CA2650813A1 - New long-acting drug combinations for the treatment of respiratory diseases - Google Patents
New long-acting drug combinations for the treatment of respiratory diseases Download PDFInfo
- Publication number
- CA2650813A1 CA2650813A1 CA002650813A CA2650813A CA2650813A1 CA 2650813 A1 CA2650813 A1 CA 2650813A1 CA 002650813 A CA002650813 A CA 002650813A CA 2650813 A CA2650813 A CA 2650813A CA 2650813 A1 CA2650813 A1 CA 2650813A1
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- Prior art keywords
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- pharmaceutical composition
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- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
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- 239000001273 butane Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- YMKDRGPMQRFJGP-UHFFFAOYSA-M cetylpyridinium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+]1=CC=CC=C1 YMKDRGPMQRFJGP-UHFFFAOYSA-M 0.000 description 1
- 229960001927 cetylpyridinium chloride Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000005796 circulatory shock Effects 0.000 description 1
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- 230000007812 deficiency Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
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- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
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- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
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- 238000002560 therapeutic procedure Methods 0.000 description 1
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- 235000019149 tocopherols Nutrition 0.000 description 1
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- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 1
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
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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 Iong-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 phannaceutical compositions containing in addition to an anticholinergic of formula 1 Me\+/Me X -N
H
A
Me \ I \ ~
R R' 1 wherein A denotes a group selected from H H' H=H and H O H
R and R' denote hydrogen or together a group selected from a single bond, -CH2- and -0-;
X" denotes an anion with a single negative charge, preferably an aruon 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 DH
y OH
H
HN )Cj')~ ~l HO
H
OH
OH
HN N OMe HO N \ \
H
OH
HN N H \ I
H
HO
OH
H
HN N I\ / O NHz HO N
H ~)a OH O
HO \ H O \ NNH2 H
HO
CI
H
HO
CI
HO (2,()?
OH
HO N 0 \ SO2NH2 HO 2.7,and OH HO \ ~ o \ soZ
HO
_~_ optionally in the fon-n 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 1 are used, wherein A denotes a group selected from ~ _ H H H~H and H O H
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 forniula 1 are used wherein X- denotes an anion with a single negative charge, selected from the group consisting of chloride, bromide and inethanesulphonate, preferably bromide.
Particularly preferred according to the invention is the salt of formula 1, wherein X"
denotes bromide.
Particularly preferred according to the inveiltion are compounds of fornmula 1, wherein A
deiiotes C-C
H H
and wlicrein R, R' and X" are as defined hereinbefore.
Particularly preferred according to the invention are compounds of formula 11 wherein A
denotes H p H
and wherein R, Rl and X- are as defined hereinbefore.
Particularly preferred according to the invention are compounds of formula 1, wherein A
denotes H XH
aiid whereii-i R, R' and X- are as defined hereinbefore.
Particularly preferred according to the iuivention are compounds of formula l., wherein R
and R denote hydrogen and wherein A and X- are as defined hereinbefore.
Particularly preferred according to the invention are coinpounds 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 forniula 1, wherein R
and R' denote -0- and wherein A and X- are as defined hereinbefore.
The compowlds of formula 1 are known from WO 02/32899, W003/64419, W003/64418 and W003/64417.
Particularly preferred according to the invention are compounds of forinula 1, selected from the group consisting of tropenol 2,2-diphenylpropionate-methobromide l.i , scopine 2,2-diphenylpropionate-methobromide (1.2), tropenol 9-nlethyl-fluorene-carboxylate methobromide (1.3), scopine 9-methyl-fluorene-9-carboxylate methobromide (1.4), tropenol9-methyl-xanthene-9-carboxylate methobromide i.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 fonn of thc solvates and hydrates thereof.
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 cil=ug 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 wllich deserve special mention in this context are the stimulant effects on the heart which may be caused by betainimetics, particularly tachycardia, a stronger heartbeat, pain resembling angina pectoris as well as arrhytlun.ia.
The abovementioned effects are observed both when the two active substances are administered simultaneously in a single active substance foi-mulation 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 fornulation.
Any reference to the compound V 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:
Mef Me -N x H
A
Me R R' In the aboveinentioned drug combinations the active substances may eitller both be contained in a single formulation or may be contained in two separate forinulations.
Pharmaceufiical compositions which contain the active substances I and 2 in a single formulation are preferred according to the invention.
