IL164291A - Propellant-free inhalable solution or suspention comprising an anticholinesterase and a betamimietic drug and use thereof for the manufacture of a medicament for treating inflammatory or obstructive respiratory disorders - Google Patents

Abstract

The invention relates to novel medicament compositions based on long-acting beta2 agonists and salts of a novel anticholinesterase drug (I), to methods for the production of these compositions and their use in treating respiratory tract diseases.

Description

Q»m»>¾>3 timv *N m typhis, fiann fwa i tsna wa>¥>m Propellant-free inhalable solution or suspension comprising an anticholinesterase and a betamimetic drug and use thereof for the manufacture of a medicament for treating inflammatory or obstructive respiratory disorders Boehringer Ingelheim Pharma GmbH & Co. KG C. 155523 80360pct.210 Medicaments containing betamimetic drugs and a novel anticholinesterase drug The present invention relates to novel pharmaceutical compositions based on beta2 agonists with a long-lasting effect and salts of a new anticholinergic, processes for preparing them and their use in the treatment of respiratory complaints.

Description of the invention The present invention relates to novel pharmaceutical compositions based on beta2 agonists with a long-lasting effect and salts of a new anticholinergic1, processes for preparing them and their use in the treatment of respiratory complaints.

Within the scope of the present invention the anticholinergic agents used are the salts of formula 1 Me. + Me 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.

Preferably, the salts of formula 1 are used wherein X " denotes an anion with a single negative charge selected from among the chloride, bromide, 4-toluenesulphonate and methanesulphonate, preferably bromide.

Most preferably, the salts of formula 1 are used wherein X " denotes an anion with a single negative charge selected from among the chloride, bromide and methanesulphonate, preferably bromide.

Particularly preferred according to the invention is the salt of formula 1 wherein X " denotes bromide.

Anticholinergics may appropriately be used to treat a number of diseases.

Particular mention should be made, for example, of the treatment of asthma or COPD (chronic obstructive pulmonary disease). For treating these diseases WO 92/16528 proposes, for example, anticholinergics which have a scopine, tropenol or tropine basic structure.

The problem on which WO 92/16528 is based is the preparation of anticholinergically active compounds which are characterised by their long-lasting activity. To solve this problem WO 92/16528 discloses inter alia benzilic acid esters of scopine, tropenol or tropine.

For treating chronic diseases it is often desirable to prepare pharmaceutical compositions with a longer-lasting effect. This will generally ensure that the concentration of the active substance needed to achieve the therapeutic effect is present in the body for a longer period of time without the need for the pharmaceutical composition to be administered repeatedly and all too frequently. Moreover, if an active substance is administered at longer intervals of time, this contributes to the feeling of well-being of the patient to a considerable degree. It is particularly desirable to provide a pharmaceutical composition which can be used to therapeutically good effect by administering it once a day (single dose). A single application per day has the advantage that the patient can become accustomed relatively quickly to the regular taking of the medicament at a particular time of the day. 164291/2 If it is to be used as a medicament for administration once a day, the active substance which is to be given must meet particular requirements. First of all, the desired onset of the activity after the administration of the pharmaceutical composition should occur relatively quickly and ideally the activity should remain 5 as constant as possible over a fairly lengthy ensuing period. On the other hand the duration of activity of the pharmaceutical composition should not greatly exceed a period of about one day. Ideally, an active substance should have an activity profile such that the preparation of a pharmaceutical composition which is intended to be administered once a day and contains the active substance in 10 therapeutically appropriate doses can be properly controlled.

It has been found that the esters of scopine, tropenol or tropine disclosed in WO 92/16528 do not meet these more stringent requirements. Because of their extremely long duration of activity, significantly exceeding the period of about one 15 day specified above, they cannot be used therapeutically in a single once-a-day dose. The salts of formula 1_however meet this requirement.

WO 02/32899 discloses new anticholinergics and their use in the treatment of disorders and further their combination with betamimetics. on Summary of the invention The present invention is directed to a propellant-free inhalable solution or suspension, characterized in that it contains one or more compounds 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, combined with one or more compounds with betamimetic function (2), optionally in the form of the enantiomers, mixtures of the enantiomers or in the form of the racemates thereof, optionally in the form of the solvates or hydrates and optionally together with a pharmaceutically acceptable excipient, wherein the solvent is selected either from ethanol alone or from ethanolic solvents mixed with aqueous solvents.

The present invention is further directed to the use of a propellant-free inhalable solution or suspension of the invention for preparing a medicament for the treatment of inflammatory or obstructive respiratory disorders.

Detailed description of the invention Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a synergistic effect can be observed in the treatment of inflammatory and/or obstructive diseases of the respiratory tract if the anticholinergic of formula 1 is used with one or more betamimetics 2. In view of this synergistic effect the pharmaceutical 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 a further positive aspect of the present invention, unwanted side effects such as may occur when beta2 agonists are administered, for example, are thus reduced. Undesirable side effects in this context are, in particular, the stimulant effects on the heart which are sometimes caused by betamimetics, especially tachycardia, palpitations, angina-pectoris-like pain and arryhthmia.

The effects mentioned above may be observed both when the two active substances are administered simultaneously in a single active substance formulation and when they are administered successively in separate formulations. According to the invention, it is preferable to administer the two active substance ingredients simultaneously in a single formulation.

Within the scope of the present invention, any reference to the compound V_ is to be regarded as a reference to the pharmacologically active cation of the following formula contained in the salts1 : Me + Me In the pharmaceutical combinations mentioned above the active substances may be combined in a single preparation or contained in two separate formulations. Pharmaceutical compositions which contain the active substances and 2 in a single preparation are preferred according to the invention.

Salmeterol salts or formoterol salts are preferably used as the long-acting betamimetics 2 according to the invention. Any reference to the term betamimetics 2 also includes a reference to the relevant enantiomers or mixtures thereof.

Accordingly, any reference to the preferred compounds 2 according to the invention, the salts of salmeterol and formoterol, also includes the relevant enantiomeric salts of ft-salmeterol, S-salmeterol, / , ?-formoterol, S,S-formoterol, f?,S-formoterol, S,R-formoterol and the mixtures thereof, while the enantiomeric salts of R-sa|meterol and /-?; -formoterol are of particular importance. The compounds 2 may also be present according to the invention in the form of the hydrates or solvates thereof.

The long-acting betamimetics 2 may also be the salts of the compounds of formula 2a', OH wherein R1 and R2 which may be identical or different denote hydrogen or Ci -C4-alkyl; R3 and R4 which may be identical or different denote hydrogen, Ci-C4-alkyl, -O-Ci-C4-alkyl, - Ci-C4-alkylene-O-Ci-C4-alkyl or R3 and R4 together denote one of the bridging groups - Ci-C4-alkylene- or -0-Ci-C4-alkylene-0- Preferably, salts of the compounds of formula 2a^ wherein R1 and R2 which may be identical or different denote hydrogen, methyl or ethyl; R3 and R4 which may be identical or different denote hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, methoxymethyl, or methoxyethyl, or R3 and R4 together denote one of the bridging groups propylene, butylene, -O-ethylene-O- or -O-propylene-O- are used in the combinations according to the invention.

More preferably, salts of the compounds of formula 2§T wherein R1 and R2 which may be identical or different denote hydrogen or ethyl, preferably hydrogen; R3 and R4 which may be identical or different denote hydrogen, methyl, ethyl, propyl, butyl or methyoxym ethyl or R3 and R4 together denote one of the bridging groups butylene or -O-ethylene-O- are used in the combinations according to the invention.

