EP2029127A1 - New long-acting drug combinations for the treatment of respiratory diseases - Google Patents

New long-acting drug combinations for the treatment of respiratory diseases

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Publication number
EP2029127A1
EP2029127A1 EP07729151A EP07729151A EP2029127A1 EP 2029127 A1 EP2029127 A1 EP 2029127A1 EP 07729151 A EP07729151 A EP 07729151A EP 07729151 A EP07729151 A EP 07729151A EP 2029127 A1 EP2029127 A1 EP 2029127A1
Authority
EP
European Patent Office
Prior art keywords
acid
pharmaceutical composition
composition according
denotes
compound
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP07729151A
Other languages
German (de)
French (fr)
Inventor
Ingo Konetzki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
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
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Priority to EP07729151A priority Critical patent/EP2029127A1/en
Publication of EP2029127A1 publication Critical patent/EP2029127A1/en
Withdrawn legal-status Critical Current

Links

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
    • A61K31/075—Ethers or acetals
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to novel pharmaceutical compositions based on a new anticholinergic and a new long-acting beta 2 -agonist, processes for the preparation thereof and the use thereof in the treatment of respiratory complaints.
  • the present invention relates to novel pharmaceutical compositions containing in addition to an anticholinergic of formula 1
  • A denotes a group selected from
  • R and R' denote hydrogen or together a group selected from a single bond
  • 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,
  • beta 2 -agonists 2 selected from the group consisting of
  • A denotes a group selected from
  • R and R' denote hydrogen or together a group selected from a single bond, and -O-;
  • 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.
  • salts of formula 1 are used wherein X " denotes an anion with a single negative charge, selected from the group consisting of chloride, bromide, 4- toluenesulphonate and methanesulphonate , preferably bromide.
  • salts of formula 1_ are used wherein X " denotes an anion with a single negative charge, selected from the group consisting of chloride, bromide and methanesulphonate, preferably bromide.
  • Particularly preferred according to the invention are compounds of formula JL 1 wherein R and R denote hydrogen and wherein A and X " are as defined hereinbefore.
  • Particularly preferred according to the invention are compounds of formula 1_, wherein R and R denote a bond and wherein A and X " are as defined hereinbefore.
  • Particularly preferred according to the invention are compounds of formula 1, wherein R and R 1 denote -O- and wherein A and X " are as defined hereinbefore.
  • the compounds of formula 1 are known from WO 02/32899, WO03/64419, WO03/64418 and WO03/64417.
  • Particularly preferred according to the invention are compounds of formula 1, selected from the group consisting of tropenol 2,2-diphenylpropionate-methobromide (IJL), scopine 2,2-diphenylpro ⁇ ionate-methobromide (1.2), tropenol 9-methyl-fluorene-9- carboxylate methobromide (1.3), scopine 9-methyl ⁇ fluorene-9 ⁇ carboxylate methobromide (1.4), tropenol 9-methyl-xanthene-9-carboxylate methobromide (1.5), scopine 9-methyl- xanthene-9-carboxylate methobromide (1.6), cyclopropyltropine 2,2-diphenylpropionate methobromide (1.7), cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide (1.8) and cyclopropyltropine 9-methyl ⁇ xanthene-9-carboxylate methobro
  • an unexpectedly beneficial therapeutic effect can be observed for instance in the treatment of inflammatory or obstructive diseases of the respiratory tract if the anticholinergic of formula 1. is administered together with the compound of formula 2.
  • the drug combinations according to the invention can be used in smaller doses than would be the case with the individual compounds used in monotherapy in the usual way, As another positive aspect of the present invention this reduces unwanted side effects such as may occur when betamimetics are administered, for example.
  • Unwanted side effects which deserve special mention in this context are the stimulant effects on the heart which may be caused by betamimetics, particularly tachycardia, a stronger heartbeat, pain resembling angina pectoris as well as arrhythmia.
  • the abovementioned effects are observed both when the two active substances are administered simultaneously in a single active substance formulation and also when the two active substances are administered successively in separate formulations. It is preferred according to the invention to administer the two active substance components simultaneously in a single formulation.
  • the active substances may either both be contained in a single formulation or may be contained in two separate formulations.
  • Pharmaceutical compositions which contain the active substances I and 2 in a single formulation are preferred according to the invention.
  • Any reference to the betamimetic 2 includes a reference to the enantiomers (R or S) or the mixtures thereof, the i? ⁇ enantiomer of the compound being of particular importance within the scope of the present invention. Process for the enantio selective preparation of the enantiomers of the compound of formula 2 are known in the art.
  • the betamimetic s 2 may also be present according to the invention in the form of its salts, as well as its hydrates or solvates.
  • Examples of novel, preferred medicament combinations according to the invention are containing the compounds Ll and 11; Ll and 12; Ll and 2.3; 1.1 and 14; Ll and 15; Ll and 2,6; Ll and 2,7; Ll and 2,8; L2 and 11; L2 and 12; L2 and 13;J ⁇ 2 and 2,4; L2 and 15; L2 and 16; L2 and 2/7; L2 and 18; L3 and 11 ; L3 and 12; L3 and 23;_L3 and 14; L3 and 15; L3 and 16j M and 2/7; L3 and 2JS; LJ and 11 ; L4 and 12; L4 and 13; LJ and IA, LJ and 15; L4 and 16; L4 and 17; LJ and 2JJ; L5 and 11; L5 and 12; L5 and 2 ⁇ 3; JL5 and IA, L5 and IS; L5 and 2 ⁇ 6; L5 and 2/7; L5 and 2 ⁇ ; L6 and 2 ⁇ ; L6 and 2.2; L6 and 2
  • betamimetics is also to be understood as reference to the term beta 2 -agonist.
  • a reference to betamimetics 2 includes a reference to the physiologically acceptable acid addition salts thereof.
