NZ536337A - Medicaments containing betamimetic drugs and a novel anticholinesterase drug - Google Patents

Medicaments containing betamimetic drugs and a novel anticholinesterase drug

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Publication number
NZ536337A
NZ536337A NZ536337A NZ53633703A NZ536337A NZ 536337 A NZ536337 A NZ 536337A NZ 536337 A NZ536337 A NZ 536337A NZ 53633703 A NZ53633703 A NZ 53633703A NZ 536337 A NZ536337 A NZ 536337A
Authority
NZ
New Zealand
Prior art keywords
acid
pharmaceutical composition
denote
inhalable
salts
Prior art date
Application number
NZ536337A
Inventor
Rolf Banholzer
Christopher John Montagu Meade
Helmut Meissner
Gerd Morschhauser
Michel Pairet
Michael P Pieper
Richard Reichl
Georg Speck
Ingo Konetzki
Gerald Pohl
Original Assignee
Boehringer Ingelheim Pharma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE10256317A external-priority patent/DE10256317A1/en
Application filed by Boehringer Ingelheim Pharma filed Critical Boehringer Ingelheim Pharma
Publication of NZ536337A publication Critical patent/NZ536337A/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Disclosed is a pharmaceutical composition which comprises one or more salts of formula 1 wherein: X - denotes an anion with a single negative charge, preferable 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, And one or more betamimetics 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. Also disclosed are inhalable formulations of the above combination and the use of the above composition in the treatment of inflammatory or obstructive respiratory complaints.

Description

1 S3 (.5 3*j ;80360pct.210 ;Medicaments containing betamimetic drugs and a novel anticholinesterase drug ;5 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. ;10 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 anticholinergic 1, processes for preparing them and their use in the treatment of respiratory 15 complaints. ;Within the scope of the present invention the anticholinergic agents used are the salts of formula 1 ;20 ;wherein X ;25 ;Me^ + Me \ / ;N ;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. ;INTELLECTUAL PROPERTY OFFICE OF N.Z. ;0 3 NOV 2004 RECEIVED ;WO 03/087097 ;2 ;PCT/EP03/03669 ;Preferably, the salts of formula lare used wherein ;X" denotes an anion with a single negative charge selected from among the chloride, bromide, 4-toluenesulphonate and methanesulphonate, preferably bromide. ;5 ;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. ;10 Particularly preferred according to the invention is the salt of formula I 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 15 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 20 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 25 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 30 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 35 particular time of the day. ;WO 03/087097 ;3 ;PCT/EP03/03669 ;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. ;Surprisingly, an unexpectedly beneficial therapeutic effect, particularly a synergistic effect can be observed in the treatment of inflammatory and/or 20 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 25 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. ;30 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. ;WO 03/087097 ;4 ;PCT/EP03/03669 ;10 ;Within the scope of the present invention, any reference to the compound Y_ is to be regarded as a reference to the pharmacologically active cation of the following formula contained in the salts 1: ;Me. ;1'. ;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 1 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 15 invention, the salts of salmeterol and formoterol, also includes the relevant enantiomeric salts of R-salmeterol, S-salmeterol, R,R-formoterol, S,S-formoterol, 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 compounds 2 may also be present according to the invention in the form of the 20 hydrates or solvates thereof. ;The long-acting betamimetics 2 may also be the salts of the compounds of formula 2a^, ;WO 03/087097 5 PCT/EP03/03669 ;wherein R1 and R2 R3 and R4 CrC4-alkyl, ;which may be identical or different denote hydrogen or Ci-C4-alkyl; which may be identical or different denote hydrogen, CrC4-alkyl, -0- ;- C-i-C4-alkylene-0-Ci-C4-alkyl or ;R3 and R4 together denote one of the bridging groups ;- CrC4-alkylene- or-0-CrC4-alkylene-0-. ;10 Preferably, salts of the compounds of formula 2a^ wherein ;15 ;R1 and R2 R3 and R4 ;which may be identical or different denote hydrogen, methyl or ethyl; 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. ;20 More preferably, salts of the compounds of formula 2a' wherein ;25 ;R1 and R2 ;R3 and R4 ;which may be identical or different denote hydrogen or ethyl, preferably hydrogen; ;which may be identical or different denote hydrogen, methyl, ethyl, propyl, butyl or methyoxymethyl 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. ;WO 03/087097 ;6 ;PCT/EP03/03669 ;Most preferably, according to the invention, the salts of the following compounds of formula 2a' wherein ;10 ;a) R1 and R2 denote b) R1 and R2 denote c) R1 and R2 denote d) R1 and R2 denote or e) R1 and R2 denote ethylene-O-; or f) R1 and R2 denote g) R1 and R2 denote h) R1 and R2 denote hydrogen and R3 and R4 denote ethyl; or hydrogen and R3 and R4 denote methyl; or ethyl and R3 and R4 denote hydrogen; or hydrogen and R3 and R4 together denote butylene; ;hydrogen and R3 and R4 together denote -O- ;hydrogen and R3 and R4 denote tert.-butyl or hydrogen and R3 and R4 denote iso-propyl; or hydrogen and R3 and R4 denote methoxymethyl ;15 are used in the combinations according to the invention ;20 ;The compounds of formula 2a! are known from WOOO/75114. ;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 : ;OH ;25 ;2aa' ;In the pharmaceutical compositions according to the invention, the salts of the compounds of formula may be present in the form of their racemates, ;WO 03/087097 ;7 ;PCT/EP03/03669 ;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 5 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 10 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 15 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-C-i-C4-alkyl groups), unless otherwise stated, are branched and unbranched alkyl groups with 1 to 4 carbon atoms which 20 are linked via an oxygen atom. The following may be mentioned, for example: methyloxy, ethyloxy, propyloxy or butyloxy. The groups methyloxy, 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, 25 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. ;30 ;WO 03/087097 ;8 ;PCT/EP03/03669 ;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 5 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 10 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. ;15 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, 20 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 25 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 30 salts, this is indicated by a reference to compounds 2\ For example, the preferred betamimetics according to the invention which are not in salt form include the free base of formoterol, salmeterol or the compounds of formula 2a^, 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 35 formula 2a*. 9 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 pharmaceutical^ 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 10 effective quantities of 1 and 2.