Most preferably, according to the invention, the salts of the following compounds of formula 2a' wherein a) R1 and R2 denote hydrogen and R3 and R4 denote ethyl; or b) R1 and R2 denote hydrogen and R3 and R4 denote methyl; or c) R1 and R2 denote ethyl and R3 and R4 denote hydrogen; or d) R1 and R2 denote hydrogen and R3 and R4 together denote butylene; or e) R1 and R2 denote hydrogen and R3 and R4 together denote -O- ethylene-O-; or f) R1 and R2 denote hydrogen and R3 and R4 denote tert.-butyl or g) R1 and R2 denote hydrogen and R3 and R4 denote iso-propyl; or h) R1 and R2 denote hydrogen and R3 and R4 denote methoxymethyl used in the combinations according to the invention The compounds of formula 2a^ are known from WO00/751 14.

Of the compounds mentioned above, the structure defined in a), wherein R1 and R2 denote hydrogen and R3 and R4 denote ethyl, are exceptionally important in the pharmaceutical combinations according to the invention. The acid addition salt of this compound is hereinafter referred to as compound 2aa, while any reference to the free base of this compound is characterised by the designation 2aa' according to the following formula : 2aa' In the pharmaceutical compositions according to the invention, the salts of the compounds of formula 2a^ may be present in the form of their racemates, enantiomers or mixtures thereof. The separation of the enantiomers from the racemates may be carried out using methods known in the art (e.g. by chromatography on chiral phases, etc.) If the salts of the compounds of formula 2a' are used in the form of their enantiomers, it is particularly preferable to use the enantiomers in the R configuration at the C-OH group.

The alkyl groups used, unless otherwise stated, are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl or butyl. The groups methyl, ethyl, propyl or butyl may optionally also be referred to by the abbreviations Me, Et, Prop or Bu. Unless otherwise stated, the definitions propyl and butyl also include all possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec. butyl and tert. -butyl, etc.

The alkylene groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms. Examples include: methylene, ethylene, propylene or butylene.

The alkyloxy groups used (also known as -0-Ci-C4-alkyl groups), unless otherwise stated, are branched and unbranched alkyl groups with 1 to 4 carbon atoms which are linked via an oxygen atom. The following may be mentioned, for example: methyloxy, ethyloxy, propyloxy or butyloxy. The groups methyloxyj ethyloxy, propyloxy or butyloxy may optionally also be referred to by the abbreviations MeO, EtO, PropO or BuO. Unless otherwise stated, the definitions propyloxy and butyloxy also include all possible isomeric forms of the groups in question. Thus, for example, propyloxy includes n-propyloxy and iso-propyloxy, butyloxy includes iso-butyloxy, sec. butyloxy and tert. -butyloxy, etc. The word alkoxy may also possibly be used within the scope of the present invention instead of the word alkyloxy. The groups methyloxy, ethyloxy, propyloxy or butyloxy may optionally also be referred to as methoxy, ethoxy, propoxy or butoxy.

The alkylene-alkyloxy groups used, unless otherwise stated, are branched and unbranched double-bonded alkyl bridges with 1 to 4 carbon atoms which may be mono-, di- or trisubstituted, preferably monosubstituted, by an alkyloxy group.

Within the scope of the present invention any reference to compounds 2 should be taken to mean a reference to physiologically acceptable acid addition salts thereof. Examples of physiologically acceptable acid addition salts of the betamimetics 2 according to the invention are the pharmaceutically acceptable salts which are selected from among 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, 4-phenylcinnamic acid, 5-(2.4-difluorophenyl)salicylic acid or maleic acid. If desired, mixtures of the abovementioned acids may also be used to prepare the salts 2.

According to the invention, the salts of the betamimetics 2 selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methanesulphonate, 4-phenylcinnamate, 5-(2.4-difluorophenyl)salicylate, maleate and xinafoate are preferred. Particularly preferred are the salts of 2 in the case of salmeterol selected from among the hydrochloride, sulphate, 4-phenylcinnamate, 5-(2.4-difluorophenyl)salicylate and xinafoate, of which the 4-phenylcinnamate, 5-(2.4-difluorophenyl)salicylate and especially xinafoate are particularly important. Particularly preferred are the salts of 2 in the case of formoterol selected from the hydrochloride, sulphate and fumarate, of which the hydrochloride and fumarate are particularly preferred. Of exceptional importance according to the invention is formoterol fumarate. Most preferably, the salts of 2 in the case of the compound 2aa' are selected from among the hydrochloride and maleate, of which the maleate is particularly preferred.

Where the present invention refers to betamimetics which are not in the form of salts, this is indicated by a reference to compounds 2\ For example, the preferred betamimetics 2 according to the invention which are not in salt form include the free base of formoterol, salmeterol or the compounds of formula 2e , whereas the particularly preferred compounds 2 according to the invention are salmeterol xinafoate, formoterol fumarate or an acid addition salt 2a of a compound of formula 2a".

Within the scope of the present invention the betamimetics 2 may possibly also be referred to as sympathomimetics or beta-2-agonists (^-agonists). All these terms are to be regarded as interchangeable for the purposes of the present invention.

In one aspect the present invention relates to the abovementioned pharmaceutical compositions which contain, in addition to therapeutically effective quantities of 1_ and 2, a pharmaceutically acceptable, carrier. In another aspect the present invention relates to the abovementioned pharmaceutical compositions which do not contain any pharmaceutically acceptable carrier in addition to therapeutically effective quantities of 1 and 2.

The present invention also relates to the use of therapeutically effective quantities of the salts Λ for preparing a pharmaceutical composition containing long-acting betamimetics 2 for treating inflammatory or obstructive diseases of the respiratory tract. Preferably, the present invention relates to the abovementioned use for preparing a pharmaceutical composition for treating asthma or COPD.

Within the scope of the present invention the compounds 1_ and 2 may be administered simultaneously or successively, while it is preferable according to the invention to administer compounds und 2 simultaneously.

The present invention further relates to the use of therapeutically effect amounts of salts 1 and long-acting betamimetics_2 for treating inflammatory or obstructive respiratory complaints, particularly asthma or COPD.

The proportions in which the active substances ± and 2 may be used in the active substance combinations according to the invention are variable. Active substances and 2 may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds 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 weight ratios specified below were based on the cation V_ and the free bases of the betamimetics salmeterol, formoterol and the compound 2aa' (= compound of formula 2a wherein R1 and R2 denote hydrogen and R3 and R4 denote ethyl) which are preferred according to the invention.

The pharmaceutical combinations according to the invention may contain V and _ in the case of formoterol, for example, in ratios by weight ranging from 1 : 10 to 300:1 , preferably from 1 :5 to 200:1 , preferably 1 :3 to 150:1 , more preferably from 1:2 to 100:1.

For example, without restricting the scope of the invention thereto, preferred combinations of 1 and 2 according to the invention may contain the cation V_ and formoterol _ in the following weight ratios: 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, 1, 36:1, 37:1, 38:1, 39:1 40 1, 41:1, 42 1, 43 1, 44 1, 45:1 46 1, 47:1 48 1, 49 1, 50:1, 51:1, 52:1, 53:1 54 1, 55:1, 56 1, 57 1, 58 1, 59:1, 60 1, 61:1, 62 1, 63 1, 64:1, 65:1, 66:1, 67:1 68 1, 69:1, 70 1, 71 1, 72 1, 73:1, 74 1, 75:1, 76 1, 77 1, 78:1, 79:1, 80:1, 81:1, 82 1, 83:1, 84 1, 85 1, 86 1, 87:1, 88 1, 89:1, 90 1, 91 1, 92:1, 93:1, 94:1, 95:1, 96 1, 97:1, 98 1, 99 1, 100:1. ' The pharmaceutical compositions according to the invention containing the combinations of and 2 are normally administered so that the pharmacologically active cation V and formoterol 2 are present together in doses of 5 to 5000 g, preferably from 10 to 2000μ9, more preferably from 5 to 1000μg, better still from 20 to 800μg, preferably, according to the invention, from 30 to 600μ9, preferably from 40 to 500μg.

