AU2002257587B2 - Novel medicament compositions on the basis of anticholinergics and PDE IV inhibitors - Google Patents

Description

WO 02/069945 1 PCT/EP02/01988 77037pct.208 New Pharmaceutical Compositions based on Anticholinergics and PDE-IV inhibitors The present invention relates to novel pharmaceutical compositions based on anticholinergics and PDE-IV inhibitors, processes for preparing them and their use in the treatment of respiratory diseases.

Description of the invention The present invention relates to novel pharmaceutical compositions based on anticholinergics and PDE-IV inhibitors, processes for preparing them and their use in the treatment of respiratory diseases.

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 one or more, preferably one, anticholinergic is used with one or more, preferably one, PDE-IV inhibitor. 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. Furthermore, this reduces unwanted side effects such as may occur when PDE- IV inhibitors are administered, for example.

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.

P;\OPER\PDB\Speci\12321970 3rdspa 092.doc-03/04/2007 1A In a first aspect, the invention provides a pharmaceutical composition wherein it contains one or more tiotropium salts combined with one or more PDE-IV inhibitors 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 PDE-IV inhibitor is selected from among enprofylline, roflumilast, ariflo, Bay-198004, CP- 325,366, BY343, D-4396 (Sch-351591), V-11294A, AWD-12-281 and the tricyclic nitrogen heterocycles of general formula 2a R1 wherein

R

1

R

2

R

3 denotes C 1

-C

5 -alkyl, C 5

-C

6 -cycloalkyl, phenyl, benzyl or a 5- or 6-membered, saturated or unsaturated heterocyclic ring which may contain one or two heteroatoms selected from among oxygen and nitrogen; denotes C 1

-C

5 -alkyl or C 2

-C

4 -alkenyl; denotes C 1

-C

5 -alkyl which may optionally be substituted by C 1

-C

4 -alkoxy, C 5

-C

6 -cycloalkyl, phenoxy or a 5- or 6-membered, saturated or unsaturated heterocyclic ring which may contain one or two heteroatoms selected from among oxygen and nitrogen; P:\OPE3\PDB\Spci\12321970 3rdspa 092.doc-03104/2007 1B 6 -cycloalkyl or phenyl or benzyl optionally M substituted by C 1

-C

4 -alkoxy, optionally in the form of their racemates, their enantiomers, in the form of the diastereomers and the mixtures thereof, 00 5 optionally in the form of their tautomers and optionally the pharmacologically acceptable acid CO addition salts thereof.

(N

In a second aspect, the invention provides for use of a composition according to the invention for preparing a medicament for treating inflammatory or obstructive diseases of the respiratory tract.

In a third aspect, the invention provides for a method for the treatment of inflammatory or obstructive diseases of the respiratory tract wherein a therapeutically effective amount of the composition of the invention is administered to a patient in need thereof.

WO 02/069945 2 PCT/EP02/01988 Within the scope of the present invention the term anticholinergics 1 denotes salts which are preferably selected from among tiotropium salts, oxitropium salts and ipratropium salts, most preferably ipratropium salts and tiotropium salts. In the above-mentioned salts the cations tiotropium, oxitropium and ipratropium are the pharmacologically active ingredients. Within the scope of the present patent application, any reference to the above cations is indicated by the use of the number 1' Any reference to compounds 1 naturally also includes a reference to the ingredients 1' (tiotropium, oxitropium or ipratropium).

By the salts 1 which may be used within the scope of the present invention are meant the compounds which contain, in addition to tiotropium, oxitropium or ipratropium as counter-ion (anion), chloride, bromide, iodide, methanesulphonate or para-toluenesulphonate or methyl sulphate. Within the scope of the present invention, the methanesulphonate, chloride, bromide and iodide are preferred of all the salts 1, the methanesulphonate and bromide being of particular importance. Of outstanding importance according to the invention are salts 1 selected from among tiotropium bromide, oxitropium bromide and ipratropium bromide. Tiotropium bromide is particularly preferred.