The present invention also relates to the use of therapeutically effective quantities of the salts \ 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 15 preparing a pharmaceutical composition for treating asthma or COPD.
Within the scope of the present invention the compounds i 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^ for treating inflammatory or obstructive respiratory complaints, particularly asthma or COPD.
The proportions in which the active substances 1 and 2 may be used in the active 25 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 salt forms. Therefore, the weight 30 ratios specified below were based on the cation V and the free bases T_ 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 2| 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 35 49 63 77 91 1, 22:1, 23:1, 24 1, 36:1, 37:1, 38 1,50:1,51:1,52 1,64:1,65:1,66 1, 78:1, 79:1, 80 1, 92:1, 93:1, 94 1, 25 1, 39 1,53 1,67 1, 81 1, 95 1,26:1,27:1,28 1,40:1,41:1,42 1,54:1,55:1,56 1,68:1,69:1,70 1, 82:1, 83:1, 84 1, 96:1, 97:1, 98 1, 29 1,43 1,57 1,71 1, 85 1, 99 1, 30:1, 31:1, 32:1, 33:1, 34 1,44:1,45:1,46:1,47:1,48 1,58:1,59:1,60:1,61:1,62 1,72:1,73:1,74:1,75:1,76 1, 86:1, 87:1, 88:1, 89:1, 90 1, 100:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are normally administered so that the pharmacologically active cation 1^ and formoterol 2^ are present together in doses of 5 to 5000ng, preferably from 10 to 2000|ag, more preferably from 15 to 1000jxg, better still from 20 to 800|ig, preferably, according to the invention, from 30 to 600[ig, preferably from 40 to 500(j,g.
For example, combinations of 1 and 2 according to the invention contain a quantity of cation V and formoterol such that the total dosage per single dose is about 25 10jjg, 15pg, 20pg, 25pg, 30pg, 35(jg, 40pg, 45pg, 50[jg, 55pg, 60pg, 65pg, 70pg, 75pg, 80|jg, 85pg, 90jjg, 95pg, 100|jg, 105|jg, 110|jg, 115pg, 120(jg, 125pg, 130pg, 135pg, 140|jg, 145pg, 150jjg, 155pg, 160pg, 165pg, 170|jg, 175|jg, 180|jg, 185pg, 190|jg, 195pg, 200pg, 205|jg, 210|jgf 215pg, 220|jg, 225pg, 230|jg, 235pg, 240pg, 245pg, 250pg, 255pg, 260|jg, 265jjg, 270|jg, 275pg, 30 280|jg, 285|jg, 290pg, 295pg, 300ijg, 305pg, 310pg, 315pg, 320gg, 325[jg, 330|jg, 335|jg, 340|jg, 345pg, 350pg, 355pg, 360pg, 365pg, 370pg, 375fjg, 380|jg, 385|jg, 390|jg, 395pg, 400Mg, 405|jg, 410pg, 415pg, 420pg, 425pg, 430|jg, 435pg, 440|jg, 445|jg, 450[jg, 455pg, 460|jg, 465|jgI 470|jg, 475|jg, 480|jg, 485jjg, 490ijg, 495pg, 500pg, 505pg, 510pg, 515pg, 520|jg, 525jjg, 11 530|jg, 535(jg, 540(jg, 545(jg, 550(jg, 555|jg, 560|jg, 565pg, 570(jg, 575(jg, 580|jg, 585gg, 590pg, 595|jg, 600|jg 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 5 about ± 2.5 ng, 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 21 may be present in the weight ratios given above.
