JP2010526763A - Novel long-acting pharmaceutical composition for the treatment of respiratory diseases - Google Patents

Abstract

  The present invention relates to a novel pharmaceutical composition based on a novel anticholinergic agent and a novel long-acting beta-2 agonist, its production method and use of the pharmaceutical composition in the treatment of respiratory diseases About.

Description

Detailed Description of the Invention

The present invention relates to a novel pharmaceutical composition based on a novel anticholinergic agent and a novel long-acting beta-2 agonist, a process for its preparation and the use of this composition in the treatment of respiratory disorders. .
(Description of the invention)
The present invention relates to an anticholinergic agent represented by the following formula 1:

(Where
A represents a group selected from the following:

R and R ¹ represent hydrogen or together represent a single bond, a group selected from —CH ₂ — and —O—,
X ⁻ represents one negatively charged anion, preferably chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate And an anion selected from the group consisting of p-toluenesulfonate)
One or more beta-2 agonists selected from the group consisting of:

And may be in the form of their pharmaceutically acceptable acid addition salts, and may be in the form of enantiomers, mixtures of enantiomers or racemates, and solvates and A beta 2 agonist, which may be in the form of a hydrate,
Furthermore, it is related with the novel pharmaceutical composition which may mix a pharmaceutically acceptable excipient | filler.
In a preferred composition according to the invention, in formula 1,
A represents a group selected from:

R and R ¹ represent hydrogen or together represent a group selected from a single bond and —O—;
X ⁻ represents one negatively charged anion, preferably chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate And a compound of formula 1 is used that represents an anion selected from the group consisting of p-toluenesulfonate.
Preference is given to salts of the formula 1 in which X ⁻ represents one negatively charged anion, preferably bromide, selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate.
Particular preference is given to using salts of the formula 1 in which X ⁻ represents one negatively charged anion, preferably bromide, selected from the group consisting of chloride, bromide and methanesulfonate.
In the formula 1, a salt in which X ⁻ represents bromide is particularly preferred in the present invention.
According to the present invention, in Formula 1, A represents the following group:

Particularly preferred are compounds of formula 1, wherein R, R ¹ and X ⁻ are as defined hereinbefore.
In Formula 1, A represents the following group,

Especially preferred according to the invention are compounds of the formula 1, in which R, R ¹ and X ^- are as defined hereinbefore.
In Formula 1, A represents the following group,

Especially preferred according to the invention are compounds of the formula 1, in which R, R ¹ and X ^- are as defined hereinbefore.
Particularly preferred in the present invention are compounds of formula 1 in which R and R ¹ represent hydrogen and A and X ⁻ are as defined hereinbefore.
Particularly preferred in the present invention are compounds of formula 1 in which R and R ¹ represent a bond, and A and X ⁻ are as defined hereinbefore.
Particularly preferred in the present invention are compounds of formula 1 in which R and R ¹ represent —O—, and A and X ⁻ are as defined hereinbefore.
Compounds of formula 1 are known from WO 02/32899, WO 03/64419, WO 03/64418 and WO 03/64417.
Compounds of formula 1 are tropenol 2,2-diphenylpropionate-methobromide (1.1), scopine 2,2-diphenylpropionate-methobromide (1.2), tropenol 9-methyl-fluorene-9-carboxylate- Metobromide (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), cyclopropyltropin 2,2-diphenylpropionate-methobromide (1.7), cyclopropyltropin 9-methyl-fluorene-9-carboxylate-methobromide (1.8), cyclopropyl The group consisting of tropine 9-methyl-xanthene-9-carboxylate-methobromide (1.9) Are al selected, may also be compound in the form of their solvates and hydrates are particularly preferred in the present invention.