Within the scope of the present invention, the word PDE- IV inhibitors (hereinafter 2) denotes compounds selected from among enprofylline, roflumilast, ariflo, Bay-198004, CP-325,366, BY343, D-4396 (Sch-351591), V-11294A, AWD-12- 281 and the tricyclic nitrogen heterocycles of general formula 2a WO 02/069945 3 PCT/EP02/01988 H 0

R

2 R N

R

3 2a wherein

R

1 denotes C 1

-C

5 -alkyl, C5-C 6 -cycloalkyl, phenyl, benzyl or a 5- or 6-membered, saturated or unsaturated heterocyclic ring which may contain one or two heteroatoms selected from among oxygen and nitrogen;

R

2 denotes C 1

-C

5 -alkyl or C 2

-C

4 -alkenyl;

R

3 denotes C 1

-C

5 -alkyl which may optionally be substituted by Ci-C 4 -alkoxy, C 5

-C

6 -cycloalkyl, phenoxy or a 5- or 6-membered, saturated or unsaturated heterocyclic ring which may contain one or two heteroatoms selected from among oxygen and nitrogen;

C

5 -Cg-cycloalkyl or phenyl or benzyl optionally substituted by C 1

-C

4 -alkoxy, optionally in the form of their racemates, their enantiomers, in the form of the diastereomers and the mixtures thereof, optionally in the form of their tautomers and optionally the pharmacologically acceptable acid addition salts thereof.

Of the abovementioned compounds of 2a those which are preferably used within the scope of the present invention are those compounds of formula 2a wherein

R

1 denotes C 1

-C

4 -alkyl, C 5

-C

6 -cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl or phenyl;

R

2 denotes C 1

-C

4 -alkyl or C 2

-C

4 -alkenyl; WO 02/069945 4 PCT/EP02/01988

R

3 denotes C1-C 4 -alkyl which may optionally be substituted by C 1

-C

4 -alkoxy, C5-C 6 -cycloalkyl, phenoxy, (C 1

-C

4 -alkoxy)phenyloxy, piperazine or pyrrole, C 5

-C

6 -cycloalkyl or phenyl or benzyl optionally substituted by C 1

-C

4 -alkoxy, optionally in the form of their racemates, their enantiomers, in the form of the diastereomers and the mixtures thereof, optionally in the form of their tautomers and optionally the pharmacologically acceptable acid addition salts thereof.

Of the compounds of formula 2a those which are most preferably used within the scope of the present invention are those compounds of formula 2a wherein

R

1 denotes ethyl, propyl, butyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, Nmorpholinyl or phenyl;

R

2 denotes ethyl, propyl, allyl or butenyl;

R

3 denotes ethyl, propyl, butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, methoxybenzyl or N-pyrolylmethyl, optionally in the form of their racemates, their enantiomers, in the form of the diastereomers and the mixtures thereof, optionally in the form of their tautomers and optionally the pharmacologically acceptable acid addition salts thereof.

Most preferably, the compounds used as component 2 are the compounds of formula 2a wherein

R

1 denotes ethyl, n-propyl, tert-butyl, cyclopentyl, 3-tetrahydrofuryl, N-morpholinyl or phenyl;

R

2 denotes ethyl or n-propyl; WO 02/069945 5 PCT/EP02/01988

R

3 denotes ethyl, i-propyl, n-propyl, n-butyl, tbutyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, 4-methoxybenzyl or N-pyrollylmethyl, optionally in.the form of their racemates, their enantiomers, in the form of the diastereomers and the mixtures thereof, optionally in the form of their tautomers and optionally the pharmacologically acceptable acid addition salts thereof.

Examples of alkyl groups (including those which are part of other groups) are branched and unbranched alkyl groups with 1 to 5 carbon atoms, such as, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.

butyl, tert.butyl, n-pentyl, isopentyl or neopentyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc.

may optionally be used for the abovementioned groups.

Examples of cycloalkyl groups with 5 or 6 carbon atoms include cyclopentyl or cyclohexyl. Examples of 5- or 6membered, saturated or unsaturated heterocyclic rings which may contain one or two heteroatoms selected from among oxygen and nitrogen include: furan, tetrahydrofuran, tetrahydrofuranone, y-butyrolactone, apyran, y-pyran, dioxolane, tetrahydropyran, dioxane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, oxazine and pyrazolidine.

Table 1 lists the compounds of general formula 2a which are most preferably used in conjunction with the compounds 1 within the scope of the invention.