For example, without restricting the scope of the invention thereto, the 10 combinations of 1 and 2 according to the invention may contain a quantity of cation Y and formoterol 21 such that, for each single dose, 8.3|jg of V and 2.5|jg of 21, 8.3jjg of Y and 4.9pg of 21, 8.3|jg of Y and 9.8(jg of 21, 8.3jjg of Y and 14,7(jg of 21, 8.3|jg of 11 and 19.6|jg of 21, 8.3|jg of Hand 24.4|jg of 21, 16.5jjg of 11 and 2.5|jg of 21, 16.5|jg of 11 and 4.9|jg of 21, 16.5|jg of 11 and 9.8|jg of 21, 16.5[jg 15 of Hand 14.7(jg of 21, 16.5|jg of Hand 19.6pg of 21, 16.5pg of Hand 24.4|jg of 21, 33.0|jg of H and 2.5(jg of 21, 33.0|jg of Y and 4.9pg of 21, 33.0|jg of Y and 9.8(jg of 21, 33.0ijg of H and 14.7pg of 21, 33.0|jg of Hand 19.6pg of 21, 33.0pg of Hand 24.4|jg of 21, 49.5|jg of Y and 2.5pg of 21, 49.5|jg of Y and 4.9|jg of 21, 49.5pg of Y and 9.8jjg of 21, 49.5|jg of Y and 14.7|jg of 21, 49.5|jg of H and 19.6|jg of 21, 20 49.5pg of Y and 24.4pg of 21, 82.6pg of Y and 2.5|jg of 21, 82.6pg of Y and 4.9pg of 21, 82.6pg of Hand 9.8|jg of 21, 82.6|jg of Hand 14.7|jg of 21, 82.6(jg of Hand 19.6pg of 21, 82.6}jg of Hand 24.4|jg of 21, 165.1pg of Hand 2.5)jg of 21, 165.1pg of Hand 4.9|jg of 21, 165.1|jg of Hand 9.8ijg of 21, 165.1jjg of Hand 14.7|jg of 21, 165.1 |jg of Hand 19.6pgof2l, 165.1 pg of Hand 24.4|jgof21, 206.4|jg of Y and 25 2.5pg of 21, 206.4pg of Y and 4.9pg of 21, 206.4pg of Y and 9.8)jg of 21, 206.4pg of Hand 14.7|jg of 21, 206.4|jg of Hand 19.6|jg of 21, 206.4|jg of Hand 24.4pg of 21, 412.8pg of Hand 2.5pg of 21, 412.8|jg of Hand 4.9pg of 21, 412.8pg of Hand 9.8jjg of 21, 412.8pg of Hand 14.7pg of 21, 412.8pg of Hand 19.6pg of 21, 412.8|jg of H and 24.4|jg of 21 are present.
If the active substance combination in which the bromide is used as the salt 1 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 21 administered per single dose mentioned by way of example correspond to the 35 following quantities of 1 and 2 administered per single dose: 10pg of 1 and 2.9(jg 12 of 2, 10|jg of land 5.7 pg of 2, 10(jg of land 11.5pg of 2, 10pg of land 17.2pg of 2,10jjg of 1 and 22.9pg of 2, 10|jg of 1 and 28.5|jg of 2, 20|jg of 1 and 2.9gg of 2, 20jjg of land 5.7|jg of 2, 20jjg of land 11.5(jg of 2, 20pg of land 17.2|jg of 2, 20jjg of 1 and 22.9(jg of 2, 20(jg of 1 and 28.5pg of 2, 40|jg of 1 and 2.9|jg of 2, 5 40pg of land 5.7|jg of 2, 40|jg of land 11.5(jg of 2, 40pg of land 17.2|jg of 2, 40|jg of 1 and 22.9|jg of 2, 40|jg of 1 and 28.5pg of 2, 60|jg of 1 and 2.9jjg of 2, 60|jg of land 5.7|jg of 2, 60|jg of land 11 -5pg of 2, 60(jg of land 17.2|jg of 2, 60|jg of 1 and 22.9(jg of 2, 60(jg of 1 and 28.5pg of 2,10Opg of 1 and 2.9|jg of 2, 100(jg of 1 and 5.7(jg of 2,100|jg of 1 and 11.5pg of 2, 10Ojjg of land 17.2(jg of 10 2,1 OOpg of 1 and 22.9(jg of 2, 100|jg of 1 and 28.5|jg of 2, 200|jg of 1 and 2.9pg of 2, 200|jg of 1 and 5.7|jg of 2, 200|jg of 1 and 11.5|jg of 2, 200pg of 1 and 17.2pg of 2, 200pg of 1 and 22.9|jg of 2, 200jjg of 1 and 28.5pg of 2, 250pg of 1 and 2.9|jg of 2, 250|jg of land 5.7 pg of 2, 250|jg of land 11.5|jg of 2, 250(jg of 1 and 17.2pg of 2, 250|jg of land 22.9pg of 2, 250(jg of land 28.5|jg of 2, 500|jg of 15 1 and 2.9(jg of 2, 500|jg of 1 and 5.7|jg of 2, 500[jg of 1 and 11.5pg of 2, 500pg of 1 and 17.2pg of 2, 500(jg of 1 and 22.9pg of 2, 500pg of 1 and 28.5pg 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 20 according to the invention, the quantities of active substance Y and administered per single dose mentioned by way of example correspond to the following quantities of 1 and 2 administered per single dose: 10(jg of 1 and 3pg of 2,10|jg of 1 and 6pg of 2, 10pg of 1 and 12|jg of 2, 10|jg of 1 and 18|jg of 2, 1Opg of 1 and 24pg of 2, 10jjg of 1 and 30|jg of 2, 20|jg of 1 and 3|jg of 2, 20|jg of 1 and 25 6jjg of 2, 20|jg of 1 and 12|jg of 2, 20|jg of 1 and 18pg of 2, 20pg of 1 and 24|jg of 2, 20pg of 1 and 30|jg of 2, 40(jg of 1 and 3^jg of 2, 40pg of 1 and 6^g of 2, 40|jg of 1 and 12jjg of 2, 40gg of 1 and 18jjg of 2, 40|jg of 1 and 24pg of 2, 40jjg of 1 and 30pg of 2, 60pg of 1 and 3|jg of 2, 60|jg of 1 and 6(jg of 2, 60|jg of 1 and 12pg of 2, 60[jg of 1 and 18|jg of 2, 60|jg of 1 and 24|jg of 2, 60|jg of 1 and 30pg of 2, 30 100|jg of 1 and 3pg of 2, 100|jg of 1 and 6|jg of 2, 100|jg of 1 and 12(jg of 2, 10Opg of 1 and 18pg of 2, 100|jg of 1 and 24\jg of 2, 100|jg of 1 and 30|jg of 2, 200pg of 1 and 3pg of 2, 200pg of 1 and 6pg of 2, 200(jg of 1 and 12|jg of 2, 200ijg of 1 and 18pg of 2, 200|jg of 1 and 24pg of 2, 200|jg of 1 and 30|jg of 2, 250|jg of 1 and 3pg of 2, 250|jg of 1 and 6pg of 2, 250pg of 1 and 12(jg of 2, 35 250|jg of 1 and 18)jg of 2, 250|jg of 1 and 24|jg of 2, 250|jg of 1 and 30|jg of 2, 13 500fjg of 1 and 3pg of 2, 500|jg of 1 and 6pg of 2, 500|jg of 1 and 12|jg of 2, 500pg of 1 and 18jjg of 2, 500|jg of 1 and 24gg of 2, 500pg of 1 and 30|jg of 2.
