I IIIII IIIIIIII II llllll lllll lllll lllll lllll lllll lllll lllll lllll lllll lllll 111111111111111111
`US 20030018019Al
`
`(19) United States
`(12) Patent Application Publication
`Meade et al.
`
`(10) Pub. No.: US 2003/0018019 Al
`Jan. 23, 2003
`(43) Pub. Date:
`
`(54) PHARMACEUTICAL COMPOSITIONS
`BASED ON ANTICHOLINERGICS,
`CORTICOSTEROIDS AND BETAMIMETICS
`
`(75)
`
`Inventors: Christopher J.M. Meade, Bingen
`(DE); Michel Pairet, Biberach (DE);
`Michael P. Pieper, Bingen (DE)
`
`Correspondence Address:
`BOEHRINGER INGELHEIM CORPORATION
`900 RIDGEBURY ROAD
`P. 0. BOX 368
`RIDGEFIELD, CT 06877 (US)
`
`(73)
`
`Assignee: Boehringer Ingelheim Pharma KG,
`Ingelheim (DE)
`
`(21)
`
`Appl. No.:
`
`10/173,194
`
`(22)
`
`Filed:
`
`Jun. 17,2002
`
`Related U.S. Application Data
`
`(60) Provisional application No. 60/304,148, filed on Jul.
`10, 2001.
`
`(30)
`
`Foreign Application Priority Data
`
`Jun. 23, 2001
`
`(DE) ........................................ 101 30 371
`
`Publication Classification
`
`Int. Cl.7 ...................... A61K 31/56; A61K 31/4745
`(51)
`(52) U.S. Cl. ........................... 514/171; 514/291; 514/367
`
`(57)
`
`ABSTRACT
`
`The present invention relates to novel pharmaceutical com(cid:173)
`positions based on anticholinergics, corticosteroids and
`betamimetics, processes for preparing them and their use in
`the treatment of respiratory diseases.
`
`Complex Ex. 1007
`
`1
`
`

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`Patent Application Publication
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`Jan. 23, 2003 Sheet 1 of 3
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`US 2003/0018019 Al
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`l1
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`FIG. 1.
`
`12
`
`9
`
`2
`
`

`

`Patent Application Publication
`
`Jan. 23, 2003 Sheet 2 of 3
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`US 2003/0018019 Al
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`66
`
`FIG.2a.
`
`3
`
`

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`Patent Application Publication
`
`Jan. 23, 2003 Sheet 3 of 3
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`US 2003/0018019 Al
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`61
`63
`62
`56
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`71
`
`65
`
`51
`
`52
`
`6'4.
`59
`
`60
`
`69
`75
`74
`76
`
`67
`
`FIG.2b.
`
`4
`
`

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`US 2003/0018019 Al
`
`Jan.23,2003
`
`1
`
`PHARMACEUTICAL COMPOSITIONS BASED ON
`ANTICHOLINERGICS, CORTICOSTEROIDS AND
`BETAMIMETICS
`
`[0001] The present invention relates to novel pharmaceu(cid:173)
`tical compositions based on anticholinergics, corticosteroids
`and betamimetics, processes for preparing them and their
`use in the treatment of respiratory diseases.
`
`DESCRIPTION OF THE INVENTION
`
`[0002] The present invention relates to novel pharmaceu(cid:173)
`tical compositions based on anticholinergics, corticosteroids
`and betamimetics, 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 inflam(cid:173)
`matory or obstructive diseases of the respiratory tract if one
`or more, preferably one, anticholinergic is used with one or
`more corticosteroids and with one or more betamimetics. In
`view of this synergistic effect the pharmaceutical combina(cid:173)
`tions 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 corticoster(cid:173)
`oids and betamimetics are administered, for example.
`
`[0003] The effects mentioned above may be observed both
`when the three active substances are administered simulta(cid:173)
`neously 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
`active substance ingredients simultaneously in a single for(cid:173)
`mulation.
`
`[0004] 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 tiotropium salts. In the
`above-mentioned salts the cations tiotropium, oxitropium
`and ipratropium are the pharmacologically active ingredi(cid:173)
`ents. Within the scope of the present patent application, an
`explicit reference to the above cations is indicated by the use
`of the number l'. Any reference to compounds 1 naturally
`also includes a reference to the ingredients l' (tiotropium,
`oxitropium or ipratropium).
`
`[0005] 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, sulphate,
`methanesulphonate or para-toluenesulphonate. Within the
`scope of the present invention, the methanesulphonate,
`chloride, bromide and iodide are preferred of all the salts 1,
`the methanesulphonate and bromide being of particular
`importance. Of outstanding importance according to the
`invention are salts 1 selected from among tiotropium bro(cid:173)
`mide, oxitropium bromide and ipratropium bromide. Tiotro(cid:173)
`pium bromide is particularly preferred.
`
`[0006] Within the scope of the present invention, the word
`corticosteroids (hereinafter 2) denotes compounds selected
`from among flunisolide, beclomethasone, triamcinolone,
`budesonide, fluticasone, mometasone, ciclesonide, rofle(cid:173)
`ponide, GW 215864, KSR 592, ST-126 and dexamethasone.
`Preferably, compound 2 is selected from among flunisolide,
`beclomethasone, triamcinolone, budesonide, fluticasone,
`
`mometasone, ciclesonide and dexamethasone. Most prefer(cid:173)
`ably, compound 2 is selected from among budesonide,
`fluticasone, mometasone and ciclesonide. In some cases,
`within the scope of the present patent application, the term
`steroids 2 may also be used on its own instead of the word
`corticosteroids 2.