  • physiologically acceptable acid addition salts of the betamimetics 2 are meant according to the invention pharmaceutically acceptable salts which include the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1 -hydroxy-2- naphthalenecarboxylic acid or maleic acid. If desired, mixtures of the abovementioned acids may be used to prepare the salts 2.
  • the salts of 2 selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methanesulphonate, maleate and xinafoate are preferred.
  • the present invention relates to the above-mentioned pharmaceutical compositions which contain, in addition to therapeutically effective quantities of 1 and 2, a pharmaceutically acceptable excipient.
  • the present invention relates to the above-mentioned pharmaceutical compositions which do not contain any pharmaceutically acceptable excipient in addition to therapeutically effective quantities of I and 2.
  • the present invention also relates to the use of therapeutically effective amounts of the active substances X for preparing a pharmaceutical composition also containing one or more, preferably one active substance 2 for the treatment of inflammatory and obstructive respiratory complaints, for inhibiting premature labour in midwifery (tocolysis), for restoring sinus rhythm in the heart in atrioventricular block, for correcting bradycardic heart rhythm disorders (antiarrhythmic), for treating circulatory shock (vasodilatation and increasing the heart volume) as well as for the treatment of skin irritations and inflammation .
  • the active substances X for preparing a pharmaceutical composition also containing one or more, preferably one active substance 2 for the treatment of inflammatory and obstructive respiratory complaints, for inhibiting premature labour in midwifery (tocolysis), for restoring sinus rhythm in the heart in atrioventricular block, for correcting bradycardic heart rhythm disorders (antiarrhythmic), for treating circulatory shock (vasodilatation and increasing the heart volume) as well as for the treatment of skin irritations and inflammation
  • the present invention relates to the use of therapeutically effective amounts of the active substance 1, for preparing a pharmaceutical composition also containing one or more, preferably one, active substance 2 for the treatment of respiratory complaints selected from the group comprising obstructive pulmonary diseases of various origins, pulmonary emphysema of various origins, restrictive pulmonary diseases, interstitial pulmonary diseases, cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary oedema.
  • respiratory complaints selected from the group comprising obstructive pulmonary diseases of various origins, pulmonary emphysema of various origins, restrictive pulmonary diseases, interstitial pulmonary diseases, cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary oedema.
  • the medicament combinations according to the invention are used as specified above for preparing a pharmaceutical composition for the treatment of obstructive pulmonary diseases selected from among bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and COPD (chronic obstructive pulmonary disease), while it is particularly preferable according to the invention to use them for preparing a pharmaceutical composition for the treatment of bronchial asthma and COPD.
  • obstructive pulmonary diseases selected from among bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and COPD (chronic obstructive pulmonary disease)
  • COPD chronic bronchitis
  • medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of pulmonary emphysema which has its origins in COPD (chronic obstructive pulmonary disease) or ⁇ l -proteinase inhibitor deficiency.
  • restrictive pulmonary diseases selected from among allergic alveolitis, restrictive pulmonary diseases triggered by work- related noxious substances, such as asbestosis or silicosis, and restriction caused by lung tumours, such as for example lymphangiosis carcinomatosa, broncho alveolar carcinoma and lymphomas.
  • interstitial pulmonary diseases selected from among pneumonia caused by infections, such as for example infection by viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonitis caused by various factors, such as for example aspiration and left heart insufficiency, radiation- induced pneumonitis or fibrosis, collagenoses, such as for example lupus erythematodes, systemic scleroderaiy or sarcoidosis, granulomatoses, such as for example Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
  • infections such as for example infection by viruses, bacteria, fungi, protozoa, helminths or other pathogens
  • pneumonitis caused by various factors, such as for example aspiration and left heart insufficiency, radiation- induced pneumonitis or fibrosis, collagenoses, such as for example lupus erythematodes, systemic
  • bronchitis such as for example bronchitis caused by bacterial or viral infection, allergic bronchitis and toxic bronchitis.
  • the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of ARDS (adult respiratory distress syndrome). It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of pulmonary oedema, for example toxic pulmonary oedema after aspiration or inhalation of toxic substances and foreign substances.
  • ARDS adult respiratory distress syndrome
  • pulmonary oedema for example toxic pulmonary oedema after aspiration or inhalation of toxic substances and foreign substances.
  • the present invention also relates to the use of therapeutically effective amounts of an active substance of formula 1 in combination with therapeutically effective amounts of active substance 2 for preparing a pharmaceutical composition for the treatment of one of the above-mentioned diseases.
  • the present invention also relates to a process for treating one of the above-mentioned diseases, which is characterised in that therapeutically effective amounts of active substance of fo ⁇ nula 1_ are administered in combination with therapeutically effective amounts of active substance 2.
  • the compounds X and 2 may be administered simultaneously or one after the other; preferably, the compounds i_and 2 are administered simultaneously.
  • the proportions in which the active substances l_and 2 may be used in the active substance combinations according to the invention are variable. Active substances l_and 2 may possibly be present in the form of their solvates or hydrates.
  • the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various salt forms. Therefore the following ratios by weight are based on the cation V_ and the free base of the compound 2 .
  • Tlie active substance combinations according to the invention may contain _T and the free base of the compound of formula 2 in ratios by weight ranging for example from about 1:30 to 400:1, preferably 1 :25 to 200:1, preferably 1:20 to 100:1, particularly preferably from 1:15 to 50:1.
  • preferred combinations of 1. and 2 according to the invention may contain the cation JT and the free base of the compound 2 in the following proportions by weight: 1 :15, 1:14, 1:13, 1 :12, 1 :11, 1 :10, 1:9, 1:8, 1:7, 1:6, 1 :5, 1:4, 1 :3, 1 :2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11 :1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1 , 19:1 , 20:1, 21 :1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31 :1, 32:1, 33:1, 34:1, 35:1.