The active substance combinations according to the invention may contain V_ and 5 21, 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 10 combinations of 1 and 2 according to the invention may contain the cation 11 and salmeterol 21 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, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1,20:1,21:1,22:1,23:1,24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1, 35:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are usually administered so that the cation Y_ and salmeterol 21 are present together in dosages of 5 to 5000pg, preferably from 10 to 2000|jg, more preferably from 15 to 1000jjg, even more preferably from 20 to 20 800|jg, and preferably according to the invention from 30 to 750)jg, preferably from 40 to 700(jg per single dose.
For example, combinations of 1 and 2 according to the invention contain an amount of 11 and salmeterol 21 such that the total dosage per single dose is about 25 15pg, 20pg, 25pg, 30|jg, 35|jg, 40Mg, 45|jg, 50(jg, 55pg, 60pg, 65|jg, 70pg, 75pg, 80|jg, 85|jg, 90|jg, 95pg, 100pg, 105pg, 110|jg, 115Mg, 120|jg, 125pg, 130jjg, 135pg, 140|jg, 145pg, 150pg, 155pg, 160Mg, 165jjg, 170pg, 175pg, 180^, 185jjg, 190(jg, 195pg, 200pg, 205|jg, 210|jg, 215|jg, 220|jg, 225pg, 230[jg, 235|jg, 240|jg, 245pg, 250pg, 255pg, 260(jg, 265|jg, 270(jg, 275pg, 280pg, 30 285pg, 290ijg, 295jjg, 300Mg, 305|jg, 310pg, 315|jg, 320jjg, 325pg, 330|jg, 335(jg, 340pg, 345pg, 350|jg, 355pg, 360|jg, 365[jg, 370pg, 375pg, 380pg, 385|jg, 390|jg, 395|jg, 400(jg, 405pg, 410pg, 415|jg, 420pg, 425|jg, 430pg, 435)jg, 440pg, 445pg, 450jjg, 455ijg, 460ijg, 465jjg, 470pg, 475|jg, 480ijg, 485pg, 490pg, 495pg, 500pg, 505pg, 510pg, 515Mg, 520|jg, 525pg, 530Mg, 35 535pg, 540pg, 545pg, 550pg, 555pg, 560|jg, 565|jg, 570pg, 575jjg, 580pg, 14 585|jg, 590jjg, 595pg, 600jjg, 605pg, 610pg, 615jjg, 620|jg, 625pg, 630|jg, 635|jg, 640(jg, 645pg, 650jjg, 655pg, 660|jg, 665|jg, 670[jg, 675ng, 680pg, 685jjg, 690|jg, 695|jg, 700|jg 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 5 being limited to the numerical values actually stated. Fluctuations of about ± 2.5 ing, 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 21 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 salmeterol 21 such that, for each single dose, 8.3|jg of V and 12.5pg of 21, 8.3|jg of 11 and 25pg of 21, 8.3|jg of H and 50pg of 21, 8.3pg of H and 75(jg of 21, 8.3|jg of H and 1OOfjg of 21, 8.3|jg of V and 200pg of 21, 16.5jjg of H and 15 12.5|jg of 21, 16.5|jg of V and 25|jg of 21, 16.5|jg of V and 50jjg of 21, 16.5pg of V and 75pg of 21, 16.5|jg of H and 10Opg of 21, 16.5pg of H and 200pg of 21, 33.0|jg of Hand 12.5pg of 21, 33.0|jg of Hand 25pg of 21, 33.0(jg of Hand 50|jg of 21, 33.0(jg of H and 75pg of 21, 33.0[jg of V and 1OOpg of 21, 33.0pg of V and 200pg of 21, 49.5pg of Hand 12.5(jg of 21, 49.5pg of Hand 25pg of 21, 49.5|jg of Hand 20 50|jg of 21, 49.5|jg of H and 75pg of 21, 49.5pg of V and 100|jg of 21, 49.5pg of V and 200[jg of 21, 82.6|jg of Hand 12.5pg of 21, 82.6|jg of Hand 25(jg of 21, 82.6(jg of Hand 50|jg of 21, 82.6|jg of Hand 75|jg of 21, 82.6jjg of V and 100pg of 21, 82.6[jg of Hand 200|jg of 21, 165.1 gg of Hand 12.5pg of 21,165.1 |jg of H and 25|jg of 21, 165.1pg of Hand 50|jg of 21, 165.1 (jg ofHand 75pg of 21, 165.1 (jg of 25 Hand 100|jgof2l, 165.1 |jg of Hand 200pg of 21, 206.4pg of V and 12.5pg of 21, 206.4|jg of H and 25pg of 21, 206.4|jg of V and 50pg of 21, 206.4pg of V and 75pg of 21, 206.4jjg of V and 100|jg of 21, 206.4|jg of V and 200|jg of 21, 412.8pg of V and 12.5pg of 21, 412.8|jg ofHand 