For example, combinations of 1 and 2 according to the invention contain a quantity of cation V and formoterol 2 such that the total dosage per single dose is about lOpg, 15 9, 20 g, 25Mg, 30Mg, 35pg, 40Mg, 45pg, 50ig, 55μg, 60μg, 65pg, 70Mg, 75Mg, 80pg, 85pg, 90Mg, 95 g, ΙΟΟμρ, 105pg, 110pg, 15Mg, 120pg, 125Mg, 130 g, 35 g, 140 g, 145 g, 150μο, 55pg, 160μ9, 165Mg,.170Mg, 175μ9, 180pg, 185 g, 190 g, 195μ9, 200μ9, 205 g, 210 g, 2^5μg, 220Mg, 225pg, 230 g, 235Mg, 240μ9, 245 g, 250 g, 255 g, 260 g, 265pg, 270 g, 275 g, 280Mg, 285 g, 290μg, 295pg, 300 g, 305pg, 310Mg, 315μ9, 320Mg, 325pg, 330μ9, 335 g, 340 g, 345 9, 350 g, 355μ9, 360μg, 365 g, 370 g, 375μ9, 380 g, 385Mg, 390μg, 395 g, 400μ9, 405μg, 410μ9, 415^g, 420μg, 425μg, 430μg, 35μg, 440μg, 445μ9, 450μg, 455μg, 460μg, 465μg, 470 g, 475μg, 480 g, 485μg, 490pg, 495μ9, 500μg, 505μg, 510μg, 515Mg, 520μg, 525μg, 530pg, 535pg, 540μ9, 545pg, 550pg, 555pg, 560pg, 565pg, 570pg, 575pg, 580pg, 585pg, 590 9, 595pg, 600pg or similar. It is clear to anyone skilled in the art that the suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated. Fluctuations of about ± 2.5 particularly in the decimal range, are also included, as will be apparent to the skilled man. In these dosage ranges, the active substances V_ and may be present in the weight ratios given above.

For example, without restricting the scope of the invention thereto, the combinations of 1 and 2 according to the invention may contain a quantity of cation V and formoterol such that, for each single dose, 8.3pg of V and 2.5pg of Z, 8.3pg of V and 4.9pg of Z, 8.3pg of V and 9.8pg of T, 8.3pg of V and 14,7pg of 2 , 8.3pg of r_ and 19.6pg of Z, 8.3pg of r and 24.4pg of Z, 16.5pg of r and 2.5pg of Z, 16.5pg of r and 4.9pg of , 16.5pg of V and 9.8pg of Z, 16.5pg of r and 14.7pg of Z, 16.5pg of V and 19.6pg of Z, 16.5pg of r and 24.4pg of , 33.0 g of r and 2.5 g of Z, 33.0pg of V and 4.9pg of Z, 33.0pg of V and 9.8 g of 2 , 33.0pg of r and 14.7pg ot Z, 33.0pg of r and 19.6pg of Z, 33.0pg of r and 24.4pg of Z, 49.5pg of r and 2.5pg of Z, 49.5pg of V and 4.9 9 of Z, 49.5pg of r and 9.8pg of Z, 49.5pg of V and 14.7pg of Z, 49.5pg of V and 19.6pg of Z, 49.5pg of r and 24.4pg of Z, 82.6pg of V and 2.5pg of , 82.6pg of V and 4.9pg of Z, 82.6pg of V and 9.8pg of Z, 82.6pg of V and 14.7pg of Z, 82.6pg of V and 19.6pg of 2 , 82.6pg of r and 24.4pg of , 165.1 pg of r and 2.5pg of Z, 165.1 pg of r and 4.9pg of Z, 165.1 pg of r and 9.8pg of Z, 165.1 pg of r and 14.7pg of Z, 165.1 pg of r and 19.6pg of , 165.1 pg of and 24.4pg of Z, 206.4pg of V and 2.5pg of Z, 206.4pg of V and 4.9pg of , 206.4pg of V and 9.8pg of Z, 206.4pg of r and 14:7pg of Z, 206.4pg of V and 19.6pg of Z, 206.4pg of V and 24.4pg of Z, 412.8pg of V and 2.5pg of Z, 412.8pg of V and 4.9pg of 2!, 4 2.8pg of V and 9.8pg of , 412.8pg of and 14.7pg of , 412.8pg of V and 19.6pg of Z, 412.8pg of V and 24.4pg of Z are present.

If the active substance combination in which the bromide is used as the salt and in which 2 denotes formoterol fumarate is used as the preferred combination of 1 and 2 according to the invention, the quantities of active substance V and Z administered per single dose mentioned by way of example correspond to the following quantities of 1 and 2 administered per single dose: 10pg of 1 and 2.9pg of 2, 10pg of 1 and 5.7 g of 2, 10pg of and 11.5\jg of 2, 10 g of 1 and 7.2 g of 2, .1 O g of 1 and 22.9pg of 2, 10pg of 1 and 28.5Mg of 2, 20pg of 1 and 2.9 g of 2, 20 g of 1 and 5.7pg of 2, 20pg of 1 and 11.5 g of 2, 20 g of 1 and 7.2pg of 2, 20pg of 1 and 22.9pg of 2, 20 g of 1 and 28.5 g of 2, 40 g of 1 and 2.9 g of 2, 40 g of and 5.7pg of 2, 40pgofland 11.5μςοί 2, 40pgofland 17.2pgof 2, 40 g of 1 and 22.9pg of 2, 40 g of 1 and 28.5 g of 2, 60pg of 1 and 2.9 g of 2, 60 g of 1 and 5.7 g of 2, 60pg of 1 and 11.5\g of 2, 60pg of 1 and 17.2pg of 2, 60 g of and 22.9pg of 2, 60 g of and 28.5 g of 2, 00 g of 1 and 2.9pg of 2, 100 g of land 5.7 g of 2,"100Mg of 1 and 11.5 g of 2, lOOpg of land 17.2 g of 2, 1 OO g of 1 and 22.9 g of 2, 10O g of 1 and 28.5 9 of 2, 200 g of and 2.9 g of 2, 200Mg of land 5.7 g of 2, 200Mg of land ^^.5μg oil, 200 g of land 17.2\jg of 2, 200 g of and 22.9 g of 2, 200pg of 1 and 28.5 g of 2, 250pg of 1 and 2.9 g of 2, 250 g of 1 and 5.7pg of 2, 250 g of 1 and 11.5Mg of 2, 250 g of 1 and 17.2pg of 2, 250pg of 1 and 22.9 g of 2, 250 g of 1 and 28.5pg of 2, 500pg of 1 and 2.9 g of 2, 500Mg of 1 and 5.7 g of 2, 500MgoM arid 11.5 gof 2, 500pg of 1 and 17.2pg of 2, SOO g of 1 and 22.9 g of 2, 500pg of 1 and 28.5 g of 2.