  • compositions according to the invention containing the combinations of 1 and 2 are normally administered so that the cation T and a compound 2 are present together in doses of 5 to 5000 ⁇ g, preferably from 10 to 2000 ⁇ g, more preferably from 15 to lOOO ⁇ g, even more preferably from 20 to 800 ⁇ g, preferably according to the invention from 30 to 750 ⁇ g, preferably from 40 to 700 ⁇ g, per single dose, these total dosages being based on the free base of compound 2 .
  • combinations of J. and 2 according to the invention contain a quantity of V. and compound of formula 2 such that the total dosage per single dose is about 5 ⁇ g, 10 ⁇ g,15 ⁇ g, 20 ⁇ g, 25 ⁇ g, 30 ⁇ g, 35 ⁇ g, 40 ⁇ g, 45 ⁇ g, 50 ⁇ g, 55 ⁇ g, 60 ⁇ g, 65 ⁇ g, 70 ⁇ g, 75 ⁇ g, 80 ⁇ g, 85 ⁇ g, 90 ⁇ g, 95 ⁇ g, lOO ⁇ g, 105 ⁇ g, HO ⁇ g, 115 ⁇ g, 120 ⁇ g, 125 ⁇ g, 130 ⁇ g, 135 ⁇ g, 140 ⁇ g, 145 ⁇ g, 150 ⁇ g, 155 ⁇ g, 160 ⁇ g, 165 ⁇ g, 170 ⁇ g, 175 ⁇ g, 180 ⁇ g, 185 ⁇ g, 190 ⁇ g, 195 ⁇ g, 200 ⁇ g, 205 ⁇ g, 210 ⁇ g, 215 ⁇ g, 220 ⁇ g, 225 ⁇ g, 230 ⁇ g, 235 ⁇ g, 240 ⁇ g, 245 ⁇
  • the active substance combinations of jl and 2 according to the invention are preferably administered by inhalation.
  • ingredients 1. and 2 have to be made available in forms suitable for inhalation.
  • Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable solutions.
  • Inhalable powders according to the invention containing the combination of active substances 1. and 2 may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients.
  • propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use.
  • the preparations according to the invention may contain the combination of active substances 1 and 2 either together in one formulation or in two separate formulations. These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.
  • the inhalable powders according to the invention may contain .1 and 2 either on their own or in admixture with suitable physiologically acceptable excipients. If the active substances 1_ and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients.
  • mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates .
  • the excipients have a maximum average particle size of up to 250 ⁇ m, preferably between 10 and 150 ⁇ m, most preferably between 15 and 80 ⁇ m. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9 ⁇ m to the excipients mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active substance 1 and 2, preferably with an average particle size of 0.5 to lO ⁇ m, more preferably from 1 to 5 ⁇ m, is added to the excipient mixture.
  • inhalable powders according to the invention by grinding and micronising and lastly mixing the ingredients together are known from the prior art.
  • the inhalable powders according to the invention may be prepared and administered either in the form of a single powder mixture which contains both J. and 2 or in the form of separate inhalable powders which contain only .1 or 2.
  • inhalable powders according to the invention may be administered using inhalers known from the prior art.
  • Inhalable powders according to the invention which contain a physiologically acceptable excipient in addition to 1. and 2 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in US 4570630A, or by other means as described in
  • 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.
  • the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to I and 2 are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.
  • FIG. 1 A particularly preferred inhaler for administering the pharmaceutical combination according to the invention in capsules is shown in Figure 1.
  • This inhaler for inhaling powdered pharmaceutical compositions from capsules is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and a mouthpiece 12 which is connected to the housing I 5 the deck 3 and a cover 1 1 via a spindle 10 to enable it to be flipped open or shut and air holes 13 for adjusting the flow resistance.
  • a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and
  • Inhalation aerosols containing propellant gas according to the invention may contain substances jL and 2 dissolved in the propellant gas or in dispersed form. 1 and 2 may be present in separate formulations or in a single preparation, in which 1 and 2 are either both dissolved, both dispersed or only one component is dissolved and the other is dispersed.
  • the propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art.
  • Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • hydrocarbons such as n-propane, n-butane or isobutane
  • halohydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the propellant gases mentioned above may be used on their own or in mixtures thereof.
  • propellant gases are halogenated alkane derivatives selected from TGl 1, TG12, TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1, 1,2,3,3, 3 ⁇ heptafiuoropropane) and mixtures thereof, the propellant gases TG134a, TG227 and mixtures thereof being preferred.
  • the propel lant-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 j[ and/or 2. If the active substances j[ and/or 2 are present in dispersed fo ⁇ n, the particles of active substance preferably have an average particle size of up to lO ⁇ m, preferably from 0.1 to 6 ⁇ m, more preferably from 1 to 5 ⁇ m.
  • MDIs metered dose inhalers
  • the present invention relates to pharmaceutical compositions in the form of propellant-driven aerosols as hereinbefore described combined with one or more inhalers suitable for administering these aerosols.
  • the present invention relates to inhalers which are characterised in that they contain the propellant gas- containing aerosols described above according to the invention.
  • the present invention also relates to cartridges which are fitted with a suitable valve and can be used in a suitable inhaler and which contain one of the above-mentioned propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges and methods of filling these cartridges with the inhalable aerosols containing propellant gas according to the invention are known from the prior art.
  • Propellant-free inhalable solutions according to the invention contain for example aqueous or alcoholic, preferably ethanolic solvents, possibly ethanolic solvents in admixture with aqueous solvents.
  • aqueous/ethanolic solvent mixtures the relative proportion of ethanol to water is not restricted, but the maximum limit is up to 70 percent by volume, more particularly up to 60 percent by volume of ethanol. The remainder of the volume is made up of water.
  • the solutions or suspensions containing .1 and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids.
  • Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid.
  • Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc.
  • Preferred inorganic acids are hydrochloric acid and sulphuric acid. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred.
  • mixtures of the above acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example.
  • EDTA edetic acid
  • sodium edetate sodium edetate
  • stabiliser or complexing agent may contain this compound or these compounds.