Surprisingly, when an anticholinergic agent of formula 1 is administered together with a compound of formula 2, an unexpected effective therapeutic effect is seen, for example, in the treatment of inflammatory or obstructive diseases of the respiratory tract. It is done. In view of this useful effect, the pharmaceutical composition of the present invention can be used in a smaller dose than when each compound is used in conventional monotherapy. Another good aspect of the present invention is that it reduces unwanted side effects that can occur, for example, during administration of beta receptor stimulants. An undesirable side effect that should be noted in this case is the excitement of the heart that can be caused by beta-receptor stimulants, especially for tachycardia, increased heart perturbation, and angina. Similar pain and arrhythmia. The above-mentioned action can be seen both when the two active ingredients are administered simultaneously as a single active ingredient formulation and when the two active ingredients are administered sequentially as separate formulations. In the present invention, it is preferable to administer these two active ingredients simultaneously as a single preparation.
In the scope of the present invention, reference to compound 1 ′ is taken to indicate a pharmacologically effective cation represented by the following formula contained in salt 1.

In the pharmaceutical composition, two active ingredients may be contained in a single preparation or may be contained in two separate preparations. A pharmaceutical composition containing active ingredients 1 and 2 in a single formulation is preferred in the present invention.
Reference to beta receptor stimulant 2 also includes enantiomers (R or S) or mixtures thereof, and the R enantiomer of a compound is particularly important within the scope of the present invention. Methods for enantioselective preparation of enantiomers of compounds of formula 2 are known in the art. In the present invention, the beta receptor stimulant 2 may be present in the form of its salt and hydrate or solvate.
Preferred enantiomers and diastereoisomers of Beta Receptor Stimulant 2 that form part of the composition of the present invention are shown below.

Examples of suitable pharmaceutical compositions of the present invention are compounds 1.1 and 2.1, 1.1 and 2.2, 1.1 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, 1.2. And 2.2, 1.2 and 2.3, 1.2 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 2.1, 1.3 and 2.2, 1.3 and 2.3, 1.3 and 2.4, 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, 1.5 and 2.1, 1.5 and 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, 1.6 and 2.3, 1.6 and 2.4, 1.6 and 2.5, 1.6 and 2.6, 1.6 and 2.7 1.6, 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, 1.9 and 2.7, 1.9 and 2.8 In combination with racemates, enantiomers or May be in the form of A stereo isomers and pharmaceutically acceptable acid addition salts may be in the form of solvates and / or hydrates thereof.
Also, within the scope of the present invention, the term beta receptor stimulant is taken to indicate a beta 2 agonist. When referring to beta receptor stimulant 2, pharmacologically acceptable acid addition salts thereof are also included. The pharmacologically acceptable acid addition salts of beta receptor stimulant 2 are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, In the present invention, pharmaceutically acceptable salts including salts of 1-hydroxy-2-naphthalenecarboxylic acid or maleic acid are meant in the present invention. If desired, salt 2 can be prepared using a mixture of the acids. According to the invention, two salts selected from hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate, maleate and xinafoate are preferred.
One aspect of the present invention relates to said pharmaceutical composition comprising a pharmaceutically acceptable excipient in addition to a therapeutically effective amount of active ingredients 1 and 2. In another aspect, the present invention relates to said pharmaceutical composition which does not contain a pharmaceutically acceptable excipient in addition to a therapeutically effective amount of active ingredients 1 and 2.
Further, the present invention provides treatment of inflammatory and obstructive respiratory diseases, prevention of preterm birth in obstetrics (suppression of labor), repair of cardiac sinus rhythm in the case of atrioventricular heart block, bradycardic heart rhythm Pharmaceutical composition comprising one or more, preferably one active ingredient 2, for the recovery of disorders (antiarrhythmic drugs), the treatment of circulatory shock (vasodilation and heart enlargement) and the treatment of skin itching and inflammation The use of a therapeutically effective amount of active ingredient 1 to produce a product.