If the active substance combination in which 2 denotes formoterol fumarate dihydrate and the salt 1 is bromide is used as a preferred combination of land 2 according to the invention, the quantities of active substance V and 2^ administered per single dose mentioned by way of example correspond to the following quantities of 1 and 2 administered per single dose: 10 g of 1 and 3 g of 2, 10pg of 1 and 6pg of 2, 10pg of 1 and 12 g of 2, 10pg of 1 and 18 g of 2, 10pg of 1 and 24μg of 2, 10 g of 1 and 30 g of 2, 20 g of and 3pg of 2, 20 g of and 6 g of 2, 20 g of 1 and 12pg of 2, 20pg of 1 and 18 g of 2, 20pg of 1 and 24pg of 2, 20 g of and 30 g of 2, 40pg of 1 and 3 g of 2, 40 g of 1 and 6 g of 2, 40 g of 1 and 12 g of 2, 40 g of 1 and 18pg of 2, 40 g of 1 and 24 g of 2, 40 g of 1 and 30 g of 2, 60 g of 1 and 3\g of 2, 60 g of 1 and 6pg of 2, 60pg of 1 and 12pg of 2, 60 g of 1 and 18pg of 2, 60 g of 1 and 24pg of 2, 60Mg of 1 and 30pg of 2, 1 OOpg of 1 and 3 g of 2, 0Opg of 1 and 6\jg of 2, 100 g of 1 and 12\jg of 2, 100pg of 1 and 18pg of 2, 00 g of 1 and 24pg of 2, 00 g of 1 and 30pg of 2, 200Mg of 1 and 3 g of 2, 200Mg of 1 and 6 g of 2, 200Mg of 1 and 12pg of 2, 200 g of 1 and 18\g of 2, 200 g of 1 and 24 g of 2, 200Mg of 1 and 30 g of 2, 250 g of land 3pg of 2, 250pg of 1 and6 g of 2, 250 g of land 12 g of 2, 250 g of 1 and 18pg of 2, 250pg of 1 and 24pg of 2, 250pg of 1 and 30vg of 2, 500 g of 1 and 3 g of 2, 500pg of 1 and 6pg of 2, 500pg of 1 and 12pg of 2, 500 g of 1 and 18μg of 2, 500pg of 1 and 24 g of 2, 500 g of 1 and 30 g of 2.

The active substance combinations according to the invention may contain IT and , in the case of salmeterol, for example, in ratios by weight in the range from about 1:30 to 400:1, preferably 1:25 to 200:1, preferably 1 :20 to 100:1, more preferably from 1 : 15 to 50: 1.

For example, without restricting the scope of the invention thereto, preferred combinations of and 2 according to the invention may contain the cation V and salmeterol in the following ratios by weight: 1:15, 1:14, 1:13, 1:12, 1: 1, 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 and 2 are usually administered so that the cation V and salmeterol are present together in dosages of 5 to 5000pg, preferably from 10 to 2000pg, more preferably from 15 to 1000pg, even more preferably from 20 to 800 g, and preferably according to the invention from 30 to 750pg, preferably from 40 to 700^g per single dose.

For example, combinations of 1 and 2 according to the invention contain an amount of V and salmeterol Z such that the total dosage per single dose is about 15pg, 20pg, 25pg, 30pg, 35pg, 40pg, 45pg, 50pg, 55pg, 60pg, 65pg, 70pg, 75pg, 80pg, 85pg, 90pg, 95pg, lOOpg, 105pg, 110pg, 115pg, 120pg, 125pg, 130pg, 135pg, 140pg, 145pg, 150pg, 155pg, 160pg, 165pg, 170pg, 175pg, 180pg, 185 g, 190pg, 195pg, 200pg, 205pg, 210pg, 215pg, 220pg, 225pg, 230 g, 235 g, 240 g, 245 g, 250 g, 255Mg, 260pg, 265 g, 270pg, 275pg, 280pg, 285 g, 290 g, 295 g, 300 g, 305Mg, 310 g, 315 g, 320pg, 325pg, 330pg, 335pg, 340pg, 345 g, 350pg, 355 g, 360Mg, 365 g, 370 g, 375μg, 380μg, 385pg, 390μg, 395μg, 400pg, 405μg, 410μg, 415 g, 420 g1425 g, 430μg, 435μg, 440μg, 445μg, 450μg, 455μg, 460μg, 465μg, 470μg, 475μg, 480μg, 485μg, 490 g, 495pg, 500μg, 505μg, 510 g, 515μg, 520μg, 525 g, 530μg, 535μg, 540μg, 545μg, 550μg, 555μg, 560μg, 565 g, 570pg, 575 g, 580 g, 585pg, 590pg, 595pg, 600 g, 605pg, 6 0pg, 615Mg, 620pg, 625pg, 630pg, 635Mg, 640pg, 645pg, 650pg, 655pg, 660pg, 665pg, 670pg, 675 g, 680pg, 685pg, 690 g, 695pg, 700 g or similar. It is clear to anyone skilled in the art that the suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated. Fluctuations of about ±2.5 μg, particularly in the decimal range, are also included, as will be apparent to the skilled man. In these dosage ranges, the active substances V and 2 may be present in the weight ratios given above.

For example, without restricting the scope of the invention thereto, the combinations of Λ and 2 according to the invention may contain a quantity of cation V and salmeterol Z such that, for each single dose, 8.3pg of V and 12.5pg of Z, 8.3 g of and 25pg o1 Z, 8.3pg of V and 50pg of Z, 8.3ig of V and 75pg of Z, 8.3 g of V and 100pg of Z, 8.3 g of V and 200 g of Z, 6.S\ig of V and 12.5Mgof , 16.5pg of V and 25Mg of Z, 16.5pg of V and 50Mg of Z, 16.5 g of V and 75 g of Z, 6.5pg of V and 10Opg of Z, 16.5pg of V and 200 g of Z, 33.0pg of and 12.5pg of Z, 33.0Mg of V and 25pg of Z, 33.0 g of V and 50pg of Z, 33.0 g of and 75pg of Z, 33.0pg of V and 100μg of Z, 33.0 g of V and 200pg of Z, 49.5 g of V and ^2.5μg of Z, 49.5pg of V and 25 g of Z, 49.5 g of and 50pg of Z, 49.5pg of V and 75 g of Z, 49.5pg of r and 100pg of , 49.5pg of V and 200 g of Z, 82.6pg of r and 12.5 g of Z, 82.6pg of V and 25pg of Z, 82.6Mg of r and 50pg of Z, 82.6pg of V and 75pg of 2!, 82.6pg of V and 100μg of , 82.6pgof r and 200 g of , 165.1pg of rand 12.5 gof2:, 165.1pg of V and 25 g of Z, 165.1 ig of and 50^g of 165.1 of V and 75pg of 165.1 g of r and 100pg of Z, 165.1pg of V and 200pg of 206.4pg of V and 12.5pg of Z, 206.4pg of V and 25pg of 21, 206.4Mg of r and 50Mg of Z, 206.4pg of V and 75pg of Z, 206.4pg of V and 10Opg of 206.4pg of V and 200pg of Z, 412.8pg of and 12.5pg of , 412.8Mg of rand 25pg of , 412.8 gof V and 50 g of , 412.8Mg of r and 75Mg of Z, 4 2.8 g of V and 100 g of 2, 4 2.8 g of and 200μg of Z are present, for example.

If a combination of active substances wherein the bromide is used as the salt 1 and 2 denotes salmeterol xinafoate is used as the preferred combination of 1 and 2 according to the invention, the amounts of active substances V and Z_ administered per single dose as specified hereinbefore correspond to the following amounts of and 2 administered per single dose: 10\g of1 and 18.2pg of 2, 10pg of and 36.3pg of 2, 1 C^g of 1 and 72.6 g of 2, 10pg of 1 and 108.9 g of 2, 1 Opg of 1 and 145.2Mg of 2, 10pg of1 and 290.4 g of 2, 20 g of1 and 18.2pg of 2, 20Mg of 1 and 36.3Mg of 2, 20pg of 1 and 72.6 g of 2, 20pg of 1 and 108.9pg of 2, 2C^g of 1 and 45.2 g of 2, 20 g of 1 and 290.4 g of 2, 40pg of 1 and 18.2 g of 2, 40pg of1 and 36.3pg of 2, 40 g of land 72.6pg of 2, 40pg of 1 and 108.9 g of 2, 40 g of 1 and 145.2pg of 2, 40pg of1 and 290.4pg of 2, 60Mg of 1 and 18.2pg of 2, 60 g of 1 and 36^g of 2, 60 g of 1 and 72.6pg of 2, 60pg of 1 and 108.9 g of 2, 60 9 of 1 and 145:2pg of 2, 60pg of 1 and 290.4ug of 2, 100 g of1 and 18.2Mg of 2, OOpg of 1 and-36.3Mg of 2, lOOpg of 1 and 72.6Mg of 2, 'lOO g of 1 and 08.9 g of 2, 100 g of land 145.2 g of 2, 100μς of 1 and 290.4μς of 2, 200 g of land 18.2pg of 2, 200 g of land 36.3 g of 2, 200 g of land 72.6pg of 2, 200pg of1 and 108.9 g of 2, 200Mg of1 and 145.2pg of 2, 200 g of1 and 290.4pg of 2, 250 g of1 and 18.2 g of 2, 250pg of and 36.3 g of 2, 250pg of1 and 72.6pg of 2, 250pg of land 108.9pg of 2, 250pg of land 145.2pg of 2, 250Mg of1 and 290.4 g of 2, 500 g of1 and 8.2 g of 2, 500 g of and 36.3pg of 2, 500 g of land 72.6 g of 2, 500 g of land 108.9Mg of 2, 500 g of land 145.2pg of 2, 500pg of1 and 290.4Mg of 2.