Any reference to the betamilnetic 2 includes a reference to the enantiomers (R
or S) or the mixtures tliereof, the R-enantiomer of the compound being of particular importance within the scope of the present invention. Process for the enantioselective preparation of the enantiomers of the compound of formula 2 are known in the art. The betaniimetics 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:
OH
y OH
HN N / I
HO / N \
H
OH O \ OH
H
HN N OMe Ho N \ \
/
H o OH / , HN N N \
H
HO
O
II-z OH
HN \ \ / O~
NHz HO N \
H
OH H ~
HO I\ N O \ ~ JNHZ
HO
OH CI
HO I\ N '-'O
CI
Ho 6 OH I
HO OH
HO I ~ O \ soz HO ~)=
Examples of novel, preferred medicament combinations according to the invention are containing the compounds 1. 1 and 2`1; 1. 1 and 2_2; l_l and 2.3; 1. 1 and 2.4; 1. 1 and 2.5;
1.1 and 2.6; 1.1 and 2.7; 1.1 and 2,8; 1.2 and 2.1; L.2 and 2.2; 1.2 and 2.3;
11 and 2.4; 1_2 and 2.5; 1.2 and 2.6; 1_2 and 2.7; 1.2 and 2.8; 1.3 and 2_I; 1.3 and 2.2; 1.3 and 2.3; 1.3 and L4; 1.3 and 2.5; 1.3 and 2.6; 1_3 and 2.7; 1.3 and 2.8; 1.4 and 2.1; 1.4 and 2.2; 1.4 and 2,3;
1.4 and 2.4; 1.4 and 2.5; 1.4 and 2.6; 1.4 and 2.7; 1,4 and 2.8; M and 2.1;
1.5 aiid 2.2; 1.5 and 2.3; 1.5 and 2.4; 1.5 and 2.5; 1.5 and 2_6; 1.5 and 2_7; 1.5 and 2.8; 1.6 and 2.1; 1.6 and 2.2; L.6 and 2.3; 1~6 and 2.4; 1.6 and 2.5; L6 and 2.6; 1.6 and 2=7; 1.6 and 2.8; 1.7 and 2.1;
1.7 and 2.2; 1.7 and 2_3; 1.7 and 2.4; 1.7 and 2.5; 1.7 and 2.6; 1.7 and 2.7;1_7 and 2.8; 1.8 and 2.1; 1_8 and 2.2; 1.8 and 2.3; 1.8 and 2.4; 1.8 and 2.5; 1.8 and 2.6; 1.8 and 2.7; 1.8 and 2.8; 1~9 and 2.1; 1.9 and 2.2; 1.9 and 2.3; 1~9 and 2.4; 1.9 and 2.5; 1.9 and 2.6; L.9 and 2.7;
and 1.9 and 2.8 , in each case optionally in the form of the raceinates, enantiomers or diastereomers thereof and optionally in the forin of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.
Within the scope of the present invention any reference to tlie term betami.metics 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, methaiiesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid or inaleic acid. If desired, mixtures of the abovementioned acids may be used to prepare the salts 2. Accordiiig to the invention the salts of 2 selected from among the hydrochloride, hydrobroiiiide, sulphate, phosphate, fumarate, methanesulphonate, maleate and xinafoate are preferred.
I.n 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, hi another aspect the present invention relates to the above-mentioned pharmaceutical compositions which do not contain any phannaceutically acceptable excipient in addition to therapeutically effective quantities of Iand2.
The present invention also relates to the use of therapeutically effective amounts of the active substances 1 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 rhytlun 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 irritatioris and inflamnlation .
In a preferred aspect the present invention relates to the use of therapeutically effective amounts of the active substance 1 for preparirig a pharmaceutical composition also containing one or more, preferably one, active substance 2 for the treatment of respiratory complaints selected fxom 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 foi-ins 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 astluna, paediatric astlu-na, severe asthma, acute astluna attacks, chronic broncliitis 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 astluna and COPD.
It is also preferable to use the medicarnent 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 a 1-proteinase inhibitor deficiency.
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for tlle 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, bronchoalveolar carcinoma and lymphomas.
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatinent of interstitial pulmonary diseases selected from among pneumonia caused by infections, such as for example infection by viruses, bacteria, fungi, protozoa, helmintlis or other pathogens, pneumonitis caused by various factors, such as for example aspiration and left heal-t insufficiency, radiation-induced pneunionitis or fibrosis, collagenoses, such as for exalnple lupus erythematodes, systemic sclerodermy or sarcoidosis, granuloinatoses, 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 exaniple 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 compowlds detailed above for preparing a pharinace-Litical composition for the treatment of asthma or COPD. Also of particular importance is the above-mentioned use of inedicament 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 treatinent of astluna 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 pharmaccutical cainposition 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 anlounts of active substaiice of fonnula I are administered in combination with therapeutically effective amounts of active substance 2.
Within the scope of the present invention the compounds 1 and 2 may be administered simultaneously or one after the other; preferably, the compounds 1 and 2 are administered simultaneously.
The propoi-tions in which the active substances I and 2may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2 may possibly be present in the form of their solvates or llydrates. Depending on the choice of the salts 1 and 2, the weight ratios wliich 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 1' and the free base of the compound 2.
The active substance combinations according to the invention may contain 1' and the free base of the coinpound 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 1' 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 1' 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 1000 g, even more preferably from 20 to 800 g, preferably according to the invention from 30 to 750lig, preferably from 40 to 700p.g, per single dose, these total dosages being based on the free base of compound 2.