WO 02/069945 6 PCT/EP02/01988

H

N

N

N

Table 1: No. R 1 R' R 3 1 cyclopentyl n-propyl i-propyl 2 cyclopentyl n-propyl ethyl 3 t-butyl ethyl 4-methoxybenzyl 4 cyclopentyl ethyl -CH 2

CH

2 phenyl 3-tetrahy- ethyl benzyl drofuryl 6 cyclopentyl n-propyl n-propyl 7 t-butyl ethyl benzyl 8 phenyl n-propyl n-propyl 9 cyclopentyl ethyl benzyl -n-propyl -n-propyl benzyl 11 cyclopentyl ethyl N-pyrrolylmethyl 12 cyclopentyl -n-propyl benzyl 13 cyclopentyl -n-propyl -t-butyl 14 cyclopentyl n-propyl n-butyl cyclopentyl ethyl -CH 2 -Ophenyl 16 N-morpholinyl -n-propyl benzyl 17 cyclopentyl ethyl cyclohexylmethyl 18 ethyl ethyl cyclohexylmethyl 19 n-propyl n-propyl cyclopentyl The compounds of general formula 2a may be prepared analogously to the method described in the prior art for certain of the above-defined compounds of general formula (Tenor et al., Chem. Ber. Vol. 97 (1964) p. 1373- 1382), to which reference is hereby made.

.0 Preferably, also, the compound 2 is selected from among enprofylline, roflumilast, ariflo and AWD-12-281, while AWD-12-281 and the abovementioned compounds of formula 2a WO 02/069945 7 PCT/EP02/01988 are particularly preferred as compound 2 according to the invention.

Any reference to the abovementioned PDE-IV inhibitors 2 within the scope of the present invention includes a reference to any pharmacologically acceptable acid addition salts thereof which may exist.

By the physiologically acceptable acid addition salts which may be formed from 2 are meant, for example, pharmaceutically acceptable salts 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 or maleic acid. Particularly preferred salts of the compounds 2 according to the invention are those selected from among the acetate, hydrochloride, hydrobromide, sulphate, phosphate and methanesulphonate.

The pharmaceutical combinations of 1 and 2 according to the invention are preferably administered by inhalation.

Suitable inhalable powders packed into suitable capsules (inhalettes) may be administered using suitable powder inhalers. Alternatively, the drug may be inhaled by the application of suitable inhalation aerosols. These also include inhalation aerosols which contain HFAl34a (also known as TG134a), HFA227 (also known as TG227) or a mixture thereof as propellant gas. The drug may also be inhaled using suitable solutions of the pharmaceutical combination consisting of I and 2.

In one aspect, therefore, the invention relates to a pharmaceutical composition which contains a combination of 1 and 2.

WO 02/069945 8 PCT/EP02/01988 In another aspect the present invention relates to a pharmaceutical composition which contains one or more salts 1 and one or more compounds 2, optionally in the form of their solvates or hydrates. Again, the active substances may be combined in a single preparation or contained in two separate formulations. Pharmaceutical compositions which contain the active substances 1 and 2 in a single preparation are preferred according to the invention.

In another aspect the present invention relates to a pharmaceutical composition which contains, in addition to therapeutically effective quantities of 1 and 2, a pharmaceutically acceptable excipient. In another aspect the present invention relates to a pharmaceutical composition which does not contain any pharmaceutically acceptable excipient in addition to therapeutically effective quantities of 1 and 2.

The present invention also relates to the use of 1 and 2 for preparing a pharmaceutical composition containing therapeutically effective quantities of 1 and 2 for treating inflammatory and/or obstructive diseases of the respiratory tract, particularly asthma or chronic obstructive pulmonary disease (COPD), and complications thereof such as pulmonary hypertension, as well as allergic and non-allergic rhinitis.

The present invention also relates to the simultaneous or successive use of therapeutically effective doses of the combination of the above pharmaceutical compositions 1 and 2 for treating inflammatory and/or obstructive diseases of the respiratory tract, particularly asthma or chronic obstructive pulmonary disease (COPD), and complications thereof such as pulmonary hypertension, as WO 02/069945 9 PCT/EP02/01988 well as allergic and non-allergic rhinitis, by simultaneous or successive administration.

In the active substance combinations of 1 and 2 according to the invention, ingredients 1 and 2 may be present in the form of their enantiomers, mixtures of enantiomers or in the form of racemates.

The proportions in which the two 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 compounds 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 compounds and their different potencies. As a rule, the pharmaceutical combinations according to the invention may contain compounds 1 and 2 in ratios by weight ranging from 1:300 to 50:1, preferably from 1:250 to 40:1. In the particularly preferred pharmaceutical combinations which contain tiotropium salt as compound 1, the weight ratios of 1 to 2 are most preferably in a range in which ipratropium or tiotropium 1' and 2 are present in proportions of 1:150 to 30:1, more preferably from 1:50 to 20:1.