25pg of 21, 412.8|jg ofHand 50|jg of21, 412.8jjg ofHand 75pg of 21, 412.8jjg ofHand 100jjg of 21, 412.8|jg ofHand 30 200ijg of 21 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 21 35 administered per single dose as specified hereinbefore correspond to the following amounts of 1 and 2 administered per single dose: 10|jg of 1 and 18.2fjg of 2, 10pg of 1 and 36.3|jg of 2,10pg of 1 and 72.6|jg of 2, 10|jg of 1 and 108.9pg of 2, 10pg of 1 and 145.2pgof2,10|jgofland 290.4jjgof2, 20jjgof 1 and 18.2|jgof2, 20pg of 1 and 36.3|jg of 2, 20(jg of 1 and 72.6pg of 2, 20pg of 1 and 108.9(jg of 2, 5 20pg of 1 and 145.2|jg of 2, 20pg of 1 and 290.4pg of 2, 40|jg of 1 and 18.2pg of 2, 40[jg of 1 and 36.3|jg of 2, 40|jg of 1 and 72.6(jg of 2, 40pg of 1 and 108.9pg of 2, 40pg of 1 and 145.2|jg of 2, 40|jg of 1 and 290.4|jg of 2, 60|jg of 1 and 18.2ng of 2, 60|jg of 1 and 36.3|jg of 2, 60|jg of 1 and 72.6|jg of 2, 60pg of 1 and 108.9[jg of 2, 60pg of land 145.2|jg of 2, 60pg of land 290.4pg of 2, 100|jg of land 10 18.2|jg of 2, 10Ojjg of 1 and 36.3(jg of 2, 10Opg of 1 and 72.6pg of 2, 10Opg of 1 and 108.9^0^, lOOpg of 1 and 145.2|jg of 2,100pgofland 290.4|jgof2, 9 200|jg of 1 and 18.2pg of 2, 200|jg of 1 and 36.3(jg of 2, 200|jg of 1 and 72.6|jg of 2, 200(jg of 1 and 108.9|jg of 2, 200|jg of 1 and 145.2pg of 2, 200|jg of 1 and 290.4|jg of 2, 250pg of 1 and 18.2|jg of 2, 250(jg of 1 and 36.3[jg of 2, 250(jg of 1 15 and 72.6^ig of 2, 250pg of land 108.9jjg of 2, 250^ig of land 145.2|jg of 2, 250pg of 1 and 290.4[jg of 2, 500pg of 1 and 18.2|jg of 2, 500pg of 1 and 36.3|jg of 2, 500pg of land 72.6[jg of 2, 500|jg of land 108.9|jg of 2, 500|jg of land 145.2|jg of 2, 500pg of 1 and 290.4|jg 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 25 preferably used according to the invention are used.
The combinations of active substances according to the invention may contain 1^ 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 30 50:1.
For example, and without restricting the scope of the invention thereto, preferred combinations of 1 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, 35 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, 16 :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 Y and the compound 2aa' together in doses of from 5 to 5000|jg, preferably from 10 to 2000jjg, more preferably from 15 to 1000(jg, even more preferably from 20 to 800|jg, preferably, according to the invention, from 30 to 750pg, preferably from 40 to 700pg.
For example, combinations of 1 and 2 according to the invention contain an amount of V and 2aa' such that the total dosage per single dose is about 15pg, 20jjg, 25pg, 30|jg, 35|jg, 40|jg, 45(jg, 50[jg, 55pg, 60|jg, 65jjg, 70pg, 75pg, 80Mg, 85|jg, 90fjg, 95|jg, 100pg, 105pg, 110pg, 115jjg, 120pg, 125(jg, 130pg, 135pg, 15 140|jg, 145|jg, 150^g, 155ng, 160ng, 165jjg, 170pg, 175|jg, 180jjg, 185jjg, 190|jg, 195jjg, 200|jg, 205|jg, 210|jg, 215jjg, 220jjg, 225pg, 230Mg, 235(jg, 240|jg, 245pg, 250(jg, 255pg, 260pg, 265|jg, 270[ig, 275pg, 280[jg, 285pg, 290pg, 295(jg, 300(jg, 305Mg, 310|jg, 315^g, 320pg, 325pg, 330jjg, 335pg, 340(jg, 345pg, 350pg, 355|jg, 360jjg, 365pg, 370pg, 375pg, 380pg, 385|jg, 20 390|jg, 395|jg, 400^, 405|jg, 410|jg, 415(jg, 420pg, 425pg, 430pg, 435pg, 440pg, 445(jg, 450pg, 455pg, 460pg, 465pg, 470|jg, 475pg, 480jjg, 485(jg, 490jjg, 495|jg, 500pg, 505(jg, 510|jg, 515|jg, 520|jg, 525|jg, 530pg, 535(jg, 540(jg, 545pg, 550pg, 555pg, 560pg, 565pg, 570jjg, 575pg, 580pg, 585pg, 590|jg, 595pg, 600pg, 605jjg, 610pg, 615pg, 620jjg, 625|jg, 630jjg, 635jjg, 25 640pg, 645|jg, 650(jg, 655|jg, 660|jg, 665|jg, 670pg, 675pg, 680pg, 685(jg, 690|jg, 695pg, 700pg 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 ng, particularly in the decimal range, are also included, as will be apparent to the 30 skilled man. In these dosage ranges, the active substances Y 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 35 cation V and 2aa' such that each single dose contains, for example, 8.3(jg of Y 17 and 12.5pg of 2aa', 8.3(jg of Y and 25pg of 2aa', 8.3|jg of V and 50pg of 2aa'. 