Preferred embodiments of the present invention include obstructive pulmonary disease due to various causes, emphysema due to various causes, restrictive lung disease, interstitial lung disease, cystic fibrosis, bronchitis due to various causes, bronchiectasis, adult For producing a pharmaceutical composition comprising one or more, preferably one active ingredient 2, for the treatment of respiratory diseases selected from the group comprising respiratory distress syndrome (ARDS) and all types of pulmonary edema The use of a therapeutically effective amount of active ingredient 1.
As described above, the pharmaceutical composition of the present invention treats obstructive pulmonary disease selected from bronchial asthma, childhood asthma, severe asthma, acute asthma attack, chronic bronchitis and chronic obstructive pulmonary disease (COPD). It is preferably used to produce a pharmaceutical composition for use. Among them, it is particularly preferable in the present invention to use it for producing a pharmaceutical composition for treating bronchial asthma and COPD.
Also preferred is the use of the pharmaceutical composition of the present invention for the manufacture of a pharmaceutical composition for the treatment of pulmonary emphysema whose cause is chronic obstructive pulmonary disease (COPD) or lack of an α1-proteinase inhibitor.
Also, restrictive lung diseases induced by occupational harmful substances such as allergic alveolar osteomyelitis, asbestosis or silicosis, and cancerous lymphangiopathy, bronchioloalveolar carcinoma, lymphoma, etc. It is also preferred to use the pharmaceutical composition of the present invention for the manufacture of a pharmaceutical composition for the treatment of restrictive lung disease selected from stenosis caused by various lung tumors.
Also, for example, pneumonia caused by infection by viruses, bacteria, fungi, protozoa, helminths or other pathogens, for example, pneumonia caused by various factors such as aspiration or left heart failure, pneumonitis caused by radiation irradiation Or from fibrosis, eg collagen disease such as lupus erythematosus, systemic scleroderma or sarcoidosis, eg granulomatosis such as Beck disease, idiopathic interstitial pneumonia or idiopathic pulmonary fibrosis (IPF) It is also preferred to use the pharmaceutical composition of the present invention to produce a selected pharmaceutical composition for the treatment of interstitial lung disease.

Also preferred is the use of the pharmaceutical composition of the present invention for the manufacture of a pharmaceutical composition for the treatment of cystic fibrosis or pancreatic fibrosis.
Also preferred is the use of the pharmaceutical composition of the present invention for producing a pharmaceutical composition for the treatment of bronchitis such as bronchitis due to bacterial or viral infection, allergic bronchitis, and toxic bronchitis.
The use of the pharmaceutical composition of the present invention for producing a pharmaceutical composition for the treatment of bronchiectasis is also preferred.
Also preferred is the use of the pharmaceutical composition of the present invention for the manufacture of a pharmaceutical composition for the treatment of adult respiratory distress syndrome (ARDS).
In addition, the use of the pharmaceutical composition of the present invention for producing a pharmaceutical composition for treating pulmonary edema such as toxic pulmonary edema caused by inhalation of toxic substances or foreign substances is also preferred.
It is particularly preferred to use the compounds detailed above for the preparation of a pharmaceutical composition for the treatment of asthma or COPD. The pharmaceutical composition of the present invention for producing a pharmaceutical composition for once-daily treatment of inflammatory and obstructive respiratory diseases, particularly for once-daily treatment of asthma or COPD. Use is particularly important.
Furthermore, the present invention provides a therapeutically effective amount of the active ingredient represented by formula 1 together with a therapeutically effective amount of active ingredient 2 to produce a therapeutic pharmaceutical composition for one of the diseases described above. About using.
The present invention also relates to a method for treating the above-mentioned diseases, wherein a therapeutically effective amount of the active ingredient represented by Formula 1 is administered together with a therapeutically effective amount of the active ingredient 2.
Within the scope of the present invention, compounds 1 and 2 may be administered simultaneously or sequentially, but compounds 1 and 2 are preferably administered simultaneously.

The ratio of active ingredients 1 and 2 that can be used in the active ingredient combination of the present invention can be varied. Active ingredients 1 and 2 may be in the form of solvates or hydrates. Depending on the choice of salt, 1 and 2 have different molecular weights depending on the various salt forms, so that the mass ratio that can be used within the scope of the present invention varies. Therefore, the mass ratio shown below is based on the cation 1 ′ and the free base compound 2.
The active ingredient combination according to the invention comprises 1 ′ and a free base compound of formula 2, for example from about 1:30 to 400: 1, preferably from 1:25 to 200: 1, preferably from 1:20 to 100: 1, in particular Preferably, it may be contained at a mass ratio in the range of 1:15 to 50: 1.
For example, but not limiting the scope of the present invention, suitable combinations of 1 and 2 according to the present invention may include cation 1 ′ and free base compound 2 in the following mass ratio. 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 composition of the present invention comprising a combination of 1 and 2 is usually 5 to 5000 μg, preferably 10 to 2000 μg, more preferably 15 to 1000 μg, in addition to cation 1 ′ and compound 2, for each single administration. It is preferably administered together in a dose of 20-800 μg, more preferably 30-750 μg, preferably 40-700 μg in the present invention. This total dose is based on the free base state of Compound 2.