For example, without restricting the scope of the invention thereto, preferred combinations of 1 and 2 according to the invention may contain tiotropium 1' and.

PDE-IV inhibitor 2 in the following weight ratios: 1:80, 1:79, 1:78, 1:77, 1:76, 1:75, 1:74, 1:73, 1:72, 1:71, 1:70, 1:69, 1:68, 1:67, 1:66, 1:65, 1:64, 1:63, 1:62, 1:61, 1:60, 1:59, 1:58, 1:57, 1:56, 1:55, 1:54, 1:53, 1:52, 1:51, 1:50; 1:49; 1:48; 1:47; 1:46; 1:45; WO 02/069945 10 -PCT/EPO2/01986 1:44; 1:43; 1:42; 1:41; 1:40; 1:39; 1:38; 1:37; 1:36; 1:35; 1:34; 1:33; 1:32; 1:31; 1:30; 1:29; 1:28; 1:27; 1:26; 1:25; 1:24; 1:23; 1:22; 1:21; 1:20; 1:19; 1:18; 1:17; 1:16; 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.

The pharmaceutical compositions according to the invent ion containing the combinations of 1 and 2 are normally administered so that 1 and 2 are present together in doses of 0.01 to l0OOpjg, preferably from 0.1 to 2000pg, more preferably from I to 1500ktg, better still from 50 to 1200 tg per single dose. For example, combinations of 1 and 2 according to the invention contain a quantity of tiotropium 1' and PDE-IV inhibitor 2 such that the total dosage per single dose is about i00ptg, 105pg, ll0 gg, llSpg, 120pg, l2Spg, l3Optg, 135.zg, 14OAg, l4Sjtg, lSOpzg, 155pg, 160kg, l6Sgg, l7Qgg, 175pg, 180pgg, 185kg, l9OAg, l9Sitg, 200gig, 2O5pg, 210/19, 2lSpg, 220gig, 225jzg, 230Ag, 235pg, 240Ag9, 245gg, 250/19, 255/19, 260Ag9, 265gg, 270gg, 275gq, 280Ag9, 285pg, 290Ag9, 295JL9, 300gg, 3O5jig, 3l0gg, 3 lS5zg, 32Optg, 325gg, 330gg, 335gg, 340Ag9, S4Sjig, 3 SO0tg, 3S5,gg, 360I19, 365gg, 370gug, 375gg, 38Opcg, 3Spg, 390gg, 395pig, 400/19, 405/19, 410/19, 415/19, 420A19, 425/ig, 430I19, 4 3 5jg, 440/19, 445pg, 450Ag, 455/19, 46Ogig, 4lG5pg, 470Ag9, 475pg, 480Ag9, 4a5jzg, 490Ag9, 49jIg, S0Og, 505/19, 510/19, 515/19, 520/19, 5 25 ktg, S3Ojig, 535fig, 540.'g, 545gtg, SS0pig, 555tig, SE0pg, SE5lig, 570 tg, 575 tg, SB0[pg, SB5 gg, 590pig, 595ptg, 600ptg, 605[ig, 610[tg, 615jLg, 620[tg, 625gLg, 630p.1, 635Jig, 640JLg, 645ptg, 650pg, 660ptq, 665pg, 670119, 675 tg, 680119, 685119, ES0pig, 695p.g, 70019g, 705119, 710119, 7151tg, 720.±g, 725p9, 730[tg, 73pg 740pg, 745pg, 750119, 755pg, 760119, 765p9, 770119, 775pg, 780pg, 785p9, 790119, 795gtg, 800119, 805pig, 8Ipg 815119, 820pg, 525pg, 830119, S3Spig, 840[ig, 845p9g, 8504g9, 855119, WO 02/069945 11 PCT/EP02/01988 860pg, 865ig, 870kg, 875pg, 880pg, 885pg, 890pg, 895pg, 900g, 905Lg, 910g, 915tg, 920pg, 925pg, 930p.g, 935pg, 940[g, 945ug, 950pg, 955g, 960tg, 965pg, 970g, 975pg, 980pg, 985g, 990pg, 995Lg, 1000 g, 1005pg, 1010g, 1015g, 1020p.g, 