  • the content based on sodium edetate is less than 1 OOmg/100ml, preferably less than 50mg/100 ml, more preferably less than 20mg/ 100 ml.
  • inhalable solutions in which the content of sodium edetate is from 0 to lOmg/lOOml are preferred.
  • Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions according to the invention.
  • Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
  • excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation.
  • these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect.
  • the excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexmg agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art.
  • the additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
  • the preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body.
  • Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.
  • the preservatives mentioned above are preferably present in concentrations of up to 50mg/100ml, more preferably between 5 and 20mg/100ml.
  • Preferred formulations contain, in addition to the solvent water and the combination of active substances l_ and 2, only benzalkonium chloride and sodium edetate. In another preferred embodiment, no sodium edetate is present.
  • the propellant-free inhalable solutions according to the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol 00
  • preferred inhalers are those in which a quantity of less than lOO ⁇ L, preferably less than 50 ⁇ L, more preferably between 10 and 30 ⁇ L of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20 ⁇ m, preferably less than lO ⁇ m, such that the inhalable part of the aerosol corresponds to the therapeutically effective quantity.
  • This nebuliser can advantageously be used to produce the inhalable aerosols according to the invention containing the combination of active substances 1[ and 2.
  • 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®.
  • the invention relates to propellant-free inhalable solutions or suspensions characterised by the combination of active substances 1 and 2 according to the invention in conjunction with the device known by the name Respimat®.
  • the present invention relates to the above-mentioned devices for inhalation, preferably the Respimat®, characterised in that they contain the propellant-free inhalable solutions or suspensions according to the invention as described hereinbefore.
  • inhalable solutions which contain the active substances 1 and 2 in a single preparation are preferred.
  • single preparation also includes preparations which contain the two ingredients 1. and 2 in two-chamber cartridges, as disclosed for example in WO 00/23037. Reference is hereby made to this publication in its entirety.
  • the propellant-free inhalable solutions or suspensions according to the invention may take the form of concentrates or sterile inhalable solutions or suspensions ready for use, as well as the above-mentioned solutions and suspensions designed for use in a Respimat®. Formulations ready for use may be produced from the concentrates, for example, by the
  • Sterile formulations ready for use may be administered using energy-operated fixed or portable nebulisers which produce inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other principles.
  • the present invention relates to pharmaceutical compositions in the form of propellant-free inhalable solutions or suspensions as described hereinbefore which take the form of concentrates or sterile formulations ready for use, combined with a device suitable for administering these solutions, characterised in that the device is an energy-operated free-standing or portable nebuliser which produces inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other methods.

Abstract

The present invention relates to novel pharmaceutical compositions based on a new anticholinergic and a new long-acting beta2~agonist, processes for the preparation thereof and the use thereof in the treatment of respiratory complaints.

Description

NEW LONG-ACTING DRUG COMBINATIONS FOR THE TREATMENT OF
RESPIRATORY DISEASES
The present invention relates to novel pharmaceutical compositions based on a new anticholinergic and a new long-acting beta2-agonist, processes for the preparation thereof and the use thereof in the treatment of respiratory complaints.
Description of the invention
The present invention relates to novel pharmaceutical compositions containing in addition to an anticholinergic of formula 1
Me
wherein
A denotes a group selected from
R and R' denote hydrogen or together a group selected from a single bond,
-CH2- and -O~; 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,
one or more beta2-agonists 2 selected from the group consisting of
.9- 00
optionally in the form of the pharmacologically acceptable acid addition salts, and optionally in the form of the enantiomers, mixtures of enantiomers or racemates, and optionally in the form of the solvates and hydrates thereof, optionally combined with physiologically acceptable excipients.
In preferred combinations according to the invention compounds of formula JL are used, wherein
A denotes a group selected from
R and R' denote hydrogen or together a group selected from a single bond, and -O-;
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.
Preferably the salts of formula 1 are used wherein X" denotes an anion with a single negative charge, selected from the group consisting of chloride, bromide, 4- toluenesulphonate and methanesulphonate , preferably bromide.
Particularly preferably the salts of formula 1_ are used wherein X" denotes an anion with a single negative charge, selected from the group consisting of chloride, bromide and methanesulphonate, preferably bromide.
Particularly preferred according to the invention is the salt of formula I., wherein X" denotes bromide.
Particularly preferred according to the invention are compounds of formula JL, wherein A denotes
\ / C=C H H and wherein R, R1 and X" are as defined hereinbefore. Particularly preferred according to the invention are compounds of formula 1, wherein A denotes
and wherein R, R1 and X" are as defined hereinbefore.
Particularly preferred according to the invention are compounds of formula JL, wherein A denotes
and wherein R, R! and X" are as defined hereinbefore.
Particularly preferred according to the invention are compounds of formula JL1 wherein R and R denote hydrogen and wherein A and X" are as defined hereinbefore.
Particularly preferred according to the invention are compounds of formula 1_, wherein R and R denote a bond and wherein A and X" are as defined hereinbefore.
Particularly preferred according to the invention are compounds of formula 1, wherein R and R1 denote -O- and wherein A and X" are as defined hereinbefore.
The compounds of formula 1 are known from WO 02/32899, WO03/64419, WO03/64418 and WO03/64417.
