5 μg and 6.5 μg, the delivered dose is between 4.5-5.6 μg, and the pulmonary dose is between 2-3 μg and the mean aerodynamic particle size is between 2.5-3.5 μm.

[0109] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the bore diameter of the spray head used has a diameter of between 0.2-0.3 mm, preferably between 0.20-0.27 mm, most preferably between 0.20 and 0.25 mm, and the aerosol formed is characterised in that the nominal dose of the single dosage is between 5.5 μg and 6.5 μg, the delivered dose is between 4.5-5.6 μg, and the pulmonary dose is between 2-3 μg and the mean aerodynamic particle size is between 2.5-3.5 μm.

[0110] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the metering chamber has a volume of between 25 μl and 100 μl, preferably 50 μl, and the aerosol formed is characterised in that the nominal dose of the single dosage is between 5.5 μg and 6.5 μg, the delivered dose is between 4.5-5.6 μg, and the pulmonary dose is between 2-3 μg and the mean aerodynamic particle size is between 2.5-3.5 μm.

[0111] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the sealing rings in the valve head are made from ethylene-propylene-diene monomer (EPDM), and the aerosol formed is characterised in that the nominal dose of the single dosage is between 5.5 μg and 6.5 μg, the delivered dose is between 4.5-5.6 μg, and the pulmonary dose is between 2-3 μg and the mean aerodynamic particle size is between 2.5-3.5 μm.

[0112] In another particular embodiment the invention relates to a medicament formulation with the properties mentioned hereinbefore or hereinafter, which is further characterised in that the active substance is tiotropium bromide.

[0113] In another particular embodiment the invention relates to the use of a tiotropium bromide-containing medicament formulation for the treatment of inflammatory or obstructive respiratory complaints, the medicament formulation being characterised by the properties mentioned hereinbefore or hereinafter.

[0114] In another particular embodiment the invention relates to the active substance tiotropium 1, which is present in one of the medicament formulations mentioned hereinbefore or hereinafter, for use as a medicament for the treatment of inflammatory or obstructive respiratory complaints, the medicament being administered [0115] once a day, [0116] in a nominal dose of between 5.5 μg and 6.5 μg, [0117] in a delivered dose of between 4.5-5.6 μg, and [0118] in a pulmonary dose of between 2-3 μg

[0119] the mean aerodynamic particle size being between 2.5-3.5 μm.

[0120] In another particular embodiment the invention relates to the active substance tiotropium 1, which is present in one of the medicament formulations mentioned hereinbefore or hereinafter, for use as a medicament for the treatment of inflammatory or obstructive respiratory complaints, the medicament being administered [0121] once a day, [0122] in a nominal dose of between 5.5 μg and 6.5 μg, [0123] in a delivered dose of between 4.5-5.6 μg and [0124] in a pulmonary dose of between 2.0-3.0 μg, preferably between 2.1-3.0 μg, particularly preferably between 2.3-2.9 μg, and most particularly preferably between 2,4-2.7 μg.

[0125] the mean aerodynamic particle size being between 2.5-3.5 μm.

[0126] In another particular embodiment the invention relates to the active substance tiotropium 1, which is present in one of the medicament formulations mentioned hereinbefore or hereinafter, for use as a medicament for the treatment of inflammatory or obstructive respiratory complaints, the medicament being administered [0127] once a day, [0128] in a nominal dose of between 5.5 μg and 6.5 μg, [0129] in a delivered dose of between 4.7-5.4 μg, preferably between 4.8-5.3 μg, [0130] particularly preferably between 4.9-5.2 μg, as well as most particularly preferably between 5-5.1 μg and [0131] in a pulmonary dose of between 2-3 μg

[0132] the mean aerodynamic particle size being between 2.5-3.5 μm.