For example, combinations of 1 and 2 according to the invention con.tain a quantity of 1' and compound of formula 2 such that the total dosage per single dose is about 5Vg, 10 pg,15Fig, 20 g, 25}Lg, 30 g, 35g.g, 40p.g, 45g.g, 50~tg, 55 g, 60~Lg, 65~ig, 70 g, 75 g, 801Lg, 85p.g, 90 g, 95 g, 100 g, 105p.g, 110 g, 115 g, 120pg, 125p.g, 130 g, 135 g, 140 g, 145 g, 150~ig, 155}tg, 160pg, 165 g, 170 g, 175 g, 180 g, 185~Lg, 190 g, 195p.g, 200~Lg, 205g.g, 210 g, 215 g, 220~ig, 225 g, 230 g, 235 g, 240 g, 245p.g, 250p.g, 255p.g, 260}rg, 265~Lg, 270~Lg, 275~Lg, 280~Lg, 285 g, 290 g, 295 .g, 300g.g, 305 g, 310 g, 315 g, 320ug, 325~Lg, 330gg, 335p.g, 340p.g, 3451Ãg, 350lZg, 355p.g, 360 g, 365Rg, 370p.g, 375 g, 380 g, 385 g, 390 g, 395 g, 400 g, 405~Lg, 410 g, 415p.g, 420pg, 425}tg, 430 g, 435 g, 440p.g, 445p,g, 450~Lg, 455 g, 460p,g, 465p.g, 470 g, 475 g, 480 g, 485g.g, 490 g, 495}Lg, 500~Ãg, 505~Lg, 510~Lg, 515 g, 520g.g, 525pg, 530[tg, 535p.g, 540 g, 545gg, 550 g, 555 g, 560 g, 565 g, 570 g, 575 g, 580[tg, 585g.g, 590~.g, 595~g, 600~.g, 605 g, 610 g, 615lag, 620~g, 625~Lg, 630Vg, 635}rg, 640 g, 645 g, 650~Lg, 655 g, 660p.g, 665g.g, 670~Lg, 675[Lg, 680 g, 685g.g, 690[ig, 695 g, 700 g 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 clear to the skilled man that these proposed dosages per single dose are not to be regarded as being restricted to the nuinerical values explicitly mentioned.
Fluctuations of around ~h 2.5p.g , 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 1' and 2 may be present in the weight ratios described above.
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. hlhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-Free inhalable solutions.
Inhalable powders according to the invention containhlg the combinatioii of active substances 1 and 2 may coiisist 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 iuivention, the term propellant-free inhalable solutions also includes concentrates or sterile iiihalable 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) lnlialable powders containing the combinations according to the invention:
The iiAialable powders according to the invention may contain 1 and 2 eitlier 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 cl-iloride, 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 iaivention the excipients have a maxinrum average particle size of up to 250 m, preferably between 10 and 150p.m, most preferably between 15 and SO~Lm. It may sometimes seem appropriate to add finer excipient fi=actions with an average particle size of I 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 10p.m, more preferably from I to 51im, 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 forzn of a single powder mixture which contains both 1 and 2 or in the forni of separate inhalable powders which contain only 1 or 2.
The inlialable powders according to the invention may be administered using inhalers klZown 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 n-ieans 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 inllalable powders according to the invention whieh contain 1 and 2 optionally in conjruiction with a physiologically acceptable excipient may be administered, for example, using the inhaler known by the name Turbuhaler or using inhalers as disclosed for example in EP 237507 A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to 1 and 2 are packed into capsules (to prodtice so-called inhalettes) which are used in inhalers as described, for exasnple, 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 iiilialer (I-landihaler) for ir-Alaling 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 chainber 6 comiected to the deck 3 on wliich 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 coiuiected to the housing 1, the deck 3 and a cover 1 I via a spindle 10 to enable it to be flipped open or shut and air holes 13 for adjusting the flow resistance.
B) Propellant gas-driven inhalation aerosols containing the combinations according to the invention:
Inlialatian aerosols containing propellant gas according to the invention may contain substances 1 and 2 dissolved in the propellant gas or in dispersed form. 1 and 2 may be present in separate formulations or in a single preparation, in which 1 and 2 are either both dissolved, both dispersed or only one component is dissolved and the other is dispersed.
The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably chlorinated and fluorinated derivatives of inethane, 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), (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof, the propellant gases TG134a, TG227 and mixtures thereof being preferred.
The propellailt-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.- /fl 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 active substance preferably have an average particle size of up to 10pm, preferably from 0.1 to 6 in, more preferably from 1 to 5~Lm.
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 pharrnaceutical 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 itAialers which are characterised in that they contain the propellant gas-containing aerosols described above according to the invention. The preseirt 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 inlialable solutions or suspensions containing the combinations according to the invention:
Propellant-free inlialable solutions according to the invention contain for exaniple 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 maximuzn 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. Exainples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fun-iaric acid, acetic acid, formic acid and/or propionic acid etc. Prefei7'ed inorganic acids are hydrochloric acid and sulphuric acid. It is also possible to use the acids which have already formed an acid addition salt witli one of the active substances. Of the organic acids, ascorbic acid, fi.unaric 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 100mg/t OOml, 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 10mg/I
OOml 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 otller 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 wliich 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 fonnulation. Preferably, tllese substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitarnins andlor other additives known in the art.
The additives also include pharinacologically 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 patllogens.
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/100m1, 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 edetate. In another preferred embodirnent, no sodium edetate is present.
The propellant-fi=ee inlialable solutions according to the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred inhalers are those in which a quantity of less than 100 L, preferably less than 50~EL, more preferably between 10 and 30 L of active substance solution can be nebulised in preferably one spray action to fomi an aerosol with an average pai-ticle size of less than 20pIn, preferably less than 10pIn, 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 pharnlaceutical composition for inhalation is described for example in International Patent Application WO 91/14468 aiid also in WO 97/12687 (cf. in particular Figures 6a and 6b).