Particularly preferred according to the invention are compounds of formula 1, selected from the group consisting of tropenol 2,2-diphenylpropionate-methobromide (IJL), scopine 2,2-diphenylproρionate-methobromide (1.2), tropenol 9-methyl-fluorene-9- carboxylate methobromide (1.3), scopine 9-methyl~fluorene-9~carboxylate methobromide (1.4), tropenol 9-methyl-xanthene-9-carboxylate methobromide (1.5), scopine 9-methyl- xanthene-9-carboxylate methobromide (1.6), cyclopropyltropine 2,2-diphenylpropionate methobromide (1.7), cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide (1.8) and cyclopropyltropine 9-methyl~xanthene-9-carboxylate methobromide (1.9), optionally in the form of the solvates and hydrates thereof. 7 054700
Surprisingly, an unexpectedly beneficial therapeutic effect can be observed for instance in the treatment of inflammatory or obstructive diseases of the respiratory tract if the anticholinergic of formula 1. is administered together with the compound of formula 2. In view of this beneficial effect the drug combinations according to the invention can be used in smaller doses than would be the case with the individual compounds used in monotherapy in the usual way, As another positive aspect of the present invention this reduces unwanted side effects such as may occur when betamimetics are administered, for example. Unwanted side effects which deserve special mention in this context are the stimulant effects on the heart which may be caused by betamimetics, particularly tachycardia, a stronger heartbeat, pain resembling angina pectoris as well as arrhythmia. The abovementioned effects are observed both when the two active substances are administered simultaneously in a single active substance formulation and also when the two active substances are administered successively in separate formulations. It is preferred according to the invention to administer the two active substance components simultaneously in a single formulation.
Any reference to the compound 1/ within the scope of the present invention is to be regarded as a reference to the pharmacologically active cation of the following formula contained in the salts 1. :
Me
In the abovementioned drug combinations the active substances may either both be contained in a single formulation or may be contained in two separate formulations. Pharmaceutical compositions which contain the active substances I and 2 in a single formulation are preferred according to the invention. Any reference to the betamimetic 2 includes a reference to the enantiomers (R or S) or the mixtures thereof, the i?~enantiomer of the compound being of particular importance within the scope of the present invention. Process for the enantio selective preparation of the enantiomers of the compound of formula 2 are known in the art. The betamimetic s 2 may also be present according to the invention in the form of its salts, as well as its hydrates or solvates.
Preferred enantiomers and diastereomers of betamimetics 2 that form part of the compositions according to the invention are outlined below:
Examples of novel, preferred medicament combinations according to the invention are containing the compounds Ll and 11; Ll and 12; Ll and 2.3; 1.1 and 14; Ll and 15; Ll and 2,6; Ll and 2,7; Ll and 2,8; L2 and 11; L2 and 12; L2 and 13;J^2 and 2,4; L2 and 15; L2 and 16; L2 and 2/7; L2 and 18; L3 and 11 ; L3 and 12; L3 and 23;_L3 and 14; L3 and 15; L3 and 16j M and 2/7; L3 and 2JS; LJ and 11 ; L4 and 12; L4 and 13; LJ and IA, LJ and 15; L4 and 16; L4 and 17; LJ and 2JJ; L5 and 11; L5 and 12; L5 and 2^3; JL5 and IA, L5 and IS; L5 and 2^6; L5 and 2/7; L5 and 2^; L6 and 2Λ; L6 and 2.2; L6 and 2J;^ and 2j4; L6 and 2^5; L6 and 2;6; L6 and 2/7; L6 and 2_;8; L7 and 2Λ; L7 and 2,2; L7 and 23; JJ and 24; L7 and 2J>; L7 and 16; L7 and 17; L7 and 18; 13. and 11 ; L8 and 12; L8 and 13; JJ and 14; L8 and 15; L8 and 16; L8 and 17; L8 and 18; L9 and 11; L9 and 12; L9 and 13; L9 and 14; L9 and 15; L9 and 16; L9 and 17; and L9 and 18 , in each case optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.
Within the scope of the present invention any reference to the term betamimetics is also to be understood as reference to the term beta2-agonist. A reference to betamimetics 2 includes a reference to the physiologically acceptable acid addition salts thereof. By physiologically acceptable acid addition salts of the betamimetics 2 are meant according to the invention pharmaceutically acceptable salts which include the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1 -hydroxy-2- naphthalenecarboxylic acid or maleic acid. If desired, mixtures of the abovementioned acids may be used to prepare the salts 2. According to the invention the salts of 2 selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate, methanesulphonate, maleate and xinafoate are preferred. In one aspect the present invention relates to the above-mentioned pharmaceutical compositions which contain, in addition to therapeutically effective quantities of 1 and 2, a pharmaceutically acceptable excipient. In another aspect the present invention relates to the above-mentioned pharmaceutical compositions which do not contain any pharmaceutically acceptable excipient in addition to therapeutically effective quantities of I and 2.
The present invention also relates to the use of therapeutically effective amounts of the active substances X for preparing a pharmaceutical composition also containing one or more, preferably one active substance 2 for the treatment of inflammatory and obstructive respiratory complaints, for inhibiting premature labour in midwifery (tocolysis), for restoring sinus rhythm in the heart in atrioventricular block, for correcting bradycardic heart rhythm disorders (antiarrhythmic), for treating circulatory shock (vasodilatation and increasing the heart volume) as well as for the treatment of skin irritations and inflammation .
In a preferred aspect the present invention relates to the use of therapeutically effective amounts of the active substance 1, for preparing a pharmaceutical composition also containing one or more, preferably one, active substance 2 for the treatment of respiratory complaints selected from the group comprising obstructive pulmonary diseases of various origins, pulmonary emphysema of various origins, restrictive pulmonary diseases, interstitial pulmonary diseases, cystic fibrosis, bronchitis of various origins, bronchiectasis, ARDS (adult respiratory distress syndrome) and all forms of pulmonary oedema.
Preferably the medicament combinations according to the invention are used as specified above for preparing a pharmaceutical composition for the treatment of obstructive pulmonary diseases selected from among bronchial asthma, paediatric asthma, severe asthma, acute asthma attacks, chronic bronchitis and COPD (chronic obstructive pulmonary disease), while it is particularly preferable according to the invention to use them for preparing a pharmaceutical composition for the treatment of bronchial asthma and COPD.
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of pulmonary emphysema which has its origins in COPD (chronic obstructive pulmonary disease) or αl -proteinase inhibitor deficiency.