[0133] The above-mentioned propellant-gas-containing solutions according to the invention may be administered using inhalers known in the art (pMDIs=pressurized metered dose inhalers). Accordingly, in another aspect, the present invention relates to medicaments in the form of solutions as described hereinbefore combined with one or more inhalers suitable for administering these solutions. Moreover the present invention relates to inhalers, characterised in that they contain the propellant-gas-containing solutions according to the invention as described above. The present invention further relates to containers (e.g. cartridges), which are fitted with a suitable valve that is prepared before use with regard to the water content. The containers may be used in a suitable inhaler and contain one of the above-mentioned propellant-gas-containing solutions according to the invention. Suitable containers (e.g. cartridges) and processes for filling these cartridges with the propellant-gas-containing solutions according to the invention are known from the prior art.

[0134] The cartridge (cf. FIG. 1, section “a”) contains the medicament as a solution. The formulation contains, besides the active substance 1, other chemical substances as well, which are important for stability and product performance. Above the liquid level, further gaseous propellant gas is present. The propellant gas in the metering chamber causes the medicament formulation to be expelled explosively when the metered dose aerosol is actuated. (For the purposes of the present invention the word cartridge is equivalent to canister).

[0135] In the nozzle (cf. FIG. 1, section “b”) are formed the small droplets of liquid that contain the medicament. The size of these droplets is important in order to obtain good deposition in the lungs. The nozzle is characterised by the bore diameter (narrowest diameter) of the spray head “b” used.

[0136] The amount of medicament expelled is metered by the metering chamber (cf. FIG. 2, section “c”).

[0137] The droplet size of a metered dose aerosol can be influenced by the nozzle design (bore diameter of the spray head, size of the metering chamber) and by the composition of the solution formulation. In particular, there is the possibility of varying the droplet size by the choice of propellant gas. The smaller the nozzle diameter of the spray head, the smaller the droplets produced—although limits are set on the design, as nozzles that are too small become blocked. The lower limit for the bore is 0.16 mm, as a smaller nozzle can easily become blocked.

[0138] The use of a spray head with a bore diameter of between 0.20-0.27 mm is particularly preferred within the scope of the present invention. It is also particularly preferable to use a metering chamber with a volume of between 25 μl and 100 μl, particularly preferably 50 μl. Commercially obtainable mouth tubes (e.g. as manufactured by RPC Formatec GmbH, Germany) may be used for the metered dose aerosols according to the invention.

[0139] In another aspect the present invention relates to a process for metering a medicament of a formulation according to the invention in order to produce propellant-gas-containing inhalable aerosols, comprising the steps of [0140] removing the lid [0141] vigorously shaking, with the canister facing upwards [0142] breathing out [0143] placing the metered dose aerosol between the lips [0144] slowly breathing in and immediately . . . [0145] . . . pressing on the canister [0146] breathing in slowly and completely [0147] holding one's breath if possible for 10 seconds

[0148] The following Examples serve to illustrate the present invention by way of example, without restricting it to their contents.

[0149] Formulation Examples (Composition)

[0150] 1.

TABLE-US-00001 Tiotropium bromide monohydrate 0.04% by weight citric acid 0.05% by weight water  1.0% by weight ethanol 30.0% by weight HFA134a 68.9% by weight Total 100% by weight (13.5 g)

[0151] 2.

TABLE-US-00002 Tiotropium bromide monohydrate 0.01% by weight citric acid 0.02% by weight water  1.5% by weight ethanol 15.0% by weight HFA134a 83.5% by weight Total 100% by weight (14.5 g)

[0152] 3.

TABLE-US-00003 Tiotropium bromide monohydrate 0.02% by weight citric acid 0.04% by weight water  2.0% by weight ethanol 35.0% by weight BHT (butylhydroxytoluene)  0.1% by weight HFA134a 62.8% by weight Total 100% by weight (13.2 g)

[0153] 4.

TABLE-US-00004 Tiotropium bromide monohydrate 0.02% by weight sulphuric acid  0.1% by weight water  1.0% by weight ethanol 20.0% by weight HFA134a 78.9% by weight Total 100% by weight (14.2 g)

[0154] 5.

TABLE-US-00005 Tiotropium bromide monohydrate 0.04% by weight hydrochloric acid  0.2% by weight water  0.5% by weight ethanol 15.0% by weight HFA134a 84.3% by weight Total 100% by weight (14.6 g)