The nebulisers (devices) described therein are known by the name Respinzat .
This nebuliser (Respimat ) can advantageously be used to produce the ilihalable aerosols according to the invention containing the combination of active substances 1.
and 2.
Accordingly, in a further aspect, the invention relates to phai-Inaceutical formulations in the form of propellant-free inhalable solutiolis or suspensions as described above combined with a device suitable for administering these formulations, preferably in conjunction with the Respilnatg. Preferably, the invention relates to propellant-free inhalable solutions or suspensions characterised by the colnbination of active substances 1 and 2 according to the invention in conjtimction with the device known by the name Respimat . In addition, the present invention relates to the above-mentioned devices for inllalation, preferably the Respiniat , characterised in that they contain the propellant-free inlZ alable 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 terln "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 publicatioii 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 Respiinate.
Formulations ready for use may be produced from the concentrates, for example, by the addition of isotonic saline solutions. Sterile formulations ready for use may be administered using energy-operated fixed or portable nebulisers which produce inhalable aerosols 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 wliich take the form of concentrates or sterile forinulations 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.
-IB-Examples of formulations In the following table examples of powder formulations are collected. The amount specified is to be understood as g per dose. As an example each dose could be placed into a capsules for use with an inhaler according to figure 1.
active amount active amount excipient amount total 1 [ttgl 2 1 1.1 200 2.11) 25 lactose 4) 24775 12500 2 1.1 100 2.0 25 lactose 4) 12375 12500 3 1.1 200 2.21) 25 lactose 4) 24775 25000 4 1.1 100 2.117 25 lactose 4) 12375 12500 5 1.2 50 2.4') 40 lactose 4) 12410 12500 6 1.2 100 2.63) 50 lactose 4) 12350 12500 7 1.2 100 2.31) 25 lactose 4) 12375 12500 8 1.2 200 2.82) 40 lactose 47 24760 25000 9 1.3 200 2.11) 25 lactose 4) 24775 25000 1.3 200 2.73) 25 lactose 4) 24775 25000 11 1.3 100 2.0 25 lactose 4} 12375 12500 12 1.3 50 2.5'j 25 lactose 4) 12425 12500 13 1.3 200 2.117 30 lactose 4) 24770 25000 14 1.4 100 2.63) 25 lactose 4) 12375 12500 1.4 200 2.0 25 lactose 4) 24775 25000 16 1.4 100 2.4'7 40 lactose 4) 12360 12500 17 1.4 50 2.0 25 lactose 4) 12425 12500 18 1.4 200 2.41) 20 lactose 4) 24780 25000 19 1.5 200 2.3E) 25 lactose 4) 24775 25000 1.5 200 2.21) 25 lactose 4) 24775 25000 21 1.5 100 2.21} 25 lactose 4) 12375 12500 22 1.5 200 2.5s) 40 lactose 4) 24760 25000 23 1.6 100 2.8') 25 glucose 12375 12500 24 1.6 50 2.82) 50 lactose 4) 12400 12500 1.6 200 2J) 25 lactose 4) 24775 25000 26 1.6 200 2.11} 25 lactose 4) 24775 25000 27 1.6 200 2.41) 25 lactose 4) 24775 25000 28 1.7 200 2.11) 25 glucose 24775 25000 29 1.7 200 2.51) 30 lactose 4) 24770 25000 30 1.7 200 2.11} 25 lactose 4) 24775 25000 31 1.7 100 2.31) 40 glucose 12360 12500 32 1.7 200 2.4E) 25 lactose 4) 24775 25000 33 L8 100 2.0 25 glucose 12375 12500 34 1.8 50 2.2') 25 lactose 4) 12425 12500 35 1.8 200 2.31) 25 lactose 4) 24775 25000 36 1.8 100 2.73) 25 glucose 12375 12500 37 1.8 200 2.82) 25 lactose 4) 24775 25000 38 1.9 100 2,73) 25 lactose 4) 12375 12500 39 1.9 100 2.0 25 glucose 12375 12500 40 1.9 100 2.631 25 lactose 4) 12375 12500 41 1.9 200 2.0 25 lactose 4) 24775 25000 42 1.9 100 2.41) 25 lactose 4} 12375 12500 l) hydrochloric acid addition salt; 2) maleic acid addition salt; 3) fumaric acid addition salt;
4} moiiohydrate;
RESPIRATORY DISEASES
The present invention relates to novel pharmaceutical compositions based on a new anticholinergic and a new Iong-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 phannaceutical compositions containing in addition to an anticholinergic of formula 1 Me\+/Me X -N
H
A
Me \ I \ ~
R R' 1 wherein A denotes a group selected from H H' H=H and H O H
R and R' denote hydrogen or together a group selected from a single bond, -CH2- and -0-;
X" denotes an anion with a single negative charge, preferably an aruon 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 DH
y OH
H
HN )Cj')~ ~l HO
H
OH
OH
HN N OMe HO N \ \
H
OH
HN N H \ I
H
HO
OH
H
HN N I\ / O NHz HO N
H ~)a OH O
HO \ H O \ NNH2 H
HO
CI
H
HO
CI
HO (2,()?