The quantities of active substance in the pharmaceutical combinations according to the invention which are administered per single dose can be calculated analogously if instead of the salmeterol xinafoate the compounds 2 salmeterol-4-phenylcinnamic acid salt (4-phenylcinnamate) and salmeterol-5-(2,4-difluorophenyl)salicylic acid salt (5-(2,4-difluorophenyl)salicylate) which are also preferably used according to the invention are used.

The combinations, of active substances according to the invention may contain V and 2aa' in weight ratios which are in the range from about 1 :30 to 400:1 , preferably 1:25 to 200:1, preferably 1:20 to 100:1, more preferably from 1:15 to 50:1.

For example, and without restricting the scope of the invention thereto, preferred combinations of1 and 2 according to the invention may contain the cation V_ and the compound 2aa' in the following ratios 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, :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 usually administered so that each single dose contains the cation V and the compound 2aa' together in doses of from 5 to 5000pg, preferably from 10 to 2000pg, more preferably from 15 to 000pg, even more preferably from 20 to 800pg, preferably, according to the invention, from 30 to 750pg, preferably from 40 to 700pg.

For example, combinations of and 2 according to the invention contain an amount of V and 2aa' such that the total dosage per single dose is about 15pg, 20pg, 25 g, 30μg, 35pg, 40pg, 45pg, 50pg, 55pg, 60pg, 65pg, 70pg, 75 g, 80pg, 85pg, 90pg, 95pg, 100pg, 105pg, 110pg, 115pg, 120pg, 125pg, 130pg, 135 g, 140pg, 145pg, 150pg, 155 g, 160pg, 165pg, 170pg, 175μ£, 180pg, 185Mg, 190pg, 195pg, 200pg, 205pg, 210pg, 215pg, 220μς, 225pg, 230pg, 235pg, 240pg, 245pg, 250Mg, 255pg, 260pg, 265pg, 270 g, 275Mg, 280pg, 285pg, 290pg, 295pg, 300pg, 305 9, 3 0pg, 315 g, 320pg, 325pg, 330Mg, 335 g, 340pg, 345pg, 350pg, 355pg, 360pg, 365pg, 370pg, 375pg, 380pg, 385pg, 390 g, 395 g, 400pg, 405 9, 4 0μο, 4 5pg, 420pg, 425 g, 430pg, 435pg, 440pg, 445pg, 450Mg, 455 g, 460pg, 465pg, 470pg, 475pg, 480 g, 485pg, 490pg, 495 g, 500Mg, 505Mg, 510Mg, 5^g, 520Mg, 525 g, 530Mg, 535 g, 540pg, 545pg, 550pg, 555Mg, 560Mg, 565Mg, 570pg, 575pg, 580Mg, 585pg, 590Mg, 595 g, δθθμς, 605 ο, 610 9, 6 5μ9, 620μ9, 625 9, 630 9, 635μ9, 640μg, 645μg, 650μg, 655μg, 660μgI 665μg, 670μg1675μg, 680μg, 685μg, 690 9, 695μg, 700μ9 or similar. It is clear to anyone skilled in the art that the suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated. Fluctuations of about ± 2.5 μ9, particularly in the decimal range, are also included, as will be apparent to the skilled man. In these dosage ranges, the active substances and 2aa' may be present in the weight ratios given above.

For example, and without restricting the scope of the invention thereto, the combinations of 1 and 2 according to the invention may contain an amount of cation V and 2aa' such that each single dose contains, for example, 8.3pg of V and 12.5pg of 2aa', 8.3μς of V and 25pg of 2aa', 8.3pg of and 50 g of 2aa', 8.3pg of and 75 g of 2aa', 8.3pg of and 10Opg of 2aa', 8.3pg of V and 200pg of 2aa', 16.5pg of 1' and 12.5gg of 2aa', 16.5pg of and 25pg of 2aa', 16.5pg of and 50pg of 2aa', 6.5 g of V and 75pg of 2aa', 6.5 g of V and 100pg of 2aa', 16.5gg of 1 ' and 200|jg of 2aa', 33.0pg of V and 12.5|jg of 2aa', 33.0pg of V and 25 g of 2aa', 33.0pg of V and 50pg of 2aa', 33.0pg of and 75pg of 2aa', 33.0ug of r and 1 OOpg of 2aa', 33.0pg of V and 200pg of 2aa', 49.5pg of and 12.5pg of 2aa', 49.5pg of V and 25pg of 2aa', 49.5pg of V and 50pg of 2aa', 49.5pg of V and 75pg of 2aa', 49.5pg of V and 00pg of 2aa', 49.5pg of and 200gg of 2aa', 82.6pg of r and 12.5pg of 2aa', 82.6pg of V and 25pg of 2aa', 82.6pg of r and 50 g of 2aa , 82.6pg of V and 75pg of 2aa;, 82.6pg of V and 1 OOpg of 2aa', 82.6pg of V and 200pg of 2aa', 165.1 pg of r and 12.5pg of 2aa', 165. pg of V and 25pg of 2aa', 165.1 pg of r and 50pg of 2aa', 165.1 pg of and 75pg of 2aa', 165.1 pg of and 1 OOpg of 2aa', 165.1 pg of and 200pg of 2aa', 206.4pg of V and 12.5pg of 2aa', 206.4pg of V and 25pg of 2aa', 206.4pg of V and 50pg of 2aa', 206.4pg of V and 75pg of 2aa', 206.4pg of V and 1 OOpg of 2aa', 206.4pg of V and 200pg of 2aa', 412.8pg of V and 12.5pg of 2aa', 412.8pg of V and 25pg of 2aa', 412.8pg of V and 50pg of 2aa', 412:8pg of and 75pg of 2aa', 412.8pg of V and 1 OOpg of 2aa', 412.8pg of and 200pg of 2aa'.