1025ug, 1030[ig, 1035ig, 1040g, 1045[g, 1050g, 1055 tg, 1060g, 1065 ig, 1070g, 1075xg, 1080ig, 1085p g, 1090pg, 1095pg, 10pg or similar. The suggested dosages per single dose specified above are not to be regarded as being limited to the numerical values actually stated, but are intended as dosages which are disclosed by way of example. Of course, dosages which may fluctuate about the abovementioned numerical values within a range of about 2.5 tg are also included in the values given above by way of example. In these dosage ranges, the active substances 1' and 2 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 tiotropium 1' and PDE-IV inhibitor 2 such that, for each single dose, Sg of 1' and 2 5g of 2, 5g of 1' and 50pg of 2, 5g of 1' and 100gg of 2, 5gg of 1' and 200gg of 2, 5g of 1' and 300gg of 2, 5pg of 1' and 400gg of 2, 5pg of 1' and 500gg of 2, 5g of 1' and 600tg of 2, 5g of 1' and 700pg of 2, 5pg of 1' and 800g of 2, 5gg of 1' and 900pg of 2, of 1' and O00OOg of 2, 10g of 1' and 25gg of 2, of 1' and 50Ag of 2, lO1g of 1' and lO0g of 2, of 1' and 200Jg of 2, 10g of 1' and 300gg of 2, lOyg of 1' and 400gg of 2, 10Og of 1' and 500pg of 2, 10g of 1' and 600g of 2, lOgg of 1' and 700jg of 2, lOg of 1' and 800g of 2, lOpg of 1' and 900zg of 2, lO1g of 1' and 0Og of 2, 18g of 1' and 25pg of 2, 18Ag of 1' and of 2, 18g of 1' and 1O0pg of 2, 18pg of 1' and 200gg of 2, 18g of 1' and 300pg of 2, 18g of 1' and 400ug of 2, 18g of 1' and 500 g of 2, 18g of 1' and WO 02/069945 12 PCT/EP02/01988 of 2, 18pg of 1' and 700ig of 2, 18gg of 1' and 800pg of 2, 18pg of 1' and 900ig of 2, 18gg of 1' and 1000g of 2, 20g of 1' and 25gg of 2, 20Ag of 1' and of 2, 20 Ag of 1' and 50pg of 2, 20pg of 1' and lO0g of 2, 20g of 1' and 200pg of 2, 20pg of 1' and 300pg of 2, 20g of 1' and 400pg of 2, 20g of 1' and 500g of 2, of 1' and 600Ag of 2, 20Ag of 1' and 700pg of 2, of 1' and 800gg of 2, 20g of 1' and 900g of 2, of 1' and lOg of 2, 36g of 1' and 25pg of 2, 36g of 1' and 50pg of 2, 36g of 1' and 100pg of 2, 36jg of 1' and 200gg of 2, 36kg of 1' and 300gg of 2, 36pg of 1' and 400Jg of 2, 36jg of 1' and 500g of 2, 36pg of 1' and 600pg of 2, 36jg of 1' and 700ig of 2, 36pg of 1' and of 2, 36pg of 1' and 900pg of 2, 36ig of 1' and l0g of 2, 40ig of 1' and 25Ag of 2, 40Ag of 1' and of 2, 40pg of 1' and 100g of 2, 40g of 1' and 200pg of 2, 40ig of 1' and 300pg of 2, 40g of 1' and 400pg of 2, 40g of 1' and 500pg of 2, 40g of 1' and 600g of 2 or 40pg of 1' and 700pg of 2, 40g of 1' and 800pg of 2, 40/g of 1' and 900pg of 2, 40g of 1' and 1000g of 2 are administered.