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of restrictive pulmonary diseases selected from among allergic alveolitis, restrictive pulmonary diseases triggered by work- related noxious substances, such as asbestosis or silicosis, and restriction caused by lung tumours, such as for example lymphangiosis carcinomatosa, broncho alveolar carcinoma and lymphomas.
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of interstitial pulmonary diseases selected from among pneumonia caused by infections, such as for example infection by viruses, bacteria, fungi, protozoa, helminths or other pathogens, pneumonitis caused by various factors, such as for example aspiration and left heart insufficiency, radiation- induced pneumonitis or fibrosis, collagenoses, such as for example lupus erythematodes, systemic scleroderaiy or sarcoidosis, granulomatoses, such as for example Boeck's disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF).
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of cystic fibrosis or mucoviscidosis.
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of bronchitis, such as for example bronchitis caused by bacterial or viral infection, allergic bronchitis and toxic bronchitis.
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of bronchiectasis.
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of ARDS (adult respiratory distress syndrome). It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatment of pulmonary oedema, for example toxic pulmonary oedema after aspiration or inhalation of toxic substances and foreign substances.
It is particularly preferable to use the compounds detailed above for preparing a pharmaceutical composition for the treatment of asthma or COPD. Also of particular importance is the above-mentioned use of medicament combinations according to the invention for preparing a pharmaceutical composition for once-a-day treatment of inflammatory and obstructive respiratory complaints, particularly for the once-a-day treatment of asthma or COPD.
The present invention also relates to the use of therapeutically effective amounts of an active substance of formula 1 in combination with therapeutically effective amounts of active substance 2 for preparing a pharmaceutical composition for the treatment of one of the above-mentioned diseases.
The present invention also relates to a process for treating one of the above-mentioned diseases, which is characterised in that therapeutically effective amounts of active substance of foπnula 1_ are administered in combination with therapeutically effective amounts of active substance 2.
Within the scope of the present invention the compounds X and 2 may be administered simultaneously or one after the other; preferably, the compounds i_and 2 are administered simultaneously.
The proportions in which the active substances l_and 2 may be used in the active substance combinations according to the invention are variable. Active substances l_and 2 may possibly be present in the form of their solvates or hydrates. Depending on the choice of the salts l_and 2, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various salt forms. Therefore the following ratios by weight are based on the cation V_ and the free base of the compound 2 . Tlie active substance combinations according to the invention may contain _T and the free base of the compound of formula 2 in ratios by weight ranging for example from about 1:30 to 400:1, preferably 1 :25 to 200:1, preferably 1:20 to 100:1, particularly preferably from 1:15 to 50:1.
For example, without restricting the scope of the invention thereto, preferred combinations of 1. and 2 according to the invention may contain the cation JT and the free base of the compound 2 in the following proportions by weight: 1 :15, 1:14, 1:13, 1 :12, 1 :11, 1 :10, 1:9, 1:8, 1:7, 1:6, 1 :5, 1:4, 1 :3, 1 :2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11 :1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1 , 19:1 , 20:1, 21 :1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31 :1, 32:1, 33:1, 34:1, 35:1.
The pharmaceutical compositions according to the invention containing the combinations of 1 and 2 are normally administered so that the cation T and a compound 2 are present together in doses of 5 to 5000μg, preferably from 10 to 2000μg, more preferably from 15 to lOOOμg, even more preferably from 20 to 800μg, preferably according to the invention from 30 to 750μg, preferably from 40 to 700μg, per single dose, these total dosages being based on the free base of compound 2 .
For example, combinations of J. and 2 according to the invention contain a quantity of V. and compound of formula 2 such that the total dosage per single dose is about 5 μg, 10 μg,15μg, 20μg, 25μg, 30μg, 35μg, 40μg, 45μg, 50μg, 55μg, 60μg, 65μg, 70μg, 75μg, 80μg, 85μg, 90μg, 95μg, lOOμg, 105μg, HOμg, 115μg, 120μg, 125μg, 130μg, 135μg, 140μg, 145μg, 150μg, 155μg, 160μg, 165μg, 170μg, 175μg, 180μg, 185μg, 190μg, 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 260μg, 265μg, 270μg, 275μg, 280μg, 285μg, 290μg, 295μg, 300μg, 3O5μg, 310μg, 315μg, 320μg, 325μg, 330μg, 335μg, 340μg, 345μg, 350μg, 355μg, 360μg, 365μg, 370μg, 375μg, 380μg, 385μg, 390μg, 395μg, 400μg, 405μg, 410μg, 415μg, 420μg, 425μg, 430μg, 435μg, 440μg, 445μg, 450μg, 455μg, 460μg, 465μg, 470μg, 475μg, 480μg, 485μg, 490μg, 495μg, 500μg, 505μg, 510μg, 515μg, 520μg, 525μg, 530μg, 535μg, 540μg, 545μg, 550μg, 555μg, 560μg5 565μg, 570μg, 575μg, 580μg, 585μg, 590μg, 595μg, 600μg, 605μg, 610μg, 615μg, 620μg, 625μg, 630μg, 635μg, 640μg, 645μg, 650μg, 655μg, 660μg, 665μg, 670μg, 675μg, 680μg, 685μg, 690μg, 695 μg, 700μg or the like. Here, too, the dosages specified are based on the content of free base of the compound 2 in the drug combinations according to the invention. It is 007/054700
clear to the skilled man that these proposed dosages per single dose are not to be regarded as being restricted to the numerical values explicitly mentioned. Fluctuations of around ± 2.5 μg , particularly fluctuations in the decimal range, are also covered as will be apparent to anyone skilled in the art. In these dosage ranges the active substances V_ and 2 may be present in the weight ratios described above.
The active substance combinations of jl and 2 according to the invention are preferably administered by inhalation. For this purpose, ingredients 1. and 2 have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable solutions. Inhalable powders according to the invention containing the combination of active substances 1. and 2 may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The preparations according to the invention may contain the combination of active substances 1 and 2 either together in one formulation or in two separate formulations. These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.