`
`[0007] Any reference to steroids 2 within the scope of the
`present invention includes a reference to salts or derivatives
`2' which may be formed from the steroids. Examples of
`possible salts or derivatives 2' include: sodium salts, sul(cid:173)
`phobenzoates, phosphates, isonicotinates, acetates, propi(cid:173)
`onates, dihydrogen phosphates, palmitates, pivalates or
`furoates. In some cases the compounds of formula 2 may
`also occur in the form of their hydrates.
`
`[0008] Examples of betamimetics 3 which may be used
`according to the invention include bambuterol, bitolterol,
`carbuterol, clenbuterol, fenoterol, formoterol, hexoprena(cid:173)
`line, ibuterol, pirbuterol, procaterol, reproterol, salmeterol,
`sulphonterol, terbutaline, tolubuterol, 4-hydroxy-7-[2-{[2-{
`[3-(2-pheny lethoxy )propy 1 ]sulphony 1 }ethy 1 ]-amino }ethy 1 ]-
`2(3H)-benzothiazolone,
`1-(2-fluoro-4-hydroxypheny 1)-2-
`[ 4-(1-benzimidazolyl)-2-methyl-2-butylamino ]ethanol,
`1-[3-( 4-methoxybenzyl-amino )-4-hydroxyphenyl ]-2-[ 4-(1-
`benzimidazolyl)-2-methyl-2-butylamino ]ethanol,
`l-[2H-5-
`hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-( 4-N,N-dim(cid:173)
`ethylaminophenyl)-2-methyl-2-propylamino ]ethanol,
`l-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-( 4-
`methoxyphenyl)-2-methyl-2-propylamino ]ethanol,
`l-[2H-
`5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl ]-2-[3-( 4-n-buty-
`loxyphenyl)-2-methyl-2-propylamino ]ethanol,
`l-[2H-5-
`hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{ 4-[3-( 4-
`methoxyphenyl)-1,2,4-triazol-3-y 1 ]-2-methy 1-2-
`butylamino }ethanol,
`5-hydroxy-8-(1-hydroxy-2-
`isopropylaminobutyl)-2H-1,4-benzoxazin-3-( 4H)-one, 1-( 4-
`amino-3-chloro-5-trifluoromethylphenyl)-2-tert.(cid:173)
`butylamino )ethanol or 1-( 4-ethoxycarbonylamino-3-cyano-
`5-fluoropheny 1)-2-( tert.-buty lamina )ethanol.
`
`[0009] According to the invention the following betami(cid:173)
`metics 3 are preferably used in the active substance combi(cid:173)
`nation: formoterol, salmeterol, 4-hydroxy-7-[2-{[2-{[3-(2-
`phenylethoxy)propyl ]sulphonyl }ethyl ]-amino }ethyl]-
`2(3H)-benzothiazolone,
`1-(2-fluoro-4-hydroxypheny 1)-2-
`[ 4-(1-benzimidazolyl)-2-methyl-2-butylamino ]ethanol,
`1-[3-( 4-methoxybenzyl-amino )-4-hydroxyphenyl ]-2-[ 4-(1-
`benzimidazolyl)-2-methyl-2-butylamino ]ethanol,
`l-[2H-5-
`hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-( 4-N,N-dim(cid:173)
`ethylaminophenyl)-2-methyl-2-propylamino ]ethanol,
`l-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-( 4-
`methoxyphenyl)-2-methyl-2-propylamino ]ethanol,
`l-[2H-
`5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl ]-2-[3-( 4-n-buty(cid:173)
`loxyphenyl)-2-methyl-2-propylamino ]ethanol or l-[2H-5-
`hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{ 4-[3-( 4-
`methoxyphenyl)-1,2,4-triazol-3-y 1 ]-2-methy 1-2-
`butylamino }ethanol.
`
`[0010] Salmeterol salts or formoterol salts are preferably
`used as the long-acting betamimetics 3 according to the
`invention. Any reference to the term betamimetics 3 also
`includes a reference to the relevant enantiomers or mixtures
`thereof. For example, any reference to the preferred com(cid:173)
`pounds 3 according to the invention, the salts of salmeterol
`and formoterol, also includes the relevant enantiomeric salts
`of R-salmeterol, S-salmeterol, R,R-formoterol, S,S-formot-
`
`5
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`

`

`US 2003/0018019 Al
`
`Jan.23,2003
`
`2
`
`erol, R,S-formoterol, S,R-formoterol and the mixtures
`thereof, while the enantiomeric salts of R-salmeterol and
`R,R-formoterol are of particular importance. The com(cid:173)
`pounds 3 may also be present according to the invention in
`the form of the hydrates or solvates thereof.
`
`[0011] Within the scope of the present invention any
`reference to compounds 3 is to be understood as being a
`reference to physiologically acceptable acid addition salts.
`By physiologically acceptable acid addition salts of the
`betamimetics 3 are meant according to the invention phar(cid:173)
`maceutically acceptable salts which are selected from the
`salts of hydrochloric acid, hydrobromic acid, sulphuric acid,
`phosphoric acid, methanesulphonic acid, acetic acid,
`fumaric acid, succinic acid, lactic acid, citric acid, tartaric
`acid, l-hydroxy-2-naphthalenecarboxylic acid or maleic
`acid. If desired, mixtures of the abovementioned acids may
`be used to prepare the salts 3.