If the active substance combination wherein the salt 1 is the bromide and the salt 2aa is the maleate of the compound 2aa' is used as the preferred combination of 1_ and 2 according to the invention, the quantities of active substances V_ and 2aa' administered per single dose as specified above by way of example correspond to the following amounts of 1 and 2aa administered per single dose: 10pg of† and 16.2pg of 2aa, 10pg of 1 and 32.4pg of 2aa, 10pg of 1 and 64.8pg of 2aa, 1 Opg of and 97.2pg of 2aa, 1 Opg of 1 and 129.6pg of 2aa, 1 Opg of and 259.2pg of 2aa, 20pg of 1 and 16.2pg of 2aa, 20pg of 1 and 32.4pg of 2aa, 20pg of and 64.8pg of 2aa, 20pg of 1 and 97.2pg of 2aa, 20pg of 1 and 129.6pg of 2aa, 20pg of 1 and 259.2pg of 2aa, 40pg of 1 and 16.2pg of 2aa, 40pg of 1 and 32.4pg of 2aa, 40pg of and 64.8pg of 2a a, 40pg of and 97.2pg of 2aa, 40pg of 1 and 129.6pg of 2aa, 40pg of 1 and 259.2pg of 2aa, 60pg of and 16.2pg of 2aa, 60pg of 1 and 32.4pg of 2aa, 60pg of 1 and 64.8pg of 2aa, 60pg of 1 and 97.2pg of 2aa, 60pg of 1 and 129.6pg of 2aa, 60pg of 1 and 259.2pg of 2aa, 100pg of 1 and 16.2gg of 2aa, 100 g of 1 and 32.4pg of 2aa, 10Ομρ of 1 and 64.8 g of 2aa, 1 OOpg of 1 and 97.2pg of 2aa, 10O g of 1 and 129.6 g of 2aa, 100Mg of 1 and 259.2pg of 2aa, 200pg of 1 and 16.2pg of 2aa, 200pg of 1 and 32.4 g of 2aa, 200 g of 1 and 64.8pg of 2aa, 200Mg of 1 and 97.2 g of 2aa, 200pg of1 and 129.6pg of 2aa, 200pg of1 and 259.2pg of 2aa, 250 g of 1 and 6.2pg of 2aa, 250pg of 1 and 32.4pg of 2aa, 250pg of 1 and 64.8pg of 2aa, 250pg of and 97.2 g of 2aa, 250 g of and 129.6pg of 2aa, 250pg of 1 and 259.2 g of 2aa, 500Mg of 1 and 16.2 g of 2aa, 500Mg of 1 and 32.4 g of 2aa, 500 g of and 64.8 g of 2aa, 500 g of 1 and 97.2pg of 2aa, 500Mg of 1 and 12¾.6Mg of 2aa, SOOpg of 1 and 259.2μ of 2aa.

The active substance combinations of 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 according to the invention include inhalable powders, propellant-containing metered dose 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 carrier may optionally be used instead of the term excipient. 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), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. 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 between 10 and 50μηη, most preferably between 15 and 80pm. It may. sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9pm to the excipient 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 Ι Ομιτι, more preferably from 1 to 6μηη, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and by finally 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 I and 2 or in the form of separate inhalable powders which contain only 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 one or more physiologically acceptable excipients 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 using 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 to the housing 1 , the deck 3 and a cover 1 1 via a spindle 10 to enable it to be flipped open or shut, as well as airholes 3 for adjusting the flow resistance.

If the inhalable powders according to the invention are packed into capsules (inhalers) for the preferred use described above, the quantities packed into each capsule should be 1 to 30mg per capsule. These capsules contain, according to the invention, either together or separately, the doses of1 or Γ and 2 or 2^ mentioned hereinbefore for each single dose.

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-butahe or isobutane and halohydrocarbons such as 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 TG1 1 , TG12, TG134a (1 , 1 ,1 ,2-tetrafluoroethane) and TG227 (1 , 1 , 1 ,2, 3,3, 3-heptafluoropropane) and mixtures thereof, of which the propellant gases TG134a, TG227 and mixtures thereof are 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 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.-%70.5 to 2 wt.-% or 0.5 to 1 wt.-% of active substance 1 and/or 2.

If the active substances i and/or 2 are present in dispersed form, the particles of active substance preferably have an average particle size of up to 10μιτι, preferably from 0.1 to βμηπ, more preferably from 1 to 5μιη.

The propellant-driven inhalation aerosols according to the invention mentioned above may be administered using inhalers known in the art (MDIs = 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 fitted with a suitable valve which 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 and suspensions according to the invention contain, for example, aqueous or alcoholic, preferably ethanolic solvents, optionally ethanolic solvents mixed with aqueous solvents. If aqueous/ethanolic solvent mixtures are used the relative proportion of ethanol compared with water is not limited but preferably the maximum 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, maleic acid, succinic acid, fuma c acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric md sulphuric acids. 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, fumahc 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.

According to the invention, the addition of editic acid (EDTA) or one of the known salts thereof, sodium editate, 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 editate is less than 100mg/100ml, preferably less than 50mg/100 ml, more preferably less than 20mg/100 ml. Generally, inhalable solutions in which the content of sodium editate is from 0 to 10mg/100ml are preferred.

Co-solve ts and/or other excipients may be added to the propellant-free 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 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/100ml, more preferably between 5 and 20mg/100ml.

Preferred formulations contain, in addition to the solvent water and the combination of active substances 1 and 2, only benzalkonium chloride and sodium editate. In another preferred embodiment, no sodium editate 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 100μΙ_, preferably less than 50μΙ_, more preferably between 20 and 30μί of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20μιη, preferably less than 10μιτι, in such a way 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. Because of its cylindrical shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide, this device can be carried at all times by the patient. The nebuliser sprays a defined volume of pharmaceutical formulation using high pressures through small nozzles so as to produce inhalable aerosols.

The preferred atomiser essentially consists of an upper housing part, a pump housing, a nozzle, a locking mechanism, a spring housing,~a spring and a storage container, characterised by - a pump housing which is secured in the upper housing part and which comprises at one end a nozzle body with the nozzle or nozzle arrangement, - a hollow plunger with valve body, - a power takeoff flange in which the hollow plunger is secured and which is located in the upper housing part, - a locking mechanism situated in the upper housing part, - a spring housing with the spring contained therein, which is rotatably mounted on the upper housing part by means of a rotary bearing, - a lower housing part which is fitted onto the spring housing in the axial direction.

The hollow plunger with valve body corresponds to a device disclosed in WO 97/12687. It projects partially into the cylinder of the pump housing and is axially movable within the cylinder. Reference is made in particular to Figures 1 to 4, especially Figure 3, and the relevant parts of the description. The hollow plunger with valve body exerts a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa (about 100 to 600 bar) on the fluid, the measured amount of active substance solution, at its high pressure end at the moment when the spring is actuated. Volumes of 10 to 50 microlitres are preferred, while volumes of to 20 microlitres are particularly preferred and a volume of 15 microlitres per spray is most particularly preferred.

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

The nozzle in the nozzle body is preferably microstructured, i.e. produced by microtechnology. Microstructured nozzle bodies are disclosed for example in WO -94/07607; reference is hereby made to the contents of this specification, particularly Figure 1 therein and the associated description.

The nozzle body consists for example of two sheets of glass and/or silicon firmly joined together, at least one of which has one or more microstructured channels which connect the nozzle inlet end to the nozzle outlet end. At the nozzle outlet end there is at least one round or non-round opening 2 to 10 microns deep and 5 to 15 microns wide, the depth preferably being 4.5 to 6.5 microns while the length is preferably 7 to 9 microns.

In the case of a plurality of nozzle openings, preferably two, the directions of spraying of the nozzles in the nozzle body may extend parallel to one another or may be inclined relative to one another in the direction of the nozzle opening. In a nozzle body with at least two nozzle openings at the outlet end the directions of spraying may be at an angle of 20 to 160° to one another, preferably 60 to 50°, most preferably 80 to 100°. The nozzle openings are preferably arranged at a spacing of 10 to 200 microns, more preferably at a spacing of 10 to 100 microns, most preferably 30 to 70 microns. Spacings of 50 microns are most preferred. The directions of spraying will therefore meet in the vicinity of the nozzle openings.

The liquid pharmaceutical preparation strikes the nozzle body with an entry pressure of up to 600 bar, preferably 200 to 300 bar, and is atomised into an inhalable aerosol through the nozzle openings. The preferred particle or droplet sizes of the aerosol are up to 20 microns, preferably 3 to 10 microns.