If the active substance combination in which 1 denotes tiotropium bromide is used as the preferred combination of 1 and 2 according to the invention, the quantities of active substance 1' and 2 administered per single dose mentioned by way of example correspond to the following quantities of 1 and 2 administered per single dose: 6pg of 1 and 25kg of 2, 6Gg of 1 and 50pg of 2, 6pg of 1 and lO0g of 2, 6pg of 1 and 200pg of 2, 6gg of 1 and 300pg of 2, 6g of 1 and 400g of 2, 6g of 1 and 500g of 2, 6pg of 1 and 60Og of 2, 6pg of 1 and 700pg of 2, 6pg of 1 and 800gg of 2, 6gg of 1 and 900yg of 2, 6pg of 1 and 1000g of 2, 12pg of 1 and 25ig of 2, 12tg of 1 and of 2, 12g of 1 and lO0pg of 2, 12pg of 1 and 200g of 2, 12gg of 1 and 300gg of 2, 121g of 1 and 400pg of 2, 12Ag wo 02/069945 13 PCT/EPO2/01988 of 1 and 500g of 2, 12gg of 1 and 600g of 2, 1249 of 1 and 70049 of 2, 12gg of 1 and 800gg of 2, 12pg of I and 9004g of 2, 12gg of 1 and 10004g of 2, 21.7g of 1 and 254g of 2, 21.7Ag of 1 and 509pg of 2, 21.7jg of 1 and 100opg of 2, 21.7g of 1 and 200pg of 2, 21.7pg of 1 and 3004g of 2, 21.7t9 of 1 and 400pg of 2, 21.7pg of 1 and SOOpg of 2, 21.74g of 1 and G600g of 2, 21.7pg of I and 700pg of 2, 21.749 of 1 and 800g of 2, 21.7jg of 1 and 900pg of 2, 21.74g of I and 1000g of 2, 24.1pg of 1 and 25Ag of 2, 24.lpg of 1 and 50gg of 2, 24.14g of 1 and 100pg of 2, 24.lg of 1 and 2004g of 2, 24.14g of 1 and 300pg of 2, 24.14g of 1 and 400I9 of 2, 24.19 of 1 and 500g of 2, 24.14g of 1 and 600pg of 2, 24.1pg of 1 and 700pg of 2, 24.14g of 1 and 8004g of 2, 24.1g of 1 and 900pg of 2, 24.1g of 1 and 10004g of 2, 43.3Lg of 1 and of 2, 43.3pg of 1 and 50pLg of 2, 43.34g of 1 and 100g of 2, 43.3jg of 1 and 2009 of 2, 43.349 of 1 and 300pg of 2, 43.34g of 1 and 400g of 2, 43.3A9 of 1 and 500pg of 2, 43.3Ag of 1 and 600gg of 2, 43.34g of I and 7004g of 2, 43.3pg of 1 and 800pg of 2, 43.349 of I and 900gg of 2, 43.3gg of I and 1000p9 of 2, 48.lpg of 1 and of 2, 48.1Ag of 1 and 504g of 2, 48.14g of 1 and 1004g of 2, 48.14g of I and 2004g of 2, 48.lg of 1 and 300ug of 2, 48.149 of I and 400pg of 2, 48.14g of 1 and 500Opg of 2, 48.lg of 1 and 600g of 2, 48.lpg of 1 and 7004g of 2, 48.1pg of 1 and 8009 of 2, 48.14g of 1 and 9004g of 2, 48.11g of 1 and 10009 of 2.

If the active substance combination in which 1 is tiotropium bromide monohydrate is used as the preferred combination of 1 and 2 according to the invention, the quantities of 1' and 2 administered per single dose specified by way of example hereinbefore correspond to the following quantities of 1 and 2 administered per single dose: 6.2pg of 1 and 254g of 2, 6.24g of 1 and WO 02/069945 14 PCT/EP02/01988 of 2, 6.2pg of 1 and 1 00 Mg of 2, 6.2g of 1 and 200pg of 2, 6.2pg of 1 and 3004g of 2, 6.2g of 1 and 400t9 of 2, 6.2gg of 1 and 500pg of 2, 6.2pg of 1 and 600g of 2, 6.2pg of 1 and 700pg of 2, 6.2pg of 1 and 800pg of 2, 6.2jig of 1 and 900g of 2, 6.