`
`[0012] According to the invention the salts of the betami(cid:173)
`metics 3 selected from among the hydrochloride, hydrobro(cid:173)
`mide, sulphate, phosphate, fumarate, methanesulphonate
`and xinafoate are preferred. Particularly preferred are the
`salts of 3 in the case of salmeterol selected from hydrochlo(cid:173)
`ride, sulphate and xinafoate, of which the sulphates and
`xinafoates are especially preferred. According to the inven(cid:173)
`tion salmeterol x Vi H2SO 4 and salmeterol xinafoate are of
`exceptional importance. Particularly preferred are the salts
`of 3 in the case of formoterol selected from the hydrochlo(cid:173)
`ride, sulphate and fumarate, of which the hydrochloride and
`fumarate are particularly preferred. According to the inven(cid:173)
`tion formoterol fumarate is of exceptional importance.
`
`If, within the scope of the present invention, there
`[0013]
`is a reference to betamimetics which are not in the salt form,
`this can be taken to mean a reference to compounds 3'. For
`example, the preferred betamimetics 3' according to the
`invention which are not in salt form are the free base of
`formoterol or salmeterol, whereas the particularly preferred
`compounds 3 according to the invention are, for example,
`salmeterol xinafoate, salmeterol x Vi H 2S04 or formoterol
`fumarate. Within the scope of the present invention the
`betamimetics 3 are optionally also referred to as sympatho(cid:173)
`mimetics or beta- 2 -receptor agonists (~ 2 -agonists). All these
`names can be regarded as equivalent within the scope of the
`present invention.
`
`[0014] The pharmaceutical combinations of 1,2 and 3
`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 HFA134a,
`HFA227 or a mixture thereof as propellant gas, for example.
`The drug may also be inhaled using suitable solutions of the
`pharmaceutical combination consisting of 1, 2 and 3.
`
`[0015]
`In one aspect, therefore, the invention relates to a
`pharmaceutical composition which contains a combination
`of 1, 2 and 3.
`
`[0016]
`In another aspect the present invention relates to a
`pharmaceutical composition which contains one or more
`salts 1, one or more compounds 2 and one or more com(cid:173)
`pounds 3, optionally in the form of their solvates or hydrates.
`
`The active substances may be combined in a single prepa(cid:173)
`ration or contained in two or three separate formulations.
`Pharmaceutical compositions which contain the active sub(cid:173)
`stances 1, 2 and 3 in a single preparation are preferred
`according to the invention.
`
`[0017]
`In another aspect the present invention relates to a
`pharmaceutical composition which contains, in addition to
`therapeutically effective quantities of 1, 2 and 3, a pharma(cid:173)
`ceutically 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, 2 and
`3.
`
`[0018] The present invention also relates to the use of 1,
`2 and 3 for preparing a pharmaceutical composition con(cid:173)
`taining therapeutically effective quantities of 1, 2 and 3 for
`treating inflammatory and/or obstructive diseases of the
`respiratory tract, particularly asthma and/or chronic obstruc(cid:173)
`tive pulmonary disease (COPD), by simultaneous or suc(cid:173)
`cessive administration. In addition the pharmaceutical com(cid:173)
`binations according to the invention may be used to prepare
`a drug for treating cystic fibrosis or allergic alveolitis
`(farmer's lung), for example, by simultaneous or successive
`administration. The combinations of active substances
`according to the invention will not be used only if treatment
`with one of the pharmaceutically active ingredients is con(cid:173)
`traindicated.
`[0019] The present invention also relates to the simulta(cid:173)
`neous or successive use of therapeutically effective doses of
`the combination of the above pharmaceutical compositions
`1, 2 and 3 for treating inflammatory and/or obstructive
`diseases of the respiratory tract, particularly asthma or
`chronic obstructive pulmonary disease (COPD), provided
`that treatment with steroids or betamimetics is not contrain(cid:173)
`dicated from a therapeutic point of view, by simultaneous or
`successive administration. The invention further relates to
`the simultaneous or successive use of therapeutically effec(cid:173)
`tive doses of the combination of the above pharmaceutical
`compositions 1, 2 and 3 for treating cystic fibrosis or allergic
`alveolitis (farmer's lung).
`In the active substance combinations of 1, 2 and 3
`[0020]
`according to the invention, ingredients 1, 2 and 3 may be
`present in the form of their enantiomers, mixtures of enan(cid:173)
`tiomers or in the form of racemates.
`[0021] The proportions in which the active substances 1,
`2 and 3 may be used in the active substance combinations
`according to the invention are variable. Active substances 1,
`2 and 3 may possibly be present in the form of their solvates
`or hydrates. Depending on the choice of the compounds 1,
`2 and 3, 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 com(cid:173)
`pounds 1 and 2 in ratios by weight ranging from 1:300 to
`50:1, preferably from 1:250 to 40:1. At the same time the
`ratio of 1 to 3 may be 1:300 to 30:1, preferably from 1:230
`to20:1, more preferably from 1:150 to 10:1, more preferably
`from 1:50 to 5:1, most preferably from 1:35 to 2:1.
`[0022]
`In the particularly preferred pharmaceutical com(cid:173)
`binations which contain tiotropium salt as compound 1 and
`a compound selected from among budesonide, fluticasone,
`
`6
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`

`US 2003/0018019 Al
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`Jan.23,2003
`
`3
`
`230 µg, 235 µg, 240 µg, 245 µg, 250 µg, 255 µg, 260 µg, 265
`µg, 270 µg, 275 µg, 280 µg, 285 µg, 290 µg, 295 µg, 300 µg,
`305 µg, 310 µg, 315 µg, 320 µg or the like. In these dosage
`ranges the active substances l', 2 and 3' may be present in
`the weight ratios described above.