A) Inhalable powders containing the combinations according to the invention:
The inhalable powders according to the invention may contain .1 and 2 either on their own or in admixture with suitable physiologically acceptable excipients. If the active substances 1_ and 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates .
Within the scope of the inhalable powders according to the invention the excipients have a maximum average particle size of up to 250μm, preferably between 10 and 150μm, most preferably between 15 and 80μm. It may sometimes seem appropriate to add finer excipient fractions with an average particle size of 1 to 9μm to the excipients mentioned above. These finer excipients are also selected from the group of possible excipients listed hereinbefore. Finally, in order to prepare the inhalable powders according to the invention, micronised active substance 1 and 2, preferably with an average particle size of 0.5 to lOμm, more preferably from 1 to 5μm, is added to the excipient mixture. Processes for producing the inhalable powders according to the invention by grinding and micronising and lastly mixing the ingredients together are known from the prior art. The inhalable powders according to the invention may be prepared and administered either in the form of a single powder mixture which contains both J. and 2 or in the form of separate inhalable powders which contain only .1 or 2.
The inhalable powders according to the invention may be administered using inhalers known from the prior art. Inhalable powders according to the invention which contain a physiologically acceptable excipient in addition to 1. and 2 may be administered, for example, by means of inhalers which deliver a single dose from a supply using a measuring chamber as described in US 4570630A, or by other means as described in
DE 36 25 685 A. The inhalable powders according to the invention which contain ,1 and 2 optionally in conjunction with a physiologically acceptable excipient may be administered, for example, using the inhaler known by the name Turbuhaler® or using inhalers as disclosed for example in EP 237507 A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to I and 2 are packed into capsules (to produce so-called inhalettes) which are used in inhalers as described, for example, in WO 94/28958.
A particularly preferred inhaler for administering the pharmaceutical combination according to the invention in capsules is shown in Figure 1. This inhaler (Handihaler) for inhaling powdered pharmaceutical compositions from capsules is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen 5 secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and a mouthpiece 12 which is connected to the housing I5 the deck 3 and a cover 1 1 via a spindle 10 to enable it to be flipped open or shut and air holes 13 for adjusting the flow resistance. 54700
B) Propellant gas-driven inhalation aerosols containing the combinations according to the invention:
Inhalation aerosols containing propellant gas according to the invention may contain substances jL and 2 dissolved in the propellant gas or in dispersed form. 1 and 2 may be present in separate formulations or in a single preparation, in which 1 and 2 are either both dissolved, both dispersed or only one component is dissolved and the other is dispersed. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are halogenated alkane derivatives selected from TGl 1, TG12, TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1, 1,2,3,3, 3~heptafiuoropropane) and mixtures thereof, the propellant gases TG134a, TG227 and mixtures thereof being preferred.
The propel lant-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 j[ and/or 2. If the active substances j[ and/or 2 are present in dispersed foπn, the particles of active substance preferably have an average particle size of up to lOμm, preferably from 0.1 to 6μm, more preferably from 1 to 5μm.
The prop ellant-dri ven inhalation aerosols according to the invention mentioned above may be administered using inhalers known in the art (MDIs = metered dose inhalers). Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-driven aerosols as hereinbefore described combined with one or more inhalers suitable for administering these aerosols. In addition, the present invention relates to inhalers which are characterised in that they contain the propellant gas- containing aerosols described above according to the invention. The present invention also relates to cartridges which are fitted with a suitable valve and can be used in a suitable inhaler and which contain one of the above-mentioned propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges and methods of filling these cartridges with the inhalable aerosols containing propellant gas according to the invention are known from the prior art.
C) Propellant-free inhalable solutions or suspensions containing the combinations according to the invention:
Propellant-free inhalable solutions according to the invention contain for example aqueous or alcoholic, preferably ethanolic solvents, possibly ethanolic solvents in admixture with aqueous solvents. In the case of aqueous/ethanolic solvent mixtures the relative proportion of ethanol to water is not restricted, but the maximum limit is up to 70 percent by volume, more particularly up to 60 percent by volume of ethanol. The remainder of the volume is made up of water. The solutions or suspensions containing .1 and 2, separately or together, are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric acid and sulphuric acid. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.
According to the invention, the addition of edetic acid (EDTA) or one of the known salts thereof, sodium edetate, as stabiliser or complexing agent is unnecessary in the present formulation. Other embodiments may contain this compound or these compounds. In a preferred embodiment the content based on sodium edetate is less than 1 OOmg/100ml, preferably less than 50mg/100 ml, more preferably less than 20mg/ 100 ml. Generally, inhalable solutions in which the content of sodium edetate is from 0 to lOmg/lOOml are preferred. Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols - particularly isopropyl alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexmg agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents.
The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins and provitamins occurring in the human body.
Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. The preservatives mentioned above are preferably present in concentrations of up to 50mg/100ml, more preferably between 5 and 20mg/100ml.
Preferred formulations contain, in addition to the solvent water and the combination of active substances l_ and 2, only benzalkonium chloride and sodium edetate. In another preferred embodiment, no sodium edetate is present.
The propellant-free inhalable solutions according to the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol 00
suitable for therapeutic inhalation. Within the scope of the present invention, preferred inhalers are those in which a quantity of less than lOOμL, preferably less than 50μL, more preferably between 10 and 30μL of active substance solution can be nebulised in preferably one spray action to form an aerosol with an average particle size of less than 20μm, preferably less than lOμm, such that the inhalable part of the aerosol corresponds to the therapeutically effective quantity.
An apparatus of this kind for propellant-free delivery of a metered quantity of a liquid pharmaceutical composition for inhalation is described for example in International Patent Application WO 91/14468 and also in WO 97/12687 (cf. in particular Figures 6a and 6b). The nebulisers (devices) described therein are known by the name Respimat®.