OH
HO N 0 \ SO2NH2 HO 2.7,and OH HO \ ~ o \ soZ
HO
_~_ optionally in the fon-n 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 1 are used, wherein A denotes a group selected from ~ _ H H H~H and H O H
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 forniula 1 are used wherein X- denotes an anion with a single negative charge, selected from the group consisting of chloride, bromide and inethanesulphonate, preferably bromide.
Particularly preferred according to the invention is the salt of formula 1, wherein X"
denotes bromide.
Particularly preferred according to the inveiltion are compounds of fornmula 1, wherein A
deiiotes C-C
H H
and wlicrein R, R' and X" are as defined hereinbefore.
Particularly preferred according to the invention are compounds of formula 11 wherein A
denotes H p H
and wherein R, Rl and X- are as defined hereinbefore.
Particularly preferred according to the invention are compounds of formula 1, wherein A
denotes H XH
aiid whereii-i R, R' and X- are as defined hereinbefore.
Particularly preferred according to the iuivention are compounds of formula l., wherein R
and R denote hydrogen and wherein A and X- are as defined hereinbefore.
Particularly preferred according to the invention are coinpounds 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 forniula 1, wherein R
and R' denote -0- and wherein A and X- are as defined hereinbefore.
The compowlds of formula 1 are known from WO 02/32899, W003/64419, W003/64418 and W003/64417.
Particularly preferred according to the invention are compounds of forinula 1, selected from the group consisting of tropenol 2,2-diphenylpropionate-methobromide l.i , scopine 2,2-diphenylpropionate-methobromide (1.2), tropenol 9-nlethyl-fluorene-carboxylate methobromide (1.3), scopine 9-methyl-fluorene-9-carboxylate methobromide (1.4), tropenol9-methyl-xanthene-9-carboxylate methobromide i.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 fonn of thc solvates and hydrates thereof.
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 cil=ug 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 wllich deserve special mention in this context are the stimulant effects on the heart which may be caused by betainimetics, particularly tachycardia, a stronger heartbeat, pain resembling angina pectoris as well as arrhytlun.ia.
The abovementioned effects are observed both when the two active substances are administered simultaneously in a single active substance foi-mulation 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 fornulation.
Any reference to the compound V 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:
Mef Me -N x H
A
Me R R' In the aboveinentioned drug combinations the active substances may eitller both be contained in a single formulation or may be contained in two separate forinulations.
Pharmaceufiical compositions which contain the active substances I and 2 in a single formulation are preferred according to the invention.
Any reference to the betamilnetic 2 includes a reference to the enantiomers (R
or S) or the mixtures tliereof, the R-enantiomer of the compound being of particular importance within the scope of the present invention. Process for the enantioselective preparation of the enantiomers of the compound of formula 2 are known in the art. The betaniimetics 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:
OH
y OH
HN N / I
HO / N \
H
OH O \ OH
H
HN N OMe Ho N \ \
/
H o OH / , HN N N \
H
HO
O
II-z OH
HN \ \ / O~
NHz HO N \
H
OH H ~
HO I\ N O \ ~ JNHZ
HO
OH CI
HO I\ N '-'O
CI
Ho 6 OH I
HO OH
HO I ~ O \ soz HO ~)=
Examples of novel, preferred medicament combinations according to the invention are containing the compounds 1. 1 and 2`1; 1. 1 and 2_2; l_l and 2.3; 1. 1 and 2.4; 1. 1 and 2.5;
1.1 and 2.6; 1.1 and 2.7; 1.1 and 2,8; 1.2 and 2.1; L.2 and 2.2; 1.2 and 2.3;
11 and 2.4; 1_2 and 2.5; 1.2 and 2.6; 1_2 and 2.7; 1.2 and 2.8; 1.3 and 2_I; 1.3 and 2.2; 1.3 and 2.3; 1.3 and L4; 1.3 and 2.5; 1.3 and 2.6; 1_3 and 2.7; 1.3 and 2.8; 1.4 and 2.1; 1.4 and 2.2; 1.4 and 2,3;
1.4 and 2.4; 1.4 and 2.5; 1.4 and 2.6; 1.4 and 2.7; 1,4 and 2.8; M and 2.1;
1.5 aiid 2.2; 1.5 and 2.3; 1.5 and 2.4; 1.5 and 2.5; 1.5 and 2_6; 1.5 and 2_7; 1.5 and 2.8; 1.6 and 2.1; 1.6 and 2.2; L.6 and 2.3; 1~6 and 2.4; 1.6 and 2.5; L6 and 2.6; 1.6 and 2=7; 1.6 and 2.8; 1.7 and 2.1;
1.7 and 2.2; 1.7 and 2_3; 1.7 and 2.4; 1.7 and 2.5; 1.7 and 2.6; 1.7 and 2.7;1_7 and 2.8; 1.8 and 2.1; 1_8 and 2.2; 1.8 and 2.3; 1.8 and 2.4; 1.8 and 2.5; 1.8 and 2.6; 1.8 and 2.7; 1.8 and 2.8; 1~9 and 2.1; 1.9 and 2.2; 1.9 and 2.3; 1~9 and 2.4; 1.9 and 2.5; 1.9 and 2.6; L.9 and 2.7;
and 1.9 and 2.8 , in each case optionally in the form of the raceinates, enantiomers or diastereomers thereof and optionally in the forin of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.