For example, the combination of 1 and 2 according to the present invention includes a total dose of about 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, 30 μg, 35 μg, 40 μg, 45 μg, 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 90 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg 195μg, 200μg, 205μg, 210μg, 215μg, 220μg, 225μg, 230μg, 235μg, 240μg, 245μg, 250μg, 255μg, 260μg, 265μg, 270μg, 275μg, 280μg, 285μg, 290μg, 295μg, 300μg, 305μg, 310μg 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, 5 15μg, 520μg, 525μg, 530μg, 535μg, 540μg, 545μg, 550μg, 555μg, 560μg, 565μg, 570μg, 575μg, 580μg, 585μg, 590μg, 595μg, 600μg, 605μg, 610μg, 615μg, 620μg, 630μg, 635μg The amount of 1 ′ compound and the compound of formula 2 are included such as 640 μg, 645 μg, 650 μg, 655 μg, 660 μg, 665 μg, 670 μg, 675 μg, 680 μg, 685 μg, 690 μg, 695 μg, 700 μg, etc. Again, the prescribed dose is based on the amount of free base in compound 2 of the pharmaceutical composition of the invention. It will be apparent to those skilled in the art that the recommended dosage for each administration is not limited to the stated values. It will also be apparent to those skilled in the art that an increase / decrease within the range of approximately ± 2.5 μg, particularly an increase / decrease in the decimal range, is included. In such a dose range, the active ingredients 1 ′ and 2 can be included in the above-mentioned mass ratio.
The active ingredient compositions 1 and 2 according to the present invention are preferably administered by inhalation. This requires that components 1 and 2 be provided in a form suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metered dose aerosols or inhalants containing no propellant. The inhalable powder of the present invention containing a combination of active ingredients 1 and 2 may be composed only of the active ingredient or a mixture of the active ingredient and a pharmaceutically acceptable excipient. Also good. Within the scope of the invention, the term propellant-free inhalation solution includes concentrates or ready-to-use sterile inhalation solutions. The preparations of the present invention may contain the combination of active ingredients 1 and 2 either together in one formulation or in two separate formulations. Such formulations that can be used within the scope of the present invention are described in more detail in the next part of the specification.

A) Inhalable powder comprising the composition of the invention:
Inhalable powders according to the present invention may contain only 1 and 2 or together with suitable pharmaceutically acceptable excipients. When active ingredients 1 and 2 are present together with pharmaceutically acceptable excipients, the following pharmaceutically acceptable excipients can be used to prepare inhalable powders according to the present invention. Monosaccharides (eg glucose or arabinose), disaccharides (eg lactose, saccharose, maltose, trehalose), oligosaccharides and polysaccharides (eg dextran), polyhydric alcohols (eg sorbitol, mannitol, xylitol), salts (For example, sodium chloride, calcium carbonate) or a mixture of these excipients. Preferably, monosaccharides or disaccharides are used, among which lactose or glucose is preferred, and without limitation, the hydrate form is particularly preferred.
In the range of inhalable powders according to the invention, the maximum average particle size of the excipient is up to 250 μm, preferably 10 to 150 μm, most preferably 15 to 80 μm. It may be considered appropriate to add a finer excipient fraction with an average particle size of 1-9 μm to the excipient. Finer excipients are also selected from the group of usable excipients listed herein above. Finally, to prepare the inhalable powder of the present invention, differentiated active ingredients 1 and 2 having an average particle size of preferably 0.5 to 10 μm, more preferably 1 to 5 μm, are added to the excipient mixture. The process for producing the inhalable powder according to the invention by grinding and differentiating and finally mixing all the components is known from the prior art. The inhalable powders of the present invention can be prepared and administered either as a single powder mixture containing both components 1 and 2, or as separate inhalable powders containing only 1 or 2. .

