CA2527178A1

CA2527178A1 - New long-acting drug combinations for the treatment of respiratory complaints

Info

Publication number: CA2527178A1
Application number: CA002527178A
Authority: CA
Inventors: Ingo Konetzki
Original assignee: Individual
Current assignee: Boehringer Ingelheim International GmbH
Priority date: 2003-05-27
Filing date: 2004-05-14
Publication date: 2004-12-09
Also published as: DE10323966A1; WO2004105759A2; EP1631287A2; WO2004105759A3; JP2007500194A

Abstract

The invention relates to novel medicament compositions based on a novel anticholinergic agent and a novel long-acting .beta.2-agonist. The invention also relates to the production and utilization of said compositions in the therapy of respiratory tract diseases.

Description

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83922fft.209 New long-acting drug combinations for the treatment of respiratory complaints The present invention relates to novel pharmaceutical compositions based on a new anticholinergic and a new long-acting beta2-agonist, processes for the preparation thereof and the use thereof in the treatment of respiratory complaints.
Descriation of the invention The present invention relates to novel pharmaceutical compositions containing in addition to an anticholinergic of formula 1 Met+~Me -N X
O H
O O
Me wherein X - denotes an anion with a single negative charge, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, the compound of formula 2 OH
HO ~ N O \ SO NH

HO

optionally in the form of the pharmacologically acceptable acid addition salts, and optionally in the form of the enantiomers, mixtures of enantiomers or Case 1/1499-ff 2 BOEHRINGER INGELHEIM PHARMA
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racemates, and optionally in the form of the solvates and hydrates thereof, optionally combined with physiologically acceptable excipients.
Preferably the salts of formula _~ are used wherein X - denotes an anion with a single negative charge, selected from the group consisting of chloride, bromide, 4-toluenesulphonate and methanesulphonate, preferably bromide.
Particularly preferably the salts of formula _~ are used wherein X - denotes an anion with a single negative charge, selected from the group consisting of chloride, bromide and methanesulphonate, preferably bromide.
Particularly preferred according to the invention is the salt of formula _~, wherein X - denotes bromide.
The compounds of formula ~ are known from WO 02/32899.
Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a synergistic effect can be observed in the treatment of inflammatory or obstructive diseases of the respiratory tract if the anticholinergic of formula ~_ is administered together with the compound of formula 2. In view of this synergistic effect the drug combinations according to the invention can be used in smaller doses than would be the case with the individual compounds used in monotherapy in the usual way. As another positive aspect of the present invention this reduces unwanted side effects such as may occur when betamimetics are administered, for example. Unwanted side effects which deserve special mention in this context are the stimulant effects on the heart which may be caused by betamimetics, particularly tachycardia, a stronger heartbeat, pain resembling angina pectoris as well as arrhythmia.
The abovementioned effects are observed both when the two active substances are administered simultaneously in a single active substance formulation and also when the two active substances are administered successively in separate formulations. It is preferred according to the invention to administer the two active substance components simultaneously in a single formulation.

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Any reference to the compound 1' within the scope of the present invention is to be regarded as a reference to the pharmacologically active cation of the following formula contained in the salts 1 Met+~Me N
O H
O O
Me 1'.
In the abovementioned drug combinations the active substances may either both be contained in a single formulation or may be contained in two separate formulations. Pharmaceutical compositions which contain the active substances 1 and 2 in a single formulation are preferred according to the invention.
Any reference to the betamimetic of formula 2 includes a reference to the enantiomers (R or S) or the mixtures thereof, the R-enantiomer of the compound being of particular importance within the scope of the present invention. Process for the enantioselective preparation of the enantiomers of the compound of formula 2 are known in the art. The compound 2 may also be present according to the invention in the form of its salts, as well as its hydrates or solvates.
Within the scope of the present invention the reference to compound 2 includes a reference to the physiologically acceptable acid addition salts thereof. By physiologically acceptable acid addition salts of the betamimetics 2 are meant according to the invention pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid or malefic acid. If desired, mixtures of the abovementioned acids may be used to prepare the salts 2. According to the invention the salts of 2 selected from among the hydrochloride, ~

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hydrobromide, sulphate, phosphate, fumarate, methanesulphonate, maleate and xinafoate are preferred.
In one aspect the present invention relates to the above-mentioned pharmaceutical compositions which contain, in addition to therapeutically effective quantities of 1 and 2, a pharmaceutically acceptable excipient. In another aspect the present invention relates to the above-mentioned pharmaceutical compositions which do not contain any pharmaceutically acceptable excipient in addition to therapeutically effective quantities of 1 and 2.
The present invention further relates to the use of therapeutically effective amounts of the salts 1 for preparing a pharmaceutical composition which also contains the compound of formula 2 for the treatment of inflammatory or obstructive respiratory complaints. Preferably the present invention relates to the above-mentioned use for preparing a pharmaceutical composition for the treatment of asthma or COPD.
Within the scope of the present invention the compounds 1 and 2 may be administered simultaneously or one after the other; preferably, the compounds 1 and 2 are administered simultaneously according to the invention.
The present invention also relates to the use of therapeutically effective quantities of salts 1 and long-acting betamimetics 2 for the treatment of inflammatory or obstructive respiratory complaints, particularly asthma or COPD.
The proportions in which the active substances 1 and 2 may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2 may possibly be present in the form of their solvates or hydrates. Depending on the choice of the salts 1 and 2, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various salt forms. Therefore the following ratios by weight are based on the cation 1' and the free base of the compound 2 .

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The active substance combinations according to the invention may contain_1' and the free base of the compound of formula 2 in ratios by weight ranging for example from about 1:30 to 400:1, preferably 1:25 to 200:1, preferably 1:20 to 100:1, particularly preferably from 1:15 to 50:1.
For example, without restricting the scope of the invention thereto, preferred combinations of 1 and 2 according to the invention may contain the cation 1' and the free base of the compound 2 in the following proportions by weight:
1:15,1:14,1:13,1:12,1:11,1:10,1:9,1:8,1:7,1:6,1:5,1:4,1:3,1:2,1:1,2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1,32:1,33:1,34:1,35:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are normally administered so that the cation 1' and the compound 2 are present together in doses of 5 to 5000pg, preferably from 10 to 2000Ng, more preferably from 15 to 1000Ng, even more preferably from 20 to 800Ng, preferably according to the invention from 30 to 750pg, preferably from 40 to 700Ng, per single dose, these total dosages being based on the free base of compound 2 .
For example, combinations of 1 and 2 according to the invention contain a quantity of 1' and compound of formula 2 such that the total dosage per single dose is about 15pg, 20Ng, 25Ng, 30Ng, 35pg, 40pg, 45Ng, 50pg, 55Ng, 60Ng, 65Ng, 70Ng, 75~Ig, 80pg, 85Ng, 90Ng, 95Ng, 100Ng, 105pg, 110Ng, 115Ng, 120Ng, 125pg, 130pg, 135Ng, 140pg, 145pg, 150pg, 155Ng, 160pg, 165pg, 170pg, 175pg, 180pg, 185pg, 190pg, 195pg, 200pg, 205Ng, 210pg, 215Ng, 220pg, 225Ng, 230Ng, 235Ng, 240Ng, 245pg, 250Ng, 255pg, 260pg, 265Ng, 270Ng, 275Ng, 280pg, 285pg, 290pg, 295Ng, 300Ng, 305Ng, 310Ng, 315Ng, 320pg, 325pg, 330Ng, 335Ng, 340Ng, 345Ng, 350pg, 355pg, 360pg, 365Ng, 370Ng, 375pg, 380pg, 385pg, 390pg, 395Ng, 400Ng, 405Ng, 410Ng, 415Ng, 420pg, 425pg, 430Ng, 435Ng, 440pg, 445pg, 450pg, 455Ng, 460pg, 465pg, 470pg, 475pg, 480pg, 485Ng, 490Ng, 495pg, 500pg, 505Ng, 510pg, 515pg, 520Ng, 525pg, 530Ng, 535Ng, 540Ng, 545pg, 550Ng, 555Ng, 560pg, 565Ng, 570pg, 575pg, 580Ng, 585Ng, 590Ng, 595Ng, 600pg, 605Ng, 610pg, 615pg, 620Ng, 625Ng, 630Ng, 635Ng, 640pg, 645Ng, 650Ng, 655pg, 660pg, 665pg, 670pg, 675pg, 680pg, 685pg, 690~Ig, 695Ng, 700Ng or the like. Here, too, the dosages specified are based on the content of free base of the compound 2 in Case 111499-ff 6 BOEHRINGER INGELHEIM PHARMA
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the drug combinations according to the invention. It is clear to the skilled man that these proposed dosages per single dose are not to be regarded as being restricted to the numerical values explicitly mentioned. Fluctuations of around ~ 2.5Ng , particularly fluctuations in the decimal range, are also covered as will be apparent to anyone skilled in the art. In these dosage ranges the active substances 1' and 2 may be present in the weight ratios described above.
The active substance combinations of 1 and 2 according to the invention are preferably administered by inhalation. For this purpose, ingredients 1 and 2 have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable solutions. Inhalable powders according to the invention containing the combination of active substances 1 and 2 may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The preparations according to the invention may contain the combination of active substances 1 and 2 either together in one formulation or in two separate formulations.
These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.
A) Inhalable powder containing the combinations of active substances 1 and 2 according to the invention:
The inhalable powders according to the invention may contain 1 and 2 either on their own or in admixture with suitable physiologically acceptable excipients. If the active substances 1 and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g.
lactose, saccharose, maltose, trehalose), oligo- and polysaccharides (e.g.
dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates.
Within the scope of the inhalable powders according to the invention the excipients have a maximum average particle size of up to 250pm, preferably Case 1/1499-ff 7 BOEHRINGER INGELHEIM PHARMA
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between 10 and 150pm, most preferably between 15 and 80pm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9Nm to the excipients mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active substance 1 and 2, preferably with an average particle size of 0.5 to 1 O~.m, more preferably from 1 to 5~,m, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and lastly mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be prepared and administered either in the form of a single powder mixture which contains both 1 and 2 or in the form of separate inhalable powders which contain only 1 or 2.
The inhalable powders according to the invention may be administered using inhalers known from the prior art. Inhalable powders according to the invention which contain a physiologically acceptable excipient in addition to and 2 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in US 4570630A, or by other means as described in DE 36 25 685 A. The inhalable powders according to the invention which contain 1 and 2 optionally in conjunction with a physiologically acceptable excipient may be administered, for example, using the inhaler known by the name Turbuhaler~
or using inhalers as disclosed for example in EP 237507 A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to 1 and 2 are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.
A particularly preferred inhaler for administering the pharmaceutical combination according to the invention in inhalettes is shown in Figure 1.
This inhaler (Handyhaler) for inhaling powdered pharmaceutical compositions from capsules is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and a mouthpiece 12 which is connected Case 1/1499-ff $ BOEHRINGER INGELHEIM PHARMA
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to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut and air holes 13 for adjusting the flow resistance.
B) Propellant gas-driven inhalation aerosols containing the combinations of active substances 1 and 2:
Inhalation aerosols containing propellant gas according to the invention may contain substances 1 and 2 dissolved in the propellant gas or in dispersed form. 1 and 2 may be present in separate formulations or in a single preparation, in which 1 and 2 are either both dissolved, both dispersed or only one component is dissolved and the other is dispersed. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are halogenated alkane derivatives selected from TG 11, TG 12, TG 134a ( 1,1,1, 2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof, the propellant gases TG134a, TG227 and mixtures thereof being preferred.
The propellant-driven inhalation aerosols according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.
The inhalation aerosols containing propellant gas according to the invention may contain up to 5 wt.% of active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%, 0.015 to 2 wt.-%, 0.1 to 2 wt.-%, 0.5 to 2 wt.-% or 0.5 to 1 wt.-% of active substance 1 and/or 2.
If the active substances 1 and/or 2 are present in dispersed form, the particles of active substance preferably have an average particle size of up to 10~,m, preferably from 0.1 to 6~m, more preferably from 1 to 5~.m.
The propellant-driven inhalation aerosols according to the invention mentioned above may be administered using inhalers known in the art (MDIs Case 1/1499-ff 9 BOEHRINGER INGELHEIM PHARMA
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= metered dose inhalers). Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-driven aerosols as hereinbefore described combined with one or more inhalers suitable for administering these aerosols. In addition, the present invention relates to inhalers which are characterised in that they contain the propellant gas-containing aerosols described above according to the invention. The present invention also relates to cartridges which are fitted with a suitable valve and can be used in a suitable inhaler and which contain one of the above-mentioned propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges and methods of filling these cartridges with the inhalable aerosols containing propellant gas according to the invention are known from the prior art.
C) Propellant-free inhalable solutions or suspensions containing the combinations of active substances 1 and 2 according to the invention:
Propellant-free inhalable solutions according to the invention contain for example aqueous or alcoholic, preferably ethanolic solvents, possibly ethanolic solvents in admixture with aqueous solvents. In the case of aqueous/ethanolic solvent mixtures the relative proportion of ethanol to water is not restricted, but the maximum limit is up to 70 percent by volume, more particularly up to 60 percent by volume of ethanol. The remainder of the volume is made up of water. The solutions or suspensions containing 1 and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. 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, malefic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric acid and sulphuric acid. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may also 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.

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According to the invention, the addition of edetic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabiliser or complexing agent is unnecessary in the present formulation. Other embodiments may contain this compound or these compounds. In a preferred embodiment the content based on sodium edetate is less than 100mg/100m1, preferably less than 50mg/100 ml, more preferably less than 20mg/ 100 ml. Generally, inhalable solutions in which the content of sodium edetate is from 0 to 10mg/100m1 are preferred.
Co-solvents and/or other excipients may be added to the propellant-free l0 inhalable solutions according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols -particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body.
Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or Case 1/1499-ff 1 1 BOEHRINGER INGELHEIM PHARMA
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benzoates such as sodium benzoate in the concentration known from the prior art. The preservatives mentioned above are preferably present in concentrations of up to 50mg/100m1, more preferably between 5 and 20mg/100m1.
Preferred formulations contain, in addition to the solvent water and the combination of active substances 1 and 2, only benzalkonium chloride and sodium edetate. In another preferred embodiment, no sodium edetate is present.
The propellant-free inhalable solutions according to the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol suitable for therapeutic inhalation.
Within the scope of the present invention, preferred inhalers are those in which a quantity of less than 100~,L, preferably less than 50~,L, more preferably between 10 and 30p,L of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20p,m, preferably less than 10pm, such that the inhalable part of the aerosol corresponds to the therapeutically effective quantity.
An apparatus of this kind for propellant-free delivery of a metered quantity of a liquid pharmaceutical composition for inhalation is described for example in International Patent Application WO 91/14468 and also in WO 97/12687 (cf. in particular Figures 6a and 6b). The nebulisers (devices) described therein are known by the name Respimat~.
This nebuliser (Respimat~) can advantageously be used to produce the inhalable aerosols according to the invention containing the combination of active substances 1 and 2.
Accordingly, in a further aspect, the invention relates to pharmaceutical formulations in the form of propellant-free inhalable solutions or suspensions as described above combined with a device suitable for administering these formulations, preferably in conjunction with the Respimat~. Preferably, the invention relates to propellant-free inhalable solutions or suspensions characterised by the combination of active substances 1 and 2 according to Case 1/1499-ff ~2 BOEHRINGER INGELHEIM PHARMA
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the invention in conjunction with the device known by the name Respimat~.
In addition, the present invention relates to the above-mentioned devices for inhalation, preferably the Respimat~, characterised in that they contain the propellant-free inhalable solutions or suspensions according to the invention as described hereinbefore.
According to the invention, inhalable solutions which contain the active substances 1 and 2 in a single preparation are preferred. The term "single preparation" also includes preparations which contain the two ingredients 1 and 2 in two-chamber cartridges, as disclosed for example in WO 00/23037.
Reference is hereby made to this publication in its entirety.
The propellant-free inhalable solutions or suspensions according to the invention may take the form of concentrates or sterile inhalable solutions or suspensions ready for use, as well as the above-mentioned solutions and suspensions designed for use in a Respimat~. Formulations ready for use may be produced from the concentrates, for example, by the addition of isotonic saline solutions. Sterile formulations ready for use may be administered using energy-operated fixed or portable nebulisers which produce inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other principles.
2o Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-free inhalable solutions or suspensions as described hereinbefore which take the form of concentrates or sterile formulations ready for use, combined with a device suitable for administering these solutions, characterised in that the device is an energy-operated free-standing or portable nebuliser which produces inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other methods.
The Examples which follow serve to illustrate the present invention in more detail without restricting the scope of the invention to the following embodiments by way of example.
The following examples of formulations which may be obtained analogously to methods known in the art serve to illustrate the invention still further without restricting the scope of the invention thereto.