The locking mechanism contains a spring, preferably a cylindrical helical compression spring, as a store for the mechanical energy. The spring acts on the power takeoff flange as an actuating member the movement of which is determined by the position of a locking member. The travel of the power takeoff flange is precisely limited by an upper and lower stop. The spring is preferably biased, via a power step-up gear, e.g. a helical thrust gear, by an external torque which is produced when the upper housing part is rotated counter to the spring housing in the lower housing part. In this case, the upper housing part and the power takeoff flange have a single or multiple V-shaped gear.

The locking member with engaging locking surfaces is arranged in a ring around the power takeoff flange. It consists, Tor example, of a ring of plastic or metal which is inherently radially elastically deformable. The ring is arranged in a plane at right angles to the atomiser axis. After the biasing of the spring, the locking surfaces of the locking member move into the path of the power takeoff flange and prevent the spring from relaxing. The locking member is actuated by means of a button. The actuating button is connected or coupled to the locking member. In order to actuate the locking mechanism, the actuating button is moved parallel to the annular plane, preferably into the atomiser; this causes the deformable ring to deform in the annular plane. Details of the construction of the locking mechanism are given in WO 97/20590.

The lower housing part is pushed axially over the spring housing and covers the mounting; the drive of the spindle and the storage container for the fluid.

When the atomiser is actuated the upper housing part is rotated relative to the lower housing part, the lower housing part taking the spring housing with it. The spring is thereby compressed and biased by means of the helical thrust gear and the locking mechanism engages automatically. The angle of rotation is preferably a whole-number fraction of 360 degrees, e.g. 180 degrees. At the same time as the spring is biased, the power takeoff part in the upper housing part is moved along by a given distance, the hollow plunger is withdrawn inside the cylinder in the pump housing, as a result of which some of the fluid is sucked out of the storage container and into the high pressure chamber in front of the nozzle.

If desired, a number of exchangeable storage containers which contain the fluid to be atomised may be pushed into the atomiser one after another and used in succession. The storage container contains the aqueous aerosol preparation according to the invention.

The atomising process is initiated by pressing gently on the actuating button. As a result, the locking mechanism opens up the path for the power takeoff member. The biased spring pushes the plunger into the cylinder of the pump housing. The fluid leaves the nozzle of the atomiser in atomised form.

Furtherdetails of construction are disclosed in PCT Applications WO 97/12683 and WO 97/20590, to which reference is hereby made.

The components of the atomiser (nebuliser) are made of a material which is suitable for its purpose. The housing of the atomiser and, if its operation permits, other parts as well, are preferably made of plastics, e.g. by injection moulding. For medicinal purposes, physiologically safe materials are used..

Figures 2a/b attached to this patent application, which are identical to Figures 6a/b of WO 97/12687, show the nebuliser (Respimat®) which can advantageously be used for inhaling the aqueous aerosol preparations according to the invention.

Figure 2a shows a longitudinal section through the atomiser with the spring biased while Figure 2b shows a longitudinal section through the atomiser with the spring relaxed.

The upper housing part (51 ) contains the pump housing. (52) on the end of which is mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle body (54) and a filter (55). The hollow plunger (57) fixed in the power takeoff flange (56) of the locking mechanism projects partially into the cylinder of the pump housing. At its end the hollow plunger carries the valve body (58). The hollow plunger is sealed off by means of the seal (59). Inside the upper housing part is the stop (60) on which the power takeoff flange abuts when the spring is relaxed. On the power takeoff flange is the stop (61 ) on which the power takeoff flange abuts when the spring is biased. After the biasing of the spring the locking member (62) moves between the stop (61 ) and a support (63) in the upper housing part. The actuating button (64) is connected to the locking member. The upper housing part ends in the mouthpiece (65) and is sealed off by means of the protective cover (66) which can be placed thereon.

The spring housing (67) with compression spring (68) is rotatably mounted on the upper housing part by means of the snap-in lugs (69) and rotary bearing. The lower housing part (70) is pushed over the spring housing. Inside the spring housing is the exchangeable storage container (71 ) for the fluid (72) which is to be atomised. The storage container is sealed off by the stopper (73) through which the hollow plunger projects into the storage container and is immersed at its end in the fluid (supply of active substance solution).

The spindle (74) for the mechanical counter is mounted in the covering of the spring housing. At the end of the spindle facing the upper housing part is the drive pinion (75). The slider (76) sits on the spindle.

The nebuliser described above is suitable for nebulising the aerosol preparations according to the invention to produce an aerosol suitable for inhalation.

If the formulation according to the invention is nebulised using the method described above (Respimat®) the quantity delivered should correspond to a defined quantity with a tolerance of not more than 25%, preferably 20% of this amount in at least 97%, preferably at least 98% of all operations of the inhaler (spray actuations). Preferably, between 5 and 30 mg of formulation, most preferably between 5 and 20 mg of formulation are delivered as a defined mass on each actuation.

However, the formulation according to the invention may also be nebulised by means of inhalers other than those described above, e.g. jet stream inhalers or other stationary nebulisers.

Accordingly, in a further aspect, the invention relates to pharmaceutical formulations in the form of propel lant-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 and 2 according to 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 free-standing or portable nebulisers which produce inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other principles.

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.

First, the preparation of compounds 1 and 2 used within the scope of the present invention which are not known in the art will be described. 1 ) Preparation of the compounds of formula 1_: 1.a.: 2,2-Diphenylpropionic acid chloride: 52.08g (0.33 mol) of oxalyl chloride are slowly added dropwise at 20°C to a suspension of 25.0 g (0.11 mol) of 2,2-diphenylpropionic acid, 100 ml of dichloromethane and 4 drops of dimethylformamide. The mixture is stirred for 1 h at 20°C and 0.5 h at 50°C. The solvent is distilled off and the residue remaining is used in the next step without any further purification.

Lb.: scopine 2,2-diphenylpropionate: The residue obtained from step la. is dissolved in 100 ml of dichloromethane and at 40°C a solution of 51.45 g (0.33 mol) of scopine in 200 nil of dichloromethane is added dropwise thereto. The resulting suspension is stirred for 24 h at 40°C, then the precipitate formed is suction filtered and the filtrate is extracted first with water, then with aqueous hydrochloric acid. The combined aqueous phases are made alkaline with aqueous sodium carbonate solution, extracted with dichloromethane, the organic phase is dried over Na2S04, evaporated to dryness and the hydrochloride is precipitated from the residue. The product is purified by recrystallisation from acetonitrile.

Yield: 20.85 g (= 47 % of theory) DC: Rf value: 0.24 (eluant: sec. butanol/formic acid/water 75:15: 0);. m.p.: 203-204°C.

■ I. c: scopine 2,2-diphenylpropionate methobromide : I I .98 g (0.033 mol) of the compound of step 1.b, 210 ml of acetonitrile, 70 ml of dichloromethane and 20.16 g (0.1 mol) of 46.92 % bromomethane in acetonitrile are combined at 20CC and left to stand for 3 days. The solution is evaporated to dryness and the residue is recrystallised from isopropanol.

Yield: 11.34 g (= 75 % of theory); m.p.: 208-209°C.

C2 H28N03xBr (458.4); Elemental analysis: calculated: C (62.89) H (6.16) N (3.06) found: C (62.85) H (6.12) N (3.07).

The salts 1 wherein X" denotes an anion with a single negative charge other than bromide may be obtained in a manner similar to step .3. 2.) Preparation of the compounds of formula 2: 2.1 : Salmeterol-4-phenylcinnamate salt 2b: 1.35 g (6 mmol) of 4-phenylcinnamic acid are dissolved by refluxing in 75 mL of ethyl acetate. To this solution is added a warm solution of 2.5 g (6 mmol) of salmeterol in 25 mL of ethyl acetate. The solution is allowed to cool and stirred for 16 h at room temperature. The suspension is filtered, the precipitate is washed with ethyl acetate and tert.-butylmethylether und dried in vacuo at 25-30°C. 47 g of the title compound are obtained as a colourless solid. Melting point: 109°C; 2.2.: Salmeterol-5-(2,4-difluorophenyl)salicylate salt 2c: g of salmeterol are dissolved by refluxing in 300 mL of ethyl acetate. 18.3 g of 5-(2,4-difluorophenyl)salicylic acid (Diflunisal) are added to- this solution. The solution is allowed to cool to ambient temperature. The suspension is filtered off, the precipitate is washed with ethyl acetate and dried in vacuo at 35°C. 46 g of the title salt are obtained as a colourless solid.

Melting point: 104°C The following examples of formulations, which may be obtained analogously to methods known in the art, serve to illustrate the present invention more fully without restricting it to the contents of these examples.

Examples of Formulations A) Inhalable powders: 1 ) Ingredients ig per capsule -bromide 200 Formoterol fumarate dihydrate 12 Lactose 24788 Total 25000 2) Ingredients per capsule -bromide 100 Salmeterol xinafoate 50 Lactose 12350 Total 12500 3) Ingredients 9 per capsule V-bromide 200 Salmeterol xinafoate 50 Lactose 12250 Total 12500 4) Ingredients pg per capsule -bromide 200 Formoterol fumarate dihydrate 24 Lactose 24776 Total 25000 ) Ingredients per capsule !>bromide 100 2b 50 Lactose 12350 Total 12500 ) Ingredients pg per capsule 1>bromide 200 2c 50 Lactose 12250 Total 12500 Ingredients μg per capsule 1^-bromide 100 2aa' maleate salt 65 Lactose 12335 Total 12500 ) Ingredients μg per capsule V-bromide 200 2aa' maleate salt 65 Lactose 12235 Total 12500 164291/2 B) Propellant-containing inhalable aerosols: 1 ) Suspension aerosol: Ingredients % by weight V-bromide 0.020 Salmeterol xinafoate 0.066 Soya lecithin 0.2 TG 11 :TG12 = 2:3 ad 100 Suspension aerosol: Ingredients % by weight I'-bromide 0.039 Salmeterol xinafoate 0.033 Absolute ethanol 0.5 Isopropyl myristate 0.1 TG 227 ad 100 *************************************** Passages of the description, which are not within the scope of the claims, do ot consist part of the claimed invention.

Claims (4)

1. 36 164291/2 CLAIMS: 1 ) Propellant-free inha!able solution or suspension, characterised contains one or more compounds of formula 1 Mev+,Me x - 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, combined with one or more compounds with betamimetic function (2), optionally in the form of the enantiomers, mixtures of the enantiomers or in the form of the racemates thereof, optionally in the form of the solvates or hydrates and optionally together with a pharmaceutically acceptable excipient, wherein the solvent is selected either from ethanol alone or from ethanoiic solvents mixed with aqueous solvents.

2. ) Propellant-free inhalable solution or suspension according to claim 1 , characterised in that the compounds with betamimetic function 2 are saimeterol salts, forrnoterol salts or acid addition salts of the compounds of formula 2a 164291/2 37 wherein wherein R1 and R2 which may be identical or different denote hydrogen or Ci-C4-alkyl; R3 and R4 which may be identical or different denote hydrogen, CrC4-alkyl, -O-C1- C4-alkyl, - CrC4-alkylene-0-Ci-C4-alkyl or R3 and R4 together denote one of the bridging groups C C4-alkylene- or -0-Ci-C4-alkylene-0-.

3. ) Propellant-free inhalable solution or suspension according to one of c!aimsl or 2, characterised in that- the compounds 2 are 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, 4-phenylcinnamic acid, 5-(2.4-difluorophenyl)salicylic acid or maleic acid. 4) Propellant-free inhalable solution or suspension according to claim 2 or 3, characterised in that the compounds 2 are salmeterdl xinafoate, salmeterol-4-phenylcinnamate or salmeterol-5-{2,4-difluorophenyl)salicylate. 5) Propellant-free inhalable solution or suspension according to claim 2 or 3, characterised in that the compounds 2 are salts of the compounds of formula 2a', wherein R1 and R2 which may be identical or different denote hydrogen, methyl or ethyl; R3 and R4 which may be identical or different denote hydrogen, methyl, ethyl, propyl, butyl, methoxy, ethoxy, methyoxymethyl, or methoxyethyl, or R3 and R4 together denote one of the bridging groups propylene, butylene, -O-ethylene-0- or -O-propylene-0-. 6) Propellant-free inhalable solution or suspension according to claim 2, 3 or 5, characterised in that the compounds 2 are salts of the compounds of formula 2a' wherein R1 and R2 which may be identical or different denote hydrogen or ethyl; R3 and R4 which may be identical or different denote hydrogen, methyl, ethyl, propyl, butyl or methyoxymethyl or 38 164291/2 R3 and R4 together denote one of the bridging groups butylene or -O-ethylene-0-. 7) Propellant-free inhalable solution or suspension according to claim 2, 3, 5 or 6, characterised in that the compounds 2 are salts of the compounds of formula 2a wherein a) R and R2 denote hydrogen and R3 and R4 denote ethyl; or b) R and R2 denote hydrogen and R3 and R4 denote methyl; or c) R and R2 denote ethyl and R3 and R4 denote hydrogen; or d) R1 and R2 denote hydrogen and R3 and R4 together denote butylene; or e) R1 and R2 denote hydrogen and R3 and R4 together denote -0- ethylene-O-; or f) R1 and R2 denote hydrogen and R3 and R4 denote tert.-butyl or g) R and R2 denote hydrogen and R3 and R4 denote iso-propyl; or n) R1 and R2 denote hydrogen and R3 and R4 denote methoxymethyl. 8) Propellant-free inhalable solution or suspension according to one of claims 2 to 4, characterised in that compound 2 is salmeterol and that the weight ratios of V e¾ + Me to salmeterol i_ are in a range from about 1 :30 to 400: 1 , preferably 1 :25 to 200:1. 9} Propellant-free inhalable solution or suspension according to one of claims 2 or 3, characterised in that the compounds 2 are formoterol hydrochloride, formoterol sulphate or formoterol fumarate. 10) Propellant-free inhalable solution or suspension according to claim 9, characterised in that compound 2 is formoterol and that the weight ratios of V 39 164291/2 Me. + Me to formoterol are in a range from about 1 :10 to 300:1 , preferably 1 :5 to 200:1. 11 ) Propellant-free inhalable solution or suspension according to one of claims 1 to 10, characterised in that it contains ethanol as solvent. 12) Propellant-free inhalable ethanolic solution or suspension according to one of claims 1 to 11 , characterised in that it contains other co-solvents and/or excipients. 13) Propellant-free inhalable solution or suspension according to claim 12, characterised in that it contains as co-solvents ingredients 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.

4. ) Propellant-free inhalable solution or suspension according to one of claims 12 or 13, characterised in that they contain as excipients surfactants, stabilisers, complexing agents, antioxidants and/or preservatives, flavourings, pharmacologically acceptable salts and/or vitamins. 164291/2 40 15) Propellant-free inhalable solution or suspension according to claim 14, characterised in that they contain as complexing agents editic acid or a salt of editic acid, preferably sodium edetate. 16) Propellant-free inhalable solution or suspension according to claim 15, characterised in that they contain as complexing agent editic acid or a salt of editic acid, preferably sodium edetate, in a concentration of less than 50 mg/ 00 ml. 17) Use of a propellant-free inhalable solution or suspension according to one of claims 1 to 16 for preparing a medicament for the treatment of inflammatory or obstructive respiratory complaints. 18) Use of propellant-free inhalable solution or suspension according to claim 17, wherein the of inflammatory or obstructive respiratory complaint is selected from asthma or COPD. For the Applicants MOLD COHN AND PARTNERS