This nebuliser (Respimat®) can advantageously be used to produce the inhalable aerosols according to the invention containing the combination of active substances 1[ and 2.
Accordingly, in a further aspect, the invention relates to pharmaceutical formulations in the form of propellant-free inhalable solutions or suspensions as described above combined with a device suitable for administering these formulations, preferably in conjunction with the Respimat®. Preferably, the invention relates to propellant-free inhalable solutions or suspensions characterised by the combination of active substances 1 and 2 according to the invention in conjunction with the device known by the name Respimat®. In addition, the present invention relates to the above-mentioned devices for inhalation, preferably the Respimat®, characterised in that they contain the propellant-free inhalable solutions or suspensions according to the invention as described hereinbefore.
According to the invention, inhalable solutions which contain the active substances 1 and 2 in a single preparation are preferred. The term "single preparation" also includes preparations which contain the two ingredients 1. and 2 in two-chamber cartridges, as disclosed for example in WO 00/23037. Reference is hereby made to this publication in its entirety.
The propellant-free inhalable solutions or suspensions according to the invention may take the form of concentrates or sterile inhalable solutions or suspensions ready for use, as well as the above-mentioned solutions and suspensions designed for use in a Respimat®. Formulations ready for use may be produced from the concentrates, for example, by the
47- addition of isotonic saline solutions. Sterile formulations ready for use may be administered using energy-operated fixed or portable nebulisers which produce inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other principles.
Accordingly, in another aspect, the present invention relates to pharmaceutical compositions in the form of propellant-free inhalable solutions or suspensions as described hereinbefore which take the form of concentrates or sterile formulations ready for use, combined with a device suitable for administering these solutions, characterised in that the device is an energy-operated free-standing or portable nebuliser which produces inhalable aerosols by means of ultrasound or compressed air by the Venturi principle or other methods.
The Examples which follow serve to illustrate the present invention in more detail without restricting the scope of the invention. The following examples of formulations may be obtained analogously to methods known in the art.
Examples of formulations
In the following table examples of powder formulations are collected. The amount specified is to be understood as μg per dose. As an example each dose could be placed into a capsules for use with an inhaler according to figure 1.
J) hydrochloric acid addition salt; 2^ maleic acid addition salt; 3^ fumaric acid addition salt; 4) monohydrate;

Claims

Patent Claims
1) Pharmaceutical compositions containing in addition to an anticholinergic of formula 1
Me
wherein
A denotes a group selected from
R and R' denote hydrogen or together a group selected from a single bond, -CH2- and -O- ;
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 ρ-toluenesulρhonate,
one or more beta2-agonists 2 selected from the group consisting of
optionally in the form of the pharmacologically acceptable acid addition salts, and optionally in the form of the enantiomers, mixtures of enantiomers or racemates, and optionally in the form of the solvates and hydrates thereof, optionally combined with physiologically acceptable excipients. 2) Pharmaceutical composition according to claim 1, wherein in the compound of formula 1
A denotes a group selected from
R and R1 denote hydrogen or together a group selected from a single bond, and -O- ;
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.
3) Pharmaceutical composition according to claim 1 or 2, wherein in the compound of formula 1 A denotes
\ / C=C H H
4) Pharmaceutical composition according to claim 1 or 2, wherein in the compound of formula 1, A denotes
5) Pharmaceutical composition according to claim 1 or 2, wherein in the compound of formula 1 A denotes
6) Pharmaceutical composition according to one of claims 1 to 5, characterised in that the active substances 1 and 2 are either present in a single formulation or are contained in two separate formulations. 7) Pharmaceutical composition according to one of claims 1 to 6, characterised in that the compound 2 is present in the form of the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, l-hydroxy-2-naphthalenecarboxylic acid or nialeic acid.
8) Pharmaceutical composition according to one of claims 1 to 7, characterised in that the compound 2 is present in the form of its R-enantiomer.
9) Pharmaceutical composition according to one of claims 1 to 4, characterised in that the ratios by weight of V_
Me
to 2 (based on the free base) are in the range from about 1 :30 to 400:1, preferably 1 :25 to 200:1.
10) Pharmaceutical composition according to one of claims 1 to 9, characterised in that it is a preparation selected from among inhalable powders, propellant-driven metered dose aerosols and propellant-free inhalable solutions.
11) Pharmaceutical composition according to claim 10, characterised in that it is an inhalable powder which contains 1 and 2 in admixture with suitable physiologically acceptable excipients selected from among monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts, or mixtures of these excipients with one another. 12) Pharmaceutical composition according to claim 10, characterised in that it is a propellant-containing inhalable aerosol which contains 1. and 2 in dissolved or dispersed form.
13) Pharmaceutical composition according to claim 10, characterised in that it is a propellant-free inhalable solution which contains water, ethanol or a mixture of water and ethanol as solvent.
14) Use of a composition according to one of claims 1 to 13 for preparing a drug for treating inflammatory or obstructive diseases of the respiratory tract, particularly asthma or COPD.
EP07729151A 2006-05-24 2007-05-15 New long-acting drug combinations for the treatment of respiratory diseases Withdrawn EP2029127A1 (en)

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DK2400950T3 (en) 2009-02-26 2019-07-29 Glaxo Group Ltd PHARMACEUTICAL FORMULA comprising 4 - {(1 R) -2 - [(6- {2 - [(2,6-DICHLORBENZYL) OXY] ETHOXY} HEXYL) AMINO] -1-HYDROXYETHYL} -2- (HYDROXYMETHYL) PHENOL
GB0921075D0 (en) 2009-12-01 2010-01-13 Glaxo Group Ltd Novel combination of the therapeutic agents

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US20050025718A1 (en) * 2003-07-31 2005-02-03 Boehringer Ingelheim International Gmbh Medicaments for inhalation comprising an anticholinergic and a betamimetic
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