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Examples of formulations A) inhalable powder:
1) 2) 3) 4) ingredients Ng per capsule 1'-brom ide 200 2 (hydrochloride) 25 lactose 24775 total 25000 ingredients Ng per capsule 1'-brom ide 100 2 (hydrochloride) 50 lactose 12350 total 12500 ingredients Ng per capsule 1'-brom ide 200 2 (fumaric acid salt) 50 lactose 12250 total 12500 ingredients Ng per capsule 1'-brom ide 200 2 (malefic acid salt) 24 lactose 24776 total 25000

Claims

1) Pharmaceutical composition containing in addition to an anticholinergic of formula 1 wherein X - denotes an anion with a single negative charge, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, the compound of formula 2 optionally in the form of the pharmacologically acceptable acid addition salts, and optionally in the form of the enantiomers, mixtures of enantiomers or racemates, and optionally in the form of the solvates and hydrates thereof, optionally combined with physiologically acceptable excipients.

2) Pharmaceutical composition according to claim 1, characterised in that the active substances 1 and 2 are either present in a single formulation or are contained in two separate formulations.

3) Pharmaceutical composition according to claim 1 or 2, characterised in that the compound 2 is present in the form of the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid or maleic acid.

4) Pharmaceutical composition according to one of claims 1, 2 or 3, characterised in that the compound 2 is present in the form of its R-enantiomer.

5) Pharmaceutical composition according to one of claims 1 to 4, characterised in that the ratios by weight of 1' to 2 (based on the free base) are in the range from about 1:30 to 400:1, preferably 1:25 to 200:1.

6) Pharmaceutical composition according to one of claims 1 to 5, characterised in that it is present in the form of a preparation suitable for inhalation.

7) Pharmaceutical composition according to claim 6, characterised in that it is a preparation selected from among inhalable powders, propellant-driven metered dose aerosols and propellant-free inhalable solutions.

8) Pharmaceutical composition according to claim 7, characterised in that it is an inhalable powder which contains 1 and 2 in admixture with suitable physiologically acceptable excipients selected from among monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures of these excipients with one another.

9) Pharmaceutical composition according to claim 7, characterised in that it is an inhalable powder which contains the active substances 1 and 2 as its sole ingredients.

10) Pharmaceutical composition according to claim 7, characterised in that it is a propellant-containing inhalable aerosol which contains 1 and 2 in dissolved or dispersed form.

11) Propellant-containing inhalable aerosol according to claim 10, characterised in that it contains as propellant gas hydrocarbons such as n-propane, n-butane or isobutane or halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.

12) Propellant-containing inhalable aerosol according to claim 11, characterised in that the propellant gas is TG11, TG12, TG134a, TG227 or mixtures thereof, preferably TG134a, TG227 or a mixture thereof.

13) Pharmaceutical composition according to claim 7, characterised in that it is a propellant-free inhalable solution which contains water, ethanol or a mixture of water and ethanol as solvent.

14) Inhalable solution according to claim 13, characterised in that it optionally contains other co-solvents and/or excipients.

15) Use of a composition according to one of claims 1 to 14 for preparing a drug for treating inflammatory or obstructive diseases of the respiratory tract, particularly asthma or COPD.