Within the scope of the present invention any reference to tlie term betami.metics 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, methaiiesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid or inaleic acid. If desired, mixtures of the abovementioned acids may be used to prepare the salts 2. Accordiiig to the invention the salts of 2 selected from among the hydrochloride, hydrobroiiiide, sulphate, phosphate, fumarate, methanesulphonate, maleate and xinafoate are preferred.
I.n 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, hi another aspect the present invention relates to the above-mentioned pharmaceutical compositions which do not contain any phannaceutically acceptable excipient in addition to therapeutically effective quantities of Iand2.
The present invention also relates to the use of therapeutically effective amounts of the active substances 1 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 rhytlun 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 irritatioris and inflamnlation .
In a preferred aspect the present invention relates to the use of therapeutically effective amounts of the active substance 1 for preparirig a pharmaceutical composition also containing one or more, preferably one, active substance 2 for the treatment of respiratory complaints selected fxom 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 foi-ins 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 astluna, paediatric astlu-na, severe asthma, acute astluna attacks, chronic broncliitis 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 astluna and COPD.
It is also preferable to use the medicarnent 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 a 1-proteinase inhibitor deficiency.
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for tlle 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, bronchoalveolar carcinoma and lymphomas.
It is also preferable to use the medicament combinations according to the invention for preparing a pharmaceutical composition for the treatinent of interstitial pulmonary diseases selected from among pneumonia caused by infections, such as for example infection by viruses, bacteria, fungi, protozoa, helmintlis or other pathogens, pneumonitis caused by various factors, such as for example aspiration and left heal-t insufficiency, radiation-induced pneunionitis or fibrosis, collagenoses, such as for exalnple lupus erythematodes, systemic sclerodermy or sarcoidosis, granuloinatoses, 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 exaniple 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 compowlds detailed above for preparing a pharinace-Litical composition for the treatment of asthma or COPD. Also of particular importance is the above-mentioned use of inedicament 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 treatinent of astluna 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 pharmaccutical cainposition 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 anlounts of active substaiice of fonnula I are administered in combination with therapeutically effective amounts of active substance 2.
Within the scope of the present invention the compounds 1 and 2 may be administered simultaneously or one after the other; preferably, the compounds 1 and 2 are administered simultaneously.
The propoi-tions in which the active substances I and 2may be used in the active substance combinations according to the invention are variable. Active substances 1 and 2 may possibly be present in the form of their solvates or llydrates. Depending on the choice of the salts 1 and 2, the weight ratios wliich 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 1' and the free base of the compound 2.
The active substance combinations according to the invention may contain 1' and the free base of the coinpound 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 1' 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 1' 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 1000 g, even more preferably from 20 to 800 g, preferably according to the invention from 30 to 750lig, preferably from 40 to 700p.g, per single dose, these total dosages being based on the free base of compound 2.
For example, combinations of 1 and 2 according to the invention con.tain a quantity of 1' and compound of formula 2 such that the total dosage per single dose is about 5Vg, 10 pg,15Fig, 20 g, 25}Lg, 30 g, 35g.g, 40p.g, 45g.g, 50~tg, 55 g, 60~Lg, 65~ig, 70 g, 75 g, 801Lg, 85p.g, 90 g, 95 g, 100 g, 105p.g, 110 g, 115 g, 120pg, 125p.g, 130 g, 135 g, 140 g, 145 g, 150~ig, 155}tg, 160pg, 165 g, 170 g, 175 g, 180 g, 185~Lg, 190 g, 195p.g, 200~Lg, 205g.g, 210 g, 215 g, 220~ig, 225 g, 230 g, 235 g, 240 g, 245p.g, 250p.g, 255p.g, 260}rg, 265~Lg, 270~Lg, 275~Lg, 280~Lg, 285 g, 290 g, 295 .g, 300g.g, 305 g, 310 g, 315 g, 320ug, 325~Lg, 330gg, 335p.g, 340p.g, 3451Ãg, 350lZg, 355p.g, 360 g, 365Rg, 370p.g, 375 g, 380 g, 385 g, 390 g, 395 g, 400 g, 405~Lg, 410 g, 415p.g, 420pg, 425}tg, 430 g, 435 g, 440p.g, 445p,g, 450~Lg, 455 g, 460p,g, 465p.g, 470 g, 475 g, 480 g, 485g.g, 490 g, 495}Lg, 500~Ãg, 505~Lg, 510~Lg, 515 g, 520g.g, 525pg, 530[tg, 535p.g, 540 g, 545gg, 550 g, 555 g, 560 g, 565 g, 570 g, 575 g, 580[tg, 585g.g, 590~.g, 595~g, 600~.g, 605 g, 610 g, 615lag, 620~g, 625~Lg, 630Vg, 635}rg, 640 g, 645 g, 650~Lg, 655 g, 660p.g, 665g.g, 670~Lg, 675[Lg, 680 g, 685g.g, 690[ig, 695 g, 700 g 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 clear to the skilled man that these proposed dosages per single dose are not to be regarded as being restricted to the nuinerical values explicitly mentioned.
Fluctuations of around ~h 2.5p.g , 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 1' and 2 may be present in the weight ratios described above.
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. hlhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-Free inhalable solutions.