8.3(jg of V and 75pg of 2aa'. 8.3|jg of Y and 10Opg of 2aa'. 8.3|jg of V and 200|jg of 2aa', 16.5pg of V and 12.5|jg of 2aa', 16.5|jg of Y and 25|jg of 2aa', 16.5|jg of V and 50jjg of 2aa'. 16.5pg of Y and 75pg of 2aa'. 16.5|jg of V and 1OOpg of 2aa'. 16.5ug of 1' and 200ug of 2aa'. 33.0|jg of V and 12.5ug of 2aa'. 33.0jjg of Y and 25pg of 2aa', 33.0pg of V and 50pg of 2aa'. 33.0|jg of Y and 75|jg of 2aa', 33.0(jg of Y and 100(jg of 2aa'. 33.0pg of Y and 200|jg of 2aa'. 49.5ijg of Y and 12.5(jg of 2aa'. 49.5(jg of V and 25|jg of 2aa'. 49.5pg of V and 50|jg of 2aa', 49.5|jg of Y and 75pg of 2aa', 49.5pg of Y and 10Opg of 2aa'. 49.5pg of Y and 200|jg of 2aa', 10 82.6|jg of Hand 12.5pg of 2aa'. 82.6(jg of Y and 25pg of 2aa'. 82.6pg of Hand 50|jg of 2aa', 82.6|jg of Y and 75pg of 2aa', 82.6|jg of Y and 1OOpg of 2aa', 82.6|jg of 1' and 200|jg of 2aa', 165.1 pg of Hand 12.5pg of 2aa', 165.1|jgofH and 25pg of 2aa'. 165.1 (jg of Y and 50pg of 2aa', 165.1 pg of Y and 75pg of 2aa'. 165.1pg ofHand 100pg of 2aa', 165.1pg ofHand 200|jg of 2aa'. 206.4pg of Y 15 and 12.5pg of 2aa', 206.4|jg ofHand 25pg of 2aa'. 206.4[jg ofHand 50(jg of 2aa'. 206.4[jg of Y and 75pg of 2aa'. 206.4(jg of Y and 10Opg of 2aa', 206.4pg of Hand 200pg of 2aa'. 412.8|jg ofHand 12.5|jg of 2aa', 412.8|jg ofHand25pg of 2aa'. 412.8|jg of H and 50pg of 2aa'. 412.8(jg of Y and 75pg of 2aa'. 412.8pg of H and 100)jg of 2aa', 412.8pg ofHand 200|jg 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 Y and 2aa' administered per single dose as specified above by way of example correspond to 25 the following amounts of 1 and 2aa administered per single dose: 10pg of 1 and 16.2(jg of 2aa, 10pg of 1 and 32.4pg of 2aa, 10|jg of 1 and 64.8(jg of 2aa, 10(jg of 1 and 97.2pg of 2aa, 10pg of 1 and 129.6|jg of 2aa. 10pg of 1 and 259.2jjg of 2aa. 20pg of 1 and 16.2pg of 2aa. 20jjg of 1 and 32.4pg of 2aa. 20pg of 1 and 64.8pg of 2aa. 20pg of land 97.2pg of 2aa. 20pg of land 129.6|jg of 30 2aa. 20pg of 1 and 259.2pg of 2aa. 40pg of 1 and 16.2(jg of 2aa. 40pg of 1 and 32.4pg of 2aa. 40pg of 1 and 64.8pg of 2aa. 40|jg of 1 and 97.2pg of 2aa. 40pg of 1 and 129.6pg of 2aa. 40pg of 1 and 259.2pg of 2aa. 60pg of 1 and 16.2jjg of 2aa. 60pg of 1 and 32.4pg of 2aa, 60|jg of 1 and 64.8pg of 2aa. 60pg of land 97.2|jg of 2aa. 60pg of land 129.6pg of 2aa. 60pg of land 35 259.2ug of 2aa. 100|jgofland 16.2ug of 2aa, 100ug of 1 and 32.4ug of 2aa. 18 100|jg of 1 and 64.8[jg of 2aa, 10Ojjg of 1 and 97.2|jg of 2aa, 10Opg of 1 and 129.6|jg of 2aa, 10Opg of 1 and 259.2|jg of 2aa. 200|jg of 1 and 16.2(jg of 2aa, 200|jg of 1 and 32.4pg of 2aa. 200pg of 1 and 64.8pg of 2aa, 200(jg of 1 and 97.2|jg of 2aa, 200|jg of 1 and 129.6|jg of 2aa. 200|jg of 1 and 259.2|jg of 2aa, 250(jg of 1 and 16.2(jg of 2aa. 250jjg of 1 and 32.4(jg of 2aa. 250|jg of 1 and 64.8|jg of 2aa, 250|jg of 1 and 97.2|jg of 2aa, 250|jg of 1 and 129.6pg of 2aa, 250|jg of 1 and 259.2(jg of 2aa, 500|jg of 1 and 16.2pg of 2aa. 500|jg of 1 and 32.4|jg of 2aa, 500pg of 1 and 64.8pg of 2aa, 500pg of 1 and 97.2pg of 2aa, 500|jg of land 129.6|jg of 2aa, 500|jg of land 259.2pg of 2aa.