`
`[0025] For example and without restricting the scope of
`the invention thereto, the combinations of 1, 2 and 3
`according to the invention may contain an amount of tiotro(cid:173)
`pium l', budesonide or fluticasone 2 and salmeterol or
`formoterol 3' such that in each single dose 5 µg of l' and 25
`µg of 2 and 25 µg of 3', 5 µg of l' and 50 µg of 2 and 25 µg
`of 3', 5 µg of l' and 100 µg of 2 and 25 µg of 3', 5 µg of l'
`and 125 µg of 2 and 25 µg of 3', 5 µg of l' and 200 µg of 2
`and 25 µg of 3', 5 µg of l' and 250 µg of 2 and 25 µg of 3',
`10 µg of l' and 25 µg of 2 and 25 µg of 3', 10 µg of l' and
`50 µg of 2 and 25 µg of 3', 1 µg of l' and 100 µg of 2 and
`25 µg of 3', 10 µg of l' and 125 µg of 2 and 25 µg of 3', 10
`µg of l' and 200 µg of 2 and 25 µg of 3', 10 µg of l' and 250
`µg of 2 and 25 µg of 3', 18 µg of l' and 25 µg of 2 and 25
`µg of 3', 18 µg of l' and 50 µg of 2 and 25 µg of 3', 18 µg
`of l' and 100 µg of 2 and 25 µg of 3', 18 µg of l' and 125
`µg of 2 and 25 µg of 3', 18 µg of l' and 200 µg of 2 and 25
`µg of 3', 18 µg of l' and 250 µg of 2 and 25 µg of 3', 20 µg
`of l' and 25 µg of 2 and 25 µg of 3', 20 µg of l' and 50 µg
`of 2 and 25 µg of 3', 20 µg of l' and 100 µg of 2 and 25 µg
`of 3', 20 µg of l' and 125 µg of 2 and 25 µg of 3', 20 µg of
`l' and 200 µg of 2 and 25 µg of 3', 20 µg of l' and 250 µg
`of 2 and 25 µg of 3', 36 µg of l' and 25 µg of 2 and 25 µg
`of 3', 36 µg of l' and 50 µg of 2 and 25 µg of 3', 36 µg of
`l' and 100 µg of 2 and 25 µg of 3', 36 µg of l' and 125 µg
`of 2 and 25 µg of 3', 36 µg of l' and 200 µg of 2 and 25 µg
`of 3', 36 µg of l' and 250 µg of 2 and 25 µg of 3', 40 µg of
`l' and 25 µg of 2 and 25 µg of 3', 40 µg of l' and 50 µg of
`2 and 25 µg of 3', 40 µg of l' and 100 µg of 2 and 25 µg of
`3', 40 µg of l' and 125 µg of 2 and 25 µg of 3', 40 µg of l'
`and 200 µg of 2 and 25 µg of 3', 40 µg of l' and 250 µg of
`2 and 25 µg of 3', 5 µg of l' and 25 µg of 2 and 50 µg of 3',
`5 µg of l' and 50 µg of 2 and 50 µg of 3', 5 µg of l' and 100
`µg of 2 and 50 µg of 3', 5 µg of l' and 125 µg of 2 and 50
`µg of 3', 5 µg of l' and 200 µg of 2 and 50 µg of 3', 5 µg of
`l' and 250 µg of 2 and 50 µg of 3', 10 µg of l' and 25 µg of
`2 and 50 µg of 3', 10 µg of l' and 50 µg of 2 and 50 µg of
`3', 10 µg of l' and 100 µg of 2 and 50 µg of 3', 10 µg of l'
`and 125 µg of 2 and 50 µg of 3', 10 µg of l' and 200 µg of
`2 and 50 µg of 3', 10 µg of l' and 250 µg of 2 and 50 µg of
`3', 18 µg of l' and 25 µg of 2 and 50 µg of 3', 18 µg of l' and
`50 µg of 2 and 50 µg of 3', 18 µg of l' and 100 µg of 2 and
`50 µg of 3', 18 µg of l' and 125 µg of 2 and 50 µg of 3', 18
`µg of l' and 200 µg of 2 and 50 µg of 3', 18 µg of l' and 250
`µg of 2 and 50 µg of 3', 20 µg of l' and 25 µg of 2 and 50
`µg of 3', 20 µg of l' and 50 µg of 2 and 50 µg of 3', 20 µg
`of l' and 100 µg of 2 and 50 µg of 3', 20 µg of l' and 125
`µg of 2 and 50 µg of 3', 20 µg of l' and 200 µg of 2 and 50
`µg of 3', 20 µg of l' and 250 µg of 2 and 50 µg of 3', 36 µg
`of l' and 25 µg of 2 and 50 µg of 3', 36 µg of l' and 50 µg
`of 2 and 50 µg of 3', 36 µg of l' and 100 µg of 2 and 50 µg
`of 3', 36 µg of l' and 125 µg of 2 and 50 µg of 3', 36 µg of
`l' and 200 µg of 2 and 50 µg of 3', 36 µg of l' and 250 µg
`of 2 and 50 µg of 3', 40 µg of l' and 25 µg of 2 and 50 µg
`of 3', 40 µg of l' and 50 µg of 2 and 50 µg of 3', 40 µg of
`l' and 100 µg of 2 and 50 µg of 3', 40 µg of l' and 125 µg
`of 2 and 50 µg of 3', 40 µg of l' and 200 µg of 2 and 50 µg
`of 3', 40 µg of l' and 250 µg of 2 and 50 µg of 3', 5 µg of
`l' and 25 µg of 2 and 100 µg of 3', 5 µg of l' and 50 µg of
`
`mometasone and ciclesonide as steroid 2, the weight ratios
`of 1 to 2 are most preferably in a range in which tiotropium
`l' and 2 are present in proportions of 1:150 to 30:1, more
`preferably from 1:50 to 20: 1. In these particularly preferred
`pharmaceutical combinations, formoterol or salmeterol is
`preferably used as the betamimetic 3. In this particularly
`preferred pharmaceutical combinations the ratio of tiotro(cid:173)
`pium l' and 3' is particularly preferably in the range from
`1:25 to 1:1, preferably in a range from 1:10 to 1:2, more
`preferably in the range from 1:5 to 1:2.5.
`[0023] For example, without restricting the scope of the
`invention thereto, preferred combinations of 1, 2 and 3
`according to the invention may contain tiotropium l', budes(cid:173)
`onide or fluticasone 2 as well as salmeterol or formoterol 3'
`in the following proportions by weight: 1:25:20; 1:24:20;
`1:23:20; 1:22:20; 1:21:20; 1:20:20; 1:19:20; 1:18:20;
`1:17:20; 1:16:20; 1:15:20; 1:14:20; 1:13:20; 1:12:20;
`1:11:20; 1:10:20; 1:9:20 ; 1:8:20 ; 1:7:20; 1:6:20; 1:5:20;
`1-4·20· 1-3·20· 1-2·20· 1 ·1-20· 2-1 ·20· 3·1-20· 4·1-20·
`5:1:20'. 6:1·20-' 1-i-20-' 8·i·20· '9-1··20· 'rni-20-' 1·25:15'.
`1:24:15; ·1:23'.15; ·1:22:i5; 1:2i:i5;' 1:20:i5;' 1:19:15'.
`1:18:15; 1:17:15; 1:16:15; 1:15:15; 1:14:15; 1:13:15;
`1:12:15; 1:11:15; 1:10:15; 1:9:15; 1:8:15; 1:7:15; 1:6:15;
`1 ·5·15· 1-4·15· 1-3·15· 1 ·2-15· 1 ·1-15· 2-1 ·15· 3·1-15·
`4:1:15'. 5."1."15'. 6."1."15.' 1·1·15.' 8·i·i5.' 9·i·i5·' 10:1:15'.
`1:25:10; ·1:·24\0;·
`:23:10;. 1'.22;10; , 1:21i10;' 1:20:10:
`1:19:10; 1:18:10; 1:17:10; 1:16:10; 1:15:10; 1:14:10;
`1:13:10; 1:12:10; 1:11:10; 1:10:10; 1:9:10; 1:8:10; 1:7:10;
`1:6:10; 1:5:10; 1:4:10; 1:3:10; 1:2:10; 1:1:10; 2:1:10;
`3-1-10· 4-1-10· 5·1-10· 6·1-10· n ·rn 8·1-10· 9-1-10·
`10:1:10; i:25:S; i:24:S; i:23:S; 1:22:s'; 1·:2.1:5'; 1:20:5'.
`1-19·5· 1-18·5· 1·17-5· 1-16·5· 1-15·5· 1-14·5· 1·13-5·
`1:12:5; 1i11:s/ 1:io:s/ 1:9:5i 1:8:5; 1:7:5i 1i6;5; 1:5:5;
`1:4:5; 1:3:5; 1:2:5; 1:1:5; 2:1:5; 3:1:5; 4:1:5; 5:1:5; 6:1:5;
`7·1·5· 8·1·5· 9·1·5· 10·1·5· 1·25·1· 1·24·1· 1·23·1· 1:22:1·
`1:2·1-'1· ·1:2'0·1·· "1'.19·1· .. i ·18·1: '1 ·11-i· , 1 ·i6-i .' 1-15·1'.
`. . ' . . ' . . ' . . ' . . ' . . ' . . '
`1:14:1; 1:13:1; 1:12:1; 1:11:1; 1:10:1; 1:9:1; 1:8:1; 1:7:1;
`1:6:1; 1:5:1; 1:4:1; 1:3:1; 1:2:1; 1:1:1; 2:1:1; 3:1:1; 4:1:1;
`5:1:1; 6:1:1; 7:1:1; 8:1:1; 9:1:1; 10:1:1; 1:25:0.75;
`1:24:0.75; 1:23:0.75; 1:22:0.75; 1:21:0.75; 1:20:0.75;
`1:19:0.75; 1:18:0.75; 1:17:0.75; 1:16:0.75; 1:15:0.75;
`1:14:0.75; 1:13:0.75; 1:12:0.75; 1:11:0.75; 1:10:0.75;
`1:9:0.75; 1:8:0.75; 1:7:0.75; 1:6:0.75; 1:5:0.75; 1:4:0.75;
`1:3:0.75; 1:2:0.75; 1:1:0.75; 2:1:0.75; 3:1:0.75; 4:1:0.75;
`5:1:0.75; 6:1:0.75; 7:1:0.75; 8:1:0.75; 9:1:0.75; 10:1:0.75;
`1:25:0.5; 1:24:0.5; 1:23:0.5; 1:22:0.5; 1:21:0.5; 1:20:0.5;
`1:19:0.5; 1:18:0.5; 1:17:0.5; 1:16:0.5; 1:15:0.5; 1:14:0.5;
`1:13:0.5; 1:12:0.5; 1:11:0.5; 1:10:0.5; 1:9:0.5; 1:8:0.5;
`1:7:0.5; 1:6:0.5; 1:5:0.5; 1:4:0.5; 1:3:0.5; 1:2:0.5; 1:1:0.5;
`2:1:0.5; 3:1:0.5; 4:1:0.5; 5:1:0.5; 6:1:0.5; 7:1:0.5; 8:1:0.5;
`9:1:0.5; 10:1:0.5.