Inhalable powders according to the invention containhlg the combinatioii of active substances 1 and 2 may coiisist 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 iuivention, the term propellant-free inhalable solutions also includes concentrates or sterile iiihalable 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) lnlialable powders containing the combinations according to the invention:
The iiAialable powders according to the invention may contain 1 and 2 eitlier 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 cl-iloride, 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 iaivention the excipients have a maxinrum average particle size of up to 250 m, preferably between 10 and 150p.m, most preferably between 15 and SO~Lm. It may sometimes seem appropriate to add finer excipient fi=actions with an average particle size of I 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 10p.m, more preferably from I to 51im, 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 forzn of a single powder mixture which contains both 1 and 2 or in the forni of separate inhalable powders which contain only 1 or 2.
The inlialable powders according to the invention may be administered using inhalers klZown 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 n-ieans 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 inllalable powders according to the invention whieh contain 1 and 2 optionally in conjruiction with a physiologically acceptable excipient may be administered, for example, using the inhaler known by the name Turbuhaler or using inhalers as disclosed for example in EP 237507 A. Preferably, the inhalable powders according to the invention which contain physiologically acceptable excipient in addition to 1 and 2 are packed into capsules (to prodtice so-called inhalettes) which are used in inhalers as described, for exasnple, 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 iiilialer (I-landihaler) for ir-Alaling 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 chainber 6 comiected to the deck 3 on wliich 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 coiuiected to the housing 1, the deck 3 and a cover 1 I via a spindle 10 to enable it to be flipped open or shut and air holes 13 for adjusting the flow resistance.
B) Propellant gas-driven inhalation aerosols containing the combinations according to the invention:
Inlialatian aerosols containing propellant gas according to the invention may contain substances 1 and 2 dissolved in the propellant gas or in dispersed form. 1 and 2 may be present in separate formulations or in a single preparation, in which 1 and 2 are either both dissolved, both dispersed or only one component is dissolved and the other is dispersed.
The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably chlorinated and fluorinated derivatives of inethane, 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), (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof, the propellant gases TG134a, TG227 and mixtures thereof being preferred.
The propellailt-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.- /fl 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 active substance preferably have an average particle size of up to 10pm, preferably from 0.1 to 6 in, more preferably from 1 to 5~Lm.
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 pharrnaceutical 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 itAialers which are characterised in that they contain the propellant gas-containing aerosols described above according to the invention. The preseirt 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 inlialable solutions or suspensions containing the combinations according to the invention:
Propellant-free inlialable solutions according to the invention contain for exaniple 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 maximuzn 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. Exainples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fun-iaric acid, acetic acid, formic acid and/or propionic acid etc. Prefei7'ed inorganic acids are hydrochloric acid and sulphuric acid. It is also possible to use the acids which have already formed an acid addition salt witli one of the active substances. Of the organic acids, ascorbic acid, fi.unaric 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 100mg/t OOml, 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 10mg/I
OOml 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 otller 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 wliich 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 fonnulation. Preferably, tllese substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitarnins andlor other additives known in the art.
The additives also include pharinacologically 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 patllogens.
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/100m1, 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 edetate. In another preferred embodirnent, no sodium edetate is present.
The propellant-fi=ee inlialable solutions according to the invention are administered in particular using inhalers of the kind which are capable of nebulising a small amount of a liquid formulation in the therapeutic dose within a few seconds to produce an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred inhalers are those in which a quantity of less than 100 L, preferably less than 50~EL, more preferably between 10 and 30 L of active substance solution can be nebulised in preferably one spray action to fomi an aerosol with an average pai-ticle size of less than 20pIn, preferably less than 10pIn, 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 pharnlaceutical composition for inhalation is described for example in International Patent Application WO 91/14468 aiid also in WO 97/12687 (cf. in particular Figures 6a and 6b).
The nebulisers (devices) described therein are known by the name Respinzat .
This nebuliser (Respimat ) can advantageously be used to produce the ilihalable aerosols according to the invention containing the combination of active substances 1.
and 2.
Accordingly, in a further aspect, the invention relates to phai-Inaceutical formulations in the form of propellant-free inhalable solutiolis or suspensions as described above combined with a device suitable for administering these formulations, preferably in conjunction with the Respilnatg. Preferably, the invention relates to propellant-free inhalable solutions or suspensions characterised by the colnbination of active substances 1 and 2 according to the invention in conjtimction with the device known by the name Respimat . In addition, the present invention relates to the above-mentioned devices for inllalation, preferably the Respiniat , characterised in that they contain the propellant-free inlZ alable 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 terln "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 publicatioii 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 Respiinate.
Formulations ready for use may be produced from the concentrates, for example, by the addition of isotonic saline solutions. Sterile formulations ready for use may be administered using energy-operated fixed or portable nebulisers which produce inhalable aerosols 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 wliich take the form of concentrates or sterile forinulations 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.
-IB-Examples of formulations In the following table examples of powder formulations are collected. The amount specified is to be understood as g per dose. As an example each dose could be placed into a capsules for use with an inhaler according to figure 1.
active amount active amount excipient amount total 1 [ttgl 2 1 1.1 200 2.11) 25 lactose 4) 24775 12500 2 1.1 100 2.0 25 lactose 4) 12375 12500 3 1.1 200 2.21) 25 lactose 4) 24775 25000 4 1.1 100 2.117 25 lactose 4) 12375 12500 5 1.2 50 2.4') 40 lactose 4) 12410 12500 6 1.2 100 2.63) 50 lactose 4) 12350 12500 7 1.2 100 2.31) 25 lactose 4) 12375 12500 8 1.2 200 2.82) 40 lactose 47 24760 25000 9 1.3 200 2.11) 25 lactose 4) 24775 25000 1.3 200 2.73) 25 lactose 4) 24775 25000 11 1.3 100 2.0 25 lactose 4} 12375 12500 12 1.3 50 2.5'j 25 lactose 4) 12425 12500 13 1.3 200 2.117 30 lactose 4) 24770 25000 14 1.4 100 2.63) 25 lactose 4) 12375 12500 1.4 200 2.0 25 lactose 4) 24775 25000 16 1.4 100 2.4'7 40 lactose 4) 12360 12500 17 1.4 50 2.0 25 lactose 4) 12425 12500 18 1.4 200 2.41) 20 lactose 4) 24780 25000 19 1.5 200 2.3E) 25 lactose 4) 24775 25000 1.5 200 2.21) 25 lactose 4) 24775 25000 21 1.5 100 2.21} 25 lactose 4) 12375 12500 22 1.5 200 2.5s) 40 lactose 4) 24760 25000 23 1.6 100 2.8') 25 glucose 12375 12500 24 1.6 50 2.82) 50 lactose 4) 12400 12500 1.6 200 2J) 25 lactose 4) 24775 25000 26 1.6 200 2.11} 25 lactose 4) 24775 25000 27 1.6 200 2.41) 25 lactose 4) 24775 25000 28 1.7 200 2.11) 25 glucose 24775 25000 29 1.7 200 2.51) 30 lactose 4) 24770 25000 30 1.7 200 2.11} 25 lactose 4) 24775 25000 31 1.7 100 2.31) 40 glucose 12360 12500 32 1.7 200 2.4E) 25 lactose 4) 24775 25000 33 L8 100 2.0 25 glucose 12375 12500 34 1.8 50 2.2') 25 lactose 4) 12425 12500 35 1.8 200 2.31) 25 lactose 4) 24775 25000 36 1.8 100 2.73) 25 glucose 12375 12500 37 1.8 200 2.82) 25 lactose 4) 24775 25000 38 1.9 100 2,73) 25 lactose 4) 12375 12500 39 1.9 100 2.0 25 glucose 12375 12500 40 1.9 100 2.631 25 lactose 4) 12375 12500 41 1.9 200 2.0 25 lactose 4) 24775 25000 42 1.9 100 2.41) 25 lactose 4} 12375 12500 l) hydrochloric acid addition salt; 2) maleic acid addition salt; 3) fumaric acid addition salt;
4} moiiohydrate;
Claims (14)
1) Pharmaceutical compositions containing in addition to an anticholinergic of formula 1 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 optionally in the form of the phamacologically 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.
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 optionally in the form of the phamacologically 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 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.
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
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 or 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, 1-hydroxy-2-naphthalenecarboxylic acid or maleic 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 1' 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.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06114540.5 | 2006-05-24 | ||
| EP06114540 | 2006-05-24 | ||
| PCT/EP2007/054700 WO2007135024A1 (en) | 2006-05-24 | 2007-05-15 | New long-acting drug combinations for the treatment of respiratory diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2650813A1 true CA2650813A1 (en) | 2007-11-29 |
Family
ID=37832901
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002650813A Abandoned CA2650813A1 (en) | 2006-05-24 | 2007-05-15 | New long-acting drug combinations for the treatment of respiratory diseases |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP2029127A1 (en) |
| JP (1) | JP2010526763A (en) |
| CA (1) | CA2650813A1 (en) |
| WO (1) | WO2007135024A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL3578169T3 (en) | 2009-02-26 | 2024-09-02 | Glaxo Group Limited | Pharmaceutical formulations comprising 4-{(1 r)-2-[(6-{2-[(2,6-dichlorobenzyl)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 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1452179A1 (en) * | 2003-02-27 | 2004-09-01 | CHIESI FARMACEUTICI S.p.A. | Novel medicament combination of a highly potent long-lasting beta2-agonist and a corticosteroid |
| DE10323966A1 (en) * | 2003-05-27 | 2004-12-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New long-acting drug combinations for the treatment of respiratory diseases |
| JP2007500146A (en) * | 2003-07-28 | 2007-01-11 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Drugs for inhalation containing beta receptor stimulants and anticholinergics |
| US20050025718A1 (en) * | 2003-07-31 | 2005-02-03 | Boehringer Ingelheim International Gmbh | Medicaments for inhalation comprising an anticholinergic and a betamimetic |
| US20060034776A1 (en) * | 2004-08-10 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Inhalable medicaments containing a new anticholinergic, corticosteroids, and betamimetics |
-
2007
- 2007-05-15 WO PCT/EP2007/054700 patent/WO2007135024A1/en active Application Filing
- 2007-05-15 JP JP2009511463A patent/JP2010526763A/en active Pending
- 2007-05-15 EP EP07729151A patent/EP2029127A1/en not_active Withdrawn
- 2007-05-15 CA CA002650813A patent/CA2650813A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007135024A1 (en) | 2007-11-29 |
| JP2010526763A (en) | 2010-08-05 |
| EP2029127A1 (en) | 2009-03-04 |
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