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 according to the invention include inhalable powders, propellant-containing 15 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 20 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 25 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, 19 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 5 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 250(jm, preferably between 10 and 150pm, most preferably between 15 and 80pm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 10 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 10|am, more preferably from 1 to 6|am, is added to the excipient mixture. Processes for 15 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 one or more physiologically acceptable excipients in addition to 1 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 25 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 30 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 5 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, as well as 10 airholes 13 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 of 1 or Y and 2 or 2^ 15 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 20 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 25 n-propane, n-butane 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 TG11, TG12, TG134a (1,1,1,2-tetrafluoroethane) and 30 TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof, of which the propellant gases TG134a, TG227 and mixtures thereof are preferred. 21 The propellant-driven inhalation aerosols according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.
The inhalation aerosols containing propellant gas according to the invention may contain up to 5 wt.-% of active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 wt.-%, 0.01 to 3 wt.-%, 0.015 to 2 wt.-%, 0.1 to 2 wt.-%, 0.5 to 2 wt.-% or 0.5 to 1 wt.-% of active substance 1 and/or 2.
If the active substances 1 and/or 2 are present in dispersed form, the particles of 10 active substance preferably have an average particle size of up to 1O^m, preferably from 0.1 to 6|xm, more preferably from 1 to 5|im.
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 15 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 20 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 30 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 22 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, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric 10 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 15 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 20 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-solvents and/or other excipients may be added to the propellant-free inhalable 25 solutions according to the invention. Preferred co-solvents are those which contain hydroxy! 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 30 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 23 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, 5 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, 10 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 15 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 20 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 25 present invention, preferred inhalers are those in which a quantity of less than 100|j.L, preferably less than 50^L, more preferably between 20 and 30|aL of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20|j.m, preferably less than 10jj,m, in such a way that the inhalable part of the aerosol corresponds to the 30 therapeutically effective quantity. 24 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 5 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 10 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 15 - 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 30 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 5 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, 10 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 15 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 20 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 150°, 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. 25 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 30 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 26 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 5 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 10 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 15 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 25 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 30 be atomised may be pushed into the atomiser one after another and used in 27 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. 5 The 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 10 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 15 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 20 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 25 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 28 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 5 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 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 29 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 5 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 10 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 15 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 25 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-Diphenvlpropionic 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 10 used in the next step without any further purification. 1.b„: scopine 2.2-diphenvlpropionate: The residue obtained from step 1 .a. is dissolved in 100 ml of dichloromethane and at 40°C a solution of 51.45 g (0.33 mol) of scopine in 200 ml of dichloromethane is 15 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 20 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 75:15:10); m.p.: 203-204°C.
I.c: scopine 2.2-diphenvlpropionate methobromide : II.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 20°C 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.
C24H28N03xBr (458.4); Elemental analysis: calculated: C (62.89) H (6.16) N (3.06) found: C (62.85) H (6.12) N (3.07). 31 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 1.3. 2.) Preparation of the compounds of formula 2: 2.1: Salmeterol-4-phenvlcinnamate 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; + HO "OOC 32 2.2.: Salmeterol-5-(2.4-difluorophenvl)salicvlate 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. 33 Examples of Formulations A) Inhalable powders: 1) Ingredients pg per capsule I'-bromide 200 Formoterol fumarate dihydrate 12 Lactose 24788 Total 25000 2) Ingredients pg per capsule I'-bromide 100 Salmeterol xinafoate 50 Lactose 12350 Total 12500 3) Ingredients pg per capsule I'-bromide 200 Salmeterol xinafoate 50 Lactose 12250 Total 12500 4) Ingredients pg per capsule I'-bromide 200 Formoterol fumarate dihydrate 24 Lactose 24776 Total 25000 WO 03/087097 34 PCT/EP03/03669 ) Ingredients |ig per capsule I'-bromide 100 2b 50 Lactose 12350 Total 12500 6) Ingredients Mg per capsule 1'-bromide 200 2c 50 Lactose 12250 Total 12500 7) Ingredients |jg per capsule 1>bromide 100 2aa' maleate salt 65 Lactose 12335 Total 12500 Ingredients |jg per capsule I'-bromide 200 2aa' maleate salt 65 Lactose 12235 Total 12500 B) Propellant-containing inhalable aerosols: 1) Suspension aerosol: Ingredients % by weight I'-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

Claims (40)

WO 03/087097 36 PCT/EP03/03669 Patent Claims 10 15 20
1) A pharmaceutical composition which comprises one or more salts 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, and one or more betamimetics (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 pharmaceutical^ acceptable excipient.
2) A pharmaceutical combination in which the active substances 1 and 2 as defined in claim 1 are present either together in a single formulation or in two separate formulations.
3) Pharmaceutical composition or combination according to claim 1 or 2 in which the betamimetics 2 are salmeterol salts, formoterol salts or acid addition salts of the compounds of formula 2a^ Me. + Me \ / N x INTELLECTUAL PROPERTY OFFICE OF N.Z. -9 NOV 2006 RECEIVED WO 03/087097 37 PCT/EP03/03669 which may be identical or different denote hydrogen or CrC4-alkyl; which may be identical or different denote hydrogen, CrC^alkyl, -O-CrC^alkyl, - Ci-C4-alkylene-0-Ci-C4-alkyl or R3 and R4 together denote one of the bridging groups CrC4-alkylene- or -0-C-rC4-alkylene-0-.
4) Pharmaceutical composition or combination according to claim 3 in which 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-2-15 naphthalenecarboxylic acid, 4-phenylcinnamic acid, 5-(2.4-difluorophenyl)salicylic acid or maleic acid. wherein R1 and R2 R3 and R4
5) Pharmaceutical composition or combination according to claim 3 or 4 in which the compounds 2 are salmeterol xinafoate, salmeterol-4-phenylcinnamate or 20 salmeterol-5-(2,4-difluorophenyl)salicylate.
6) Pharmaceutical composition or combination according to claim 3 or 4 in which the compounds 2 are salts of the compounds of formula 2a'. wherein 25 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-O- or -O-propylene-O-. 30 INTELLECTUAL PROPERTY OFFICE OF N.Z. -9 NOV 2006 RECEIVED 38
7) Pharmaceutical composition or combination according to claim 3, 4 or 6, in which 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 R3 and R4 together denote one of the bridging groups butylene or -O-ethylene-O-.
8) Pharmaceutical composition or combination according to claim 3, 4, 6 or 7, in which the compounds 2 are salts of the 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.
9) Pharmaceutical composition or combination according to any one of claims 3 to 5, in which the weight ratios of Y Mev + Me \ / N to salmeterol T are in a range from about 1:30 to 400:1. office of n.z. i 1 8 JAN 2007 RECEIVER 39
10) Pharmaceutical composition or combination according to claim 9, in which the weight ratios of V to salmeterol T_ are in a range from about 1:25 to 200:1.
11) Pharmaceutical composition or combination according to any one of claims 3 or 4, in which the compounds 2 are formoterol hydrochloride, formoterol sulphate or formoterol fumarate.
12) Pharmaceutical composition or combination according to claim 11, in which the weight ratios of V to formoterol 2£ are in a range from about 1:10 to 300:1, preferably 1:5 to 200:1. Me, + Me \ / Me. + Me \ / intellectual property office of n.z. 18 JAN 2007 received 40
13) Pharmaceutical composition or combination according to claim 12, in which the weight ratios of V to formoterol £ are in a range from about 1:5 to 200:1.
14) Pharmaceutical composition or combination according to any one of claims 1 to 13, in which the composition or each of the active substances 1 and 2 is present in the form of a preparation suitable for inhalation.
15) Pharmaceutical composition or combination according to claim 14, in which the or each formulation is selected from among the inhalable powders, propellant-containing metered-dose aerosols and propellant-free inhalable solutions.
16) Pharmaceutical composition according to claim 15, comprising an inhalable powder which contains ± and 2 in admixture with suitable physiologically acceptable excipients selected from among the monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures of these excipients with one another.
17) Inhalable powder according to claim 16, in which the excipient has a maximum average particle size of up to 250nm.
18) Inhalable powder according to claim 17, in which the excipient has a maximum average particle size between 10 and 150}xm.
19) Pharmaceutical composition according to claim 15, which is an inhalable powder which contains only the active substances 1 and 2 as its ingredients. Me + Me N intellectual property office of n.z. 18 JAN 2007 received 41
20) Pharmaceutical composition or combination according to claim 15, which is a propellant-containing inhalable aerosol which contains 1 and/or 2 in dissolved or dispersed form.
21) Propellant-containing inhalable aerosol according to claim 20, which contains, as propellant gas, hydrocarbons such as n-propane, n-butane or isobutane or halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
22) Propellant-containing inhalable aerosol according to claim 21, in which the propellant gas is TG11, TG12, TG134a, TG227 or mixtures thereof.
23) Propellant-containing inhalable aerosol according to claim 22,in which the propellant gas is TG134a, TG227 or a mixture thereof.
24) Propellant-containing inhalable aerosol according to any one of claims 20 to 23, which may contain up to 5 % by weight of active substance V and/or 2V
25) Pharmaceutical composition according to claim 15, in which the or each formulation is a propellant-free inhalable solution which contains water, ethanol or a mixture of water and ethanol as solvent.
26) Inhalable solution according to claim 25, which it optionally contains other co-solvents and/or excipients.
27) Inhalable solution according to claim 26, which 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.
28) Inhalable solutions according to one of claims 26 or 27, which contain as excipients surfactants, stabilisers, complexing agents, antioxidants and/or preservatives, flavourings, pharmacologically acceptable salts and/or vitamins.
29) Inhalable solutions according to claim 28, which contain as complexing agents editic acid or a salt of editic acid. intellectual property office of n.z. 18 JAN 2007 received 42
30) Inhalable solutions according to claim 29, in which the complexing agent is sodium edetate.
31) Use of a composition according to any one of claims 1 and 3 to 28 for preparing a medicament for the treatment of inflammatory or obstructive respiratory complaints.
32) Use of a combination according to any one of claims 2 to 15 and 20 -29 in the preparation of separate formulations of substances 1 and 2 for simultaneous or successive administration to a subject in the treatment of inflammatory or obstructive respiratory complaints.
33) A pharmaceutical composition according to any one of claims 1-15, 17, 18 or 23 for the treatment of inflammatory or obstructive respiratory complaints.
34) Use according to any one of claims 31 to 33, wherein the inflammatory or obstructive respiratory complaint is asthma or COPD.
35) A pharmaceutical composition according to any one of claims 1-15, 17, 18 or 23 substantially as hereinbefore described and with reference to the Examples.
36) An inhalable powder according to claim 16 substantially as hereinbefore described and with reference to the Examples.
37) A propellant-containing inhalable aerosol according to any one of claims 20-22 substantially as hereinbefore described and with reference to the Examples.
38) An inhalable solution according to any one of claims 24-27 substantially as hereinbefore described and with reference to the Examples.
39) A use according to claim 28 substantially as hereinbefore described.
40) A pharmaceutical composition according to claim 31 substantially as hereinbefore described. intellectual property office of n.z. 18 JAN 2007 received
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