`[0024] The pharmaceutical compositions according to the
`invention containing the combinations of 1, 2 and 3 are
`normally administered so that 1, 2 and 3 are present together
`in doses of 1 to 1000 µg, preferably from 10 to 2000 µg,
`more preferably from 50 to 1000 µg, even more preferably
`from 60 to 750 µg, preferably according to the invention
`from 70 to 500 µg, preferably from 100 to 350 µg per single
`dose. For example, combinations of 1, 2 and 3 according to
`the invention contain a quantity of tiotropium l', budesonide
`or fluticasone 2 and salmeterol or formoterol 3' such that the
`total dosage per single dose is about 140 µg, 145 µg, 150 µg,
`155 µg, 160 µg, 165 µg, 170 µg, 175 µg, 180 µg, 185 µg, 190
`µg, 195 µg, 200 µg, 205 µg, 210 µg, 215 µg, 220 µg, 225 µg,
`
`01
`
`7
`
`

`

`US 2003/0018019 Al
`
`Jan.23,2003
`
`4
`
`2 and 100 µg of 3', 5 µg of l' and 100 µg of 2 and 100 µg
`of 3', 5 µg of l' and 125 µg of 2 and 100 µg of 3', 5 µg of
`l' and 200 µg of 2 and 100 µg of 3', 5 µg of l' and 250 µg
`of 2 and 100 µg of 3', 10 µg of l' and 25 µg of 2 and 100 µg
`of 3', 10 µg of l' and 50 µg of 2 and 100 µg of 3', 10 µg of
`l' and 100 µg of 2 and 100 µg of 3', 10 µg of l' and 125 µg
`of 2 and 100 µg of 3', 10 µg of l' and 200 µg of 2 and 100
`µg of 3', 10 µg of l' and 250 µg of 2 and 100 µg of 3', 18 µg
`of l' and 25 µg of 2 and 100 µg of 3', 18 µg of l' and 50 µg
`of 2 and 100 µg of 3', 18 µg of l' and 100 µg of 2 and 100
`µg of 3', 18 µg of l' and 125 µg of 2 and 100 µg of 3', 18 µg
`of l' and 200 µg of 2 and 100 µg of 3', 18 µg of l' and 250
`µg of 2 and 100 µg of 3', 20 µg of l' and 25 µg of 2 and 100
`µg of 3', 20 µg of l' and 50 µg of 2 and 100 µg of 3', 20 µg
`of l' and 100 µg of 2 and 100 µg of 3', 20 µg of l' and 125
`µg of 2 and 100 µg of 3', 20 µg of l' and 200 µg of 2 and 100
`µg of 3', 20 µg of l' and 250 µg of 2 and 100 µg of 3', 36 µg
`of l' and 25 µg of 2 and 100 µg of 3', 36 µg of l' and 50 µg
`of 2 and 100 µg of 3', 36 µg of l' and 100 µg of 2 and 100
`µg of 3', 36 µg of l' and 125 µg of 2 and 100 µg of 3', 36 µg
`of l' and 200 µg of 2 and 100 µg of 3', 36 µg of l' and 250
`µg of 2 and 100 µg of 3', 40 µg of l' and 25 µg of 2 and 100
`µg of 3', 40 µg of l' and 50 µg of 2 and 100 µg of 3', 40 µg
`of l' and 100 µg of 2 and 100 µg of 3', 40 µg of l' and 125
`µg of 2 and 100 µg of 3' are administered.
`
`[0026] Particularly preferred pharmaceutical combina(cid:173)
`tions according to the invention contain 5-30 µg of tiotro(cid:173)
`pium l', 125-250 µg of budesonide or fluticasone 2 and 10
`to 40 µg of salmeterol or formoterol 3'.