2 pg of 1 and 1000pg of 2, 12.5Ag of 1 and 25Ag of 2, 12.5g of 1 and of 2, 12.5Ag of 1 and 100pg of 2, 12.5pg of 1 and 200pg of 2, 12.5pg of 1 and 300.g of 2, 12.5g of I and 4 0 0 mg of 2, 12.5g of 1 and 500Spg of 2, 12.5pg of 1 and 600pg of 2, 12.5g of 1 and 700jig of 2, 12.5kg of 1 and 800 g of 2, 12.5pg of 1 and 900pg of 2, 12.5pg of 1 and 1000 g of 2, 22.5gg of 1 and 25tg of 2, 22.5g of 1 and of 2, 22.5kg of 1 and 100g of 2, 22.5zg of 1 and 200jg of 2, 22.5pg of 1 and 300gg of 2, 22.5kg of 1 and 4 00p9 of 2, 22.5pg of 1 and 500g of 2, 22.5pg of 1 and 600g of 2, 22.5gg of 1 and 700gg of 2, 22.5Ag of 1 and 800ug of 2, 22.5pg of 1 and 900/g of 2, 22.5pg of 1 and 1000g of 2, 25pg of 1 and 25pg of 2, 25gg of 1 and of 2, 25jg of 1 and 100pg of 2, 25pg of 1 and 200kg of 2, 25kg of 1 and 300pg of 2, 25kg of I and 400g of 2, of 1 and 500g of 2, 2 5 Mg of I and 6OOpg of 2, 25g of 1 and 700pg of 2, 25pg of 1 and 800gg of 2, 25jg of 1 and 900pg of 2, 25pg of 1 and 1000g of 2, 45pg of I and of 2, 45kg of 1 and 50pg of 2, 45pg of 1 and 100pg of 2, 45jg of 1 and 2 0 0 9 of 2, 45jg of 1 and 300Ig of 2, of 1 and 400pg of 2, 45gg of 1 and 500pg of 2, 454g of 1 and 600gq of 2, 454g of 1 and 700jg of 2, 454g of 1 and 8004g of 2, 4Spg of 1 and 9004g of 2, 459 of 1 and 1000pg of 2, 50pg of 1 and 25g of 2, 504g of 1 and 504g of 2, 504g of 1 and 1004g of 2, 50pg of 1 and 2004g of 2, 504g of 1 and 300gg of 2, 50pg of 1 and 4004g of 2, 504g of 1 and 500pg of 2, 504g of 1 and 6009 of 2, 504g of 1 and 700pg of 2, 50pg of 1 and 8004g of 2, 504g of 1 and 9004g of 2 or 50pg of 1 and 10009 of 2.

WO 02/069945 15 PCT/EP02/01988 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 sclutions. 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 glucose or arabinose), disaccharides lactose, saccharose, maltose), oligoand polysaccharides dextran), polyalcohols (e.g.

sorbitol, mannitol, xylitol), salts sodium chloride, calcium carbonate) or mixtures of these WO 02/069945 16 PCT/EP02/01988 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. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.

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 150pm, most preferably between 15 and 80gm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9gm 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 10om, more preferably from 1 to 5pm, 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 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 1 and 2 may be administered, for example, by means of inhalers which deliver a single dose from a WO 02/069945 17 PCT/EP02/01988 supply using a measuring chamber as described in US 4570630A, or by other means as described in DE 36 25 685 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 11 via a spindle 10 to enable it to be flipped open or shut.

If the inhalable powders according to the invention are packed into capsules (inhalettes) for the preferred use described above, the quantities packed into each capsule should be 1 to 30mg, preferably 3 to 20mg, more particularly 5 to 10mg of inhalable powder per capsule.

These capsules contain, according to the invention, either together or separately, the doses of 1' and 2 mentioned hereinbefore for each single dose.

B) Propellant gas-driven inhalation aerosols containing the combinations of active substances 1 and 2: WO 02/069945 18 PCT/EP02/01988 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 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 TGI34a, TG227 and mixtures thereof.

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 of active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 0.01 to 3 0.015 to 2 0.1 to 2 0.5 to 2 wt.-O or 0.5 to 1 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 WO 02/069945 19 PCT/EPO2/01988 preferably from 0.1 to 5pm, more preferably from 1 to 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 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: It is particularly preferred to use the active substance combination according to the invention in the form of propellant-free inhalable solutions and suspensions. The solvent used may be an aqueous or alcoholic, preferably an ethanolic solution. The solvent may be water on its own or a mixture of water and ethanol. The relative proportion of ethanol compared with water is not limited but the maximum is up to 70 percent by volume, more particularly up to 60 percent by volume and most preferably up to 30 percent by volume. The remainder of I I wo 02/069945 20 PCT/EP02/01988 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 suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc.

Preferred inorganic acids are hydrochloric and 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, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.

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.

WO 02/069945 21 PCT/EP02/01988 Co-solvents and/or other exqipients 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 k t.

WO 02/069945 22 PCT/EP02/01988 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 1OO0L, preferably less than more preferably between 20 and 30pL of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20km, preferably less than 10km, 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®.

WO 02/069945 23 PCT/EP02/01988 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 WO 02/069945 24 PCT/EP02/01988 (about 50 to 600 bar), preferably 10 to O60 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 microlitres are preferred, while volumes of 10 to microlitres are particularly preferred and a volume of 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 valve 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 valve 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 microns wide, the depth preferably being 4.5 to 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 1600 to one another, preferably 60 to 1500, most preferably 80 to 1000. The nozzle openings are preferably arranged at a spacing of

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wo 02/069945 25 PCT/EP02/01988 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, for 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 I wo 02/069945 26 PCT/EP02/01988 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 annual 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

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WO 02/069945 27 PCT/EP02/01988 biased spring pushes the plunger into the cylinder of the pump housing. The fluid leaves the nozzle of the atomiser in atomised form.

Further details 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 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 The hollow plunger is sealed off by means of the seal Inside the upper housing part is the stop on which the power takeoff flange abuts when the WO 02/069945 28 PCT/EPO2/01988 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 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 preferably 20% of this amount in at least 97%, preferably at least 98% of all operations of the inhaler (spray wO 02/069945 29 PCT/EP02/01988 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 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 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.

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 WO 02/069945 30 PCT/EP02/01988 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 energyoperated 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.

Starting materials Tiotropium bromide: The tiotropium bromide used in the following formulations examples may be obtained as described in European Patent Application 418 716 Al.

In order to prepare the inhalable powders according to the invention, crystalline tiotropium bromide monohydrate may also be used. This crystalline tiotropium bromide monohydrate may be obtained by the method described below.

15.0 kg of tiotropium bromide are placed in 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 0 C and stirred at constant temperature until a clear solution is formed. Activated charcoal WO 02/069945 31 PCT/EP02/01988 (0.8 kg) moistened with water is suspended in 4.4 kg of water, this mixture is added to the solution containing the tiotropium bromide and the resulting mixture is rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 minutes at 80-90 0 C and then filtered through a heated filter into an apparatus preheated to an external temperature of 70 0 C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled at 3-5 0 C for every 20 minutes to a temperature of 20-25 0 C. The apparatus is cooled further to l0-15 0 C using cold water and crystallisation is completed by stirring for at least another hour. The crystals are isolated using a suction filter dryer, the crystal slurry isolated is washed with 9 litres of cold water (l0-15 0 C) and cold acetone (10-15 0 The crystals obtained are dried at 25 0 C in a nitrogen current over a period of 2 hours.

Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory).

The crystalline tiotropium bromide monohydrate thus obtained is micronised by known methods in order to prepare the active substance in the form of the average particle size corresponding to the specifications according to the invention.

WO 02/069945 32 PCT/EP02/01988 Examples of Formulations A) Inhalable powders: 1) 2) 3) 4) Ingredients pg per capsule Tiotropium bromide 21.7 AWD-12-281 200 Lactose 4778.3 Total 5000 Ingredients pg per capsule Tiotropium bromide 21.7 AWD-12-281 125 Lactose 4853.3 Total 5000 Ingredients gg per capsule Tiotropium bromide x H,0 22.5 AWD-12-281 250 Lactose 4727.5 Total 5000 Ingredients pg per capsule Tiotropium bromide 21.7 AWD-12-281 250 Lactose 4728.3 Total 5000 t

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WO 02/069945 33 wo 0/06945 -33 -PCT/EP02/01988 Ingredients pg per capsule Tiotropium bromide x 110 22.5 AWD-12-281 495 Lactose 4482-5 LTotal 5000 Ingredients Ag per capsule Tiotropium bromide 21.7 AWD-12-281 400 Lactose 4578.3 Total 5000 7) Ingredients pg per capsule Tiotropium bromnide x 1120 22.5 Compound of formula 2a 250 Lactose 4727.5 Total 5000 B) Propellant gras-containing aerosols for inhalation: 1) suspension aerosol: Ingredients wt. Tiotropiun bromide 0.015 AWD-12-281 0.066 Soya lecithin 0.2 TG 134a: TG227 2:3 ad 100 WO 02/069945 34 PCT/EP02/01988 2) Suspension aerosol: Ingredients wt.-% Tiotropium bromide 0.029 AWD-12-281 0.033 absolute ethanol isopropyl myristate 0.1 TG 227 ad 100 3) Suspension aerosol: Ingredients wt.-% Tiotropium bromide 0.029 AWD-12-281 0.033 absolute ethanol isopropyl myristate 0.1 TG 227 ad 100 4) Suspension aerosol: Ingredients wt.-% Tiotropium bromide 0.029 AWD-12-281 0.033 absolute ethanol isopropyl myristate 0.1 TG 227 ad 100 35 Suspension aerosol: Ingredients wt.-% Tiotropium bromide 0.029 Compound of formula 2a 0.033 absolute ethanol isopropyl myristate 0.1 TG 227 ad 100 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.