The inhalable powders according to the invention can be administered using inhalers known from the prior art. An inhaler powder according to the invention comprising pharmaceutically acceptable excipients in addition to 1 and 2 is an inhaler that releases a single dose from a source using, for example, a metering chamber as described in US Pat. Or by other means as described in DE 3625685A. Inhalable powders according to the invention comprising 1 and 2 and which may further contain pharmaceutically acceptable excipients are administered, for example, using an inhaler known under the trade name Turbuhaler® Alternatively, it can be administered using an inhaler as disclosed in EP237507A. Preferably, the inhalable powders according to the invention containing pharmaceutically acceptable excipients in addition to 1 and 2 are filled into capsules (so-called inhalette formation) as described, for example, in WO 94/28958 Use with inhaler.
FIG. 1 shows an inhaler that is particularly suitable for administering the pharmaceutical composition of the present invention filled in a capsule. This inhaler (handy heller) for inhaling a powdered pharmaceutical composition from a capsule has a housing 1 including two windows 2, an air inlet, and a screen 5 fixed via a screen housing 4. A deck 3, which is connected to the deck 3, a suction chamber 6 which has two pointed pins 7 and a movable push button 8 with respect to a spring 8, a housing 10, a deck 3 and a cover via a spindle 10 11 and a mouthpiece 12 that can be opened and closed in a flip-up manner, and an air hole 13 for adjusting the flow resistance.

B) Propellant gas driven inhalation aerosol comprising the composition of the invention:
In the propellant gas-containing inhalation aerosol according to the present invention, the active ingredients 1 and 2 may be contained in the propellant gas in a dissolved or dispersed state. 1 and 2 can be present in separate formulations or single preparations, in which both 1 and 2 are either dissolved or dispersed, or only one component is dissolved and the other component is dispersed Either. Propellant gases that can be used for the preparation of the inhaled aerosols according to the invention are known from the prior art. Suitable propellant gases include hydrocarbon compounds such as n-propane, n-butane or isobutane, and halohydrocarbons such as methane, ethane, propane, butane, cyclopropane or cyclobutane, preferably chlorinated and fluorinated derivatives. Selected from compounds. The propellant gas can be used alone or as a mixture thereof. Particularly preferred propellant gases are TG11, TG12, TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. TG134a, TG227 and mixtures thereof are preferred with halogenated alkane derivatives selected from
The propellant-driven inhalation aerosol of the present invention can also contain other components such as cosolvents, stabilizers, surfactants, antioxidants, lubricants and pH adjusters. All of these components are known in the art.
The propellant gas-containing inhalation aerosol according to the present invention may contain up to 5% by mass of active ingredient 1 and / or 2. For example, the aerosol of the present invention contains 0.002 to 5% by mass, 0.01 to 3% by mass, 0.012 to 2% by mass, 0.1 to 2% by mass, 0.5 to 2% by mass, or 0.5 to 1% by mass of the active ingredient 1 and / or 2. % Is included.