`
`If the active substance combinations wherein 1
`[0027]
`denotes tiotropium bromide and wherein 3 denotes salme(cid:173)
`terol x Y2H2S04 , for example, are used as one of the
`preferred combinations of 1, 2 and 3 according to the
`invention, the quantities of active substances l', 2 and 3'
`administered per single dose as mentioned above by way of
`example correspond to the following quantities of 1, 2 and
`3 administered per single dose:
`
`[0028] 6 µg of 1 and 25 µg of 2 and 27.9 µg of 3, 6 µg of
`1 and 50 µg of 2 and 27.9 µg of 3, 6 µg of 1 and 100 µg of
`2 and 27.9 µg of 3, 6 µg of 1 and 125 µg of 2 and 27.9 µg
`of 3, 6 µg of 1 and 200 µg of 2 and 27.9 µg of 3, 6 µg of 1
`and 250 µg of 2 and 27.9 µg of 3, 12 µg of 1 and 25 µg of
`2 and 27.9 µg of 3, 12 µg of 1 and 50 µg of 2 and 27.9 µg
`of 3, 12 µg of 1 and 100 µg of 2 and 27.9 µg of 3, 12 µg of
`1 and 125 µg of 2 and 27.9 µg of 3, 12 µg of 1 and 200 µg
`of 2 and 27.9 µg of 3, 12 µg of 1 and 250 µg of 2 and 27.9
`µg of 3, 21.7 µg of 1 and 25 µg of 2 and 27.9 µg of 3, 21.7
`µg of 1 and 50 µg of 2 and 27.9 µg of 3, 21.7 µg of 1 and
`100 µg of 2 and 27.9 µg of 3, 21.7 µg of 1 and 125 µg of 2
`and 27.9 µg of 3, 21.7 µg of 1 and 200 µg of 2 and 27.9 µg
`of 3, 21.7 µg of 1 and 250 µg of 2 and 27.9 µg of 3, 24.1 µg
`of 1 and 25 µg of 2 and 27.9 µg of 3, 24.1 µg of 1 and 50
`µg of 2 and 27.9 µg of 3, 24.1 µg of 1 and 100 µg of 2 and
`27.9 µg of 3, 24.1 µg of 1 and 125 µg of 2 and 27.9 µg of
`3, 24.1 µg of 1 and 200 µg of 2 and 27.9 µg of 3, 24.1 µg of
`1 and 250 µg of 2 and 27.9 µg of 3, 43.3 µg of 1 and 25 µg
`of 2 and 27.9 µg of 3, 43.3 µg of 1 and 50 µg of 2 and 27.9
`µg of 3, 43.3 µg of 1 and 100 µg of 2 and 27.9 µg of 3, 43.3
`µg of 1 and 125 µg of 2 and 27.9 µg of 3, 43.3 µg of 1 and
`200 µg of 2 and 27.9 µg of 3, 43.3 µg of 1 and 250 µg of 2
`and 27.9 µg of 3, 48.1 µg of 1 and 25 µg of 2 and 27.9 µg
`of 3, 48.1 µg of 1 and 50 µg of 2 and 27.9 µg of 3, 48.1 µg
`of 1 and 100 µg of 2 and 27.9 µg of 3, 48.1 µg of 1 and 125
`
`µg of 2 and 27.9 µg of 3, 48.1 µg of 1 and 200 µg of 2 and
`27.9 µg of 3, 48.1 µg of 1 and 250 µg of 2 and 27.9 µg of
`3, 6 µg of 1 and 25 µg of 2 and 55.9 µg of 3, 6 µg of 1 and
`50 µg of 2 and 55.9 µg of 3, 6 µg of 1 and 100 µg of 2 and
`55.9 µg of 3, 6 µg of 1 and 125 µg of 2 and 55.9 µg of 3, 6
`µg of 1 and 200µg of 2 and 55.9 µg of 3, 6 µg of 1 and 250
`µg of 2 and 55.9 µg of 3, 12 µg of 1 and 25 µg of 2 and 55.9
`µg of 3, 12 µg of 1 and 50 µg of 2 and 55.9 µg of 3, 12 µg
`of 1 and 100 µg of 2 and 55.9 µg of 3, 12 µg of 1 and 125
`µg of 2 and 55.9 µg of 3, 12 µg of 1 and 200 µg of 2 and 55.9
`µg of 3, 12 µg of 1 and 250 µg of 2 and 55.9 µg of 3, 21.7
`µg of 1 and 25 µg of 2 and 55.9 µg of 3, 21.7 µg of 1 and
`50 µg of 2 and 55.9 µg of 3, 21.7 µg of 1 and 100 µg of 2
`and 55.9 µg of 3, 21.7 µg of 1 and 125 µg of 2 and 55.9 µg
`of 3, 21.7 µg of 1 and 200 µg of 2 and 55.9 µg of 3, 21.7 µg
`of 1 and 250 µg of 2 and 55.9 µg of 3, 24.1 µg of 1 and 25
`µg of 2 and 55.9 µg of 3, 24.1 µg of 1 and 50 µg of 2 and
`55.9 µg of 3, 24.1 µg of 1 and 100 µg of 2 and 55.9 µg of
`3, 24.1 µg of 1 and 125 µg of 2 and 55.9 µg of 3, 24.1 µg of
`1 and 200 µg of 2 and 55.9 µg of 3, 24.1 µg of 1 and 250 µg
`of 2 and 55.9 µg of 3, 43.3 µg of 1 and 25 µg of 2 and 55.9
`µg of 3, 43.3 µg of 1 and 50 µg of 2 and 55.9 µg of 3, 43.3
`µg of 1 and 100 µg of 2 and 55.9 µg of 3, 43.3 µg of 1 and
`125 µg of 2 and 55.9 µg of 3, 43.3 µg of 1 and 200 µg of 2
`and 55.9 µg of 3, 43.3 µg of 1 and 250 µg of 2 and 55.9 µg
`of 3, 48.1 µg of 1 and 25 µg of 2 and 55.9 µg of 3, 48.1 µg
`of 1 and 50 µg of 2 and 55.9 µg of 3, 48.1 µg of 1 and 100
`µg of 2 and 55.9 µg of 3, 48.1 µg of 1 and 125 µg of 2 and
`55.9 µg of 3, 48.1 µg of 1 and 200 µg of 2 and 55.9 µg of
`3, 48.1 µg of 1 and 250 µg of 2 and 55.9 µg of 3, 6 µg of 1
`and 25 µg of 2 and 111.8 µg of 3, 6 µg of 1 and 50 µg of 2
`and 111.8 µg of 3, 6 µg of 1 and 100 µg of 2 and 111.8 µg
`of 3, 6 µg of 1 and 125 µg of 2 and 111.8 µg of 3, 6 µg of
`1 and 200 µg of 2 and 111.8 µg of 3, 6 µg of 1 and 250 µg
`of 2 and 111.8 µg of 3, 12 µg of 1 and 25 µg of 2 and 111.8
`µg of 3, 12 µg of 1 and 50 µg of 2 and 111.8 µg of 3, 12 µg
`of 1 and 100 µg of 2 and 111.8 µg of 3, 12 µg of 1 and 125
`µg of 2 and 111.8 µg of 3, 12 µg of 1 and 200 µg of 2 and
`111.8 µg of 3, 12 µg of 1 and 250 µg of 2 and 111.8 µg of
`3, 21.7 µg of 1 and 25 µg of 2 and 111.8 µg of 3, 21.7 µg of
`1 and 50 µg of 2 and 111.8 µg of 3, 21.7 µg of 1 and 100 µg
`of 2 and 111.8 µg of 3, 21.7 µg ofl and 125 µg of 2 and 111.8
`µg of 3, 21.7 µg of 1 and 200 µg of 2 and 111.8 µg of 3,
`21.7µg of 1 and 250 µg of 2 and 111.8 µg of 3, 24.1 µg of
`1 and 25 µg of 2 and 111.8 µg of 3, 24.1 µg of 1 and 50 µg
`of 2 and 111.8 µg of 3, 24.1 µg ofl and 100 µg of 2 and 111.8
`µg of 3, 24.1 µg of 1 and 125 µg of 2 and 111.8 µg of 3, 24.1
`µg of 1 and 200 µg of 2 and 111.8 µg of 3, 24.1 µg of 1 and
`250 µg of 2 and 111.8 µg of 3, 43.3 µg of 1 and 25 µg of 2
`and 111.8 µg of 3, 43.3 µg of 1 and 50 µg of 2 and 111.8 µg
`of 3, 43.3 µg of 1 and 100 µg of 2 and 111.8 µg of 3, 43.3
`µg of 1 and 125 µg of 2 and 111.8 µg of 3, 43.3 µg of 1 and
`200 µg of 2 and 111.8 µg of 3, 43.3 µg of 1 and 250 µg of
`2 and 111.8 µg of 3, 48.1 µg of 1 and 25 µg of 2 and 111.8
`µg of 3, 48.1 µg of 1 and 50 µg of 2 and 111.8 µg of 3, 48.1
`µg of 1 and 100 µg of 2 and 111.8 µg of 3, 48.1 µg of 1 and
`125 µg of 2 and 111.8 µg of 3, 48.1 µg of 1 and 200 µg of
`2 and 111.8 µg of 3, 48.1 µg of 1 and 250 µg of 2 and 111.8
`µg of 3.
`
`If the active substance combinations wherein 1
`[0029]
`denotes tiotropium bromide monohydrate and wherein 3
`denotes formoterol fumarate, for example, are used as one of
`the preferred combinations of 1, 2 and 3 according to the
`invention, the quantities of active substances l', 2 and 3'
`
`8
`
`

`

`US 2003/0018019 Al
`
`Jan.23,2003
`
`5
`
`administered per single dose as mentioned above by way of
`example correspond to the following quantities of 1, 2 and
`3 administered per single dose:
`
`[0030] 6.2 µg of 1 and 25 µg of 2 and 29.2 µg of 3, 6.2 µg
`of 1 and 50 µg of 2 and 29.2 µg of 3, 6.2 µg of 1 and 100
`µg of 2 and 29.2 µg of 3, 6.2 µg of 1 and 125 µg of 2 and
`29.2 µg of 3, 6.2 µg of 1 and 200 µg of 2 and 29.2 µg of 3,
`6.2 µg of 1 and 250 µg of 2 and 29.2 µg of 3, 12.5 µg of 1
`and 25 µg of 2 and 29.2 µg of 3, 12.5 µg of 1 and 50 µg of
`2 and 29.2 µg of 3, 12.5 µg of 1 and 100 µg of 2 and 29.2
`µg of 3, 12.Sµg of 1 and 125 µg of 2 and 29.2 µg of 3, 12.5
`µg of 1 and 200 µg of 2 and 29.2 µg of 3, 12.5 µg of 1 and
`250 µg of 2 and 29.2 µg of 3, 22.5 µg of 1 and 25 µg of 2
`and 29.2 µg of 3, 22.5 µg of 1 and 50 µg of 2 and 29.2 µg
`of 3, 22.5 µg of 1 and 100 µg of 2 and 29.2 µg of 3, 22.5 µg
`of 1 and 125 µg of 2 and 29.2 µg of 3, 22.5 µg of 1 and 200
`µg of 2 and 29.2 µg of 3, 22.5 µg of 1 and 250 µg of 2 and
`29.2 µg of 3, 25 µg of 1 and 25 µg of 2 and 29.2 µg of 3, 25
`µg of 1 and 50 µg of 2 and 29.2 µg of 3, 25 µg of 1 and 100
`µg of 2 and 29 .2 µg of 3, 25 µg of 1 and 125 µg of 2 and 29 .2
`µg of 3, 25 µg of 1 and 200 µg of 2 and 29.2 µg of 3, 25 µg
`of 1 and 250 µg of 2 and 29.2 µg of 3, 45 µg of 1 and 25 µg
`of