When the active ingredients 1 and / or 2 are present in a dispersed state, the average particle diameter of the active ingredient particles is preferably up to 10 μm, more preferably 0.1 to 6 μm, more preferably 1 to 5 μm.
The propellant-driven inhalation aerosol according to the present invention described above can be administered using an inhaler known in the art (metered dose inhaler (MDI)). Accordingly, another aspect of the present invention relates to a propellant-driven aerosol pharmaceutical composition in combination with one or more inhalers suitable for administering the propellant-driven aerosol described above. Furthermore, the present invention relates to an inhaler characterized in that it contains the propellant gas-containing aerosol according to the present invention. The invention also relates to a cartridge provided with a suitable valve, usable with a suitable inhaler, and containing one of the propellant gas-containing inhalation aerosols according to the invention. Suitable cartridges, as well as methods for filling the cartridges with the propellant gas-containing inhalation aerosol according to the invention are known from the prior art.
C) A propellant-free inhalation solution or suspension comprising the composition of the invention:
The inhalation solution containing no propellant of the present invention contains, for example, an aqueous solvent or an alcohol solvent, preferably an ethanol solvent, but may contain a mixture of an ethanol solvent and an aqueous solvent. In the case of an aqueous / ethanol-based mixed solvent, the relative ratio of ethanol to water is not limited, but up to 70% by volume, more specifically, up to 60% by volume of ethanol. The remaining volume is made up of water. Solutions or suspensions containing active ingredients 1 and 2 separately or together are adjusted to pH 2-7, preferably pH 2-5, using a suitable acid. The pH value may be adjusted using an acid selected from inorganic acids or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric 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. Recommended inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids that have already formed acid addition salts with one of the active ingredients. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids can also be used, especially in the case of acids having properties as perfumes, antioxidants or complexing agents, for example citric acid or ascorbic acid, in addition to acidifying properties. May be used as a mixture. According to the invention, it is particularly preferred to adjust the pH value with hydrochloric acid.

In the present invention, it is not necessary in the formulation of the present invention to add edetic acid (EDTA) or one of its known salts, sodium edetate, as a stabilizer or complexing agent. In some embodiments, one or more of this compound may be included. A preferred embodiment has a content based on sodium edetate of less than 100 mg / 100 ml, preferably less than 50 mg / 100 ml, more preferably less than 20 mg / 100 ml. In general, an inhalation solution with a sodium edetate content in the range of 0 to 10 mg / 100 ml is preferred.
Co-solvents and / or other excipients can be added to the inhalation solution containing no propellant of the present invention. Preferred cosolvents are those containing hydroxyl groups or other polar groups such as alcohols, especially isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and poly Oxyethylene fatty acid esters. The terms excipients and additives herein are not active substances per se, but may be one or more in a pharmaceutically suitable solvent in order to improve the qualitative properties of a formulation containing the active substance. It means any pharmacologically acceptable substance that can be formulated with more active substance. These substances preferably have no pharmacological action, but preferably have no pharmacological action that can be easily recognized in the context of the desired therapy, or at least have no undesirable pharmacological action. Examples of excipients and additives include soy lecithin, oleic acid, sorbitan esters such as polysorbate, surfactants such as polyvinylpyrrolidone, other stabilizers, complexing agents, and quality retention period of the final pharmaceutical preparation. Antioxidants and / or preservatives, flavoring agents, vitamins and / or other additives known in the art to guarantee or prolong the protection. Additives also include pharmaceutically acceptable salts such as sodium chloride as isotonic agents.

Preferred excipients include, for example, antioxidants such as ascorbic acid if not used for pH adjustment, and vitamin A, vitamin E, tocopherol and similar vitamins and provitamins produced in the human body. Agents.
Preservatives can be used to protect the formulation from contamination by pathogens. Suitable preservatives are known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoates such as benzoic acid or sodium benzoate in concentrations known from the prior art. The preservative is preferably present in a concentration of up to 50 mg / 100 ml, more preferably 5-20 mg / 100 ml.
Preferred formulations are those containing only benzalkonium chloride and sodium edetate in addition to the combination of water as solvent and active ingredients 1 and 2. There are also recommended embodiments in which no sodium edetate is included.
The administration of the inhalation liquid not containing the propellant of the present invention uses an inhaler of a type capable of generating an aerosol suitable for therapeutic inhalation by atomizing a small amount of liquid preparation as a therapeutic dose within a few seconds. Do it. Within the scope of the present invention, the active ingredient solution is preferably atomized in an amount of less than 100 μL, preferably less than 50 μL, more preferably 10-30 μL in a single spray operation, with an average particle size of less than 20 μm, preferably less than 10 μm. Nebulizers that are capable of forming an aerosol of the same amount such that the inhalable portion of the aerosol represents a therapeutically effective amount are preferred nebulizers.
Devices of the type that release a quantitative amount of a liquid pharmaceutical composition for inhalation without the use of a propellant are described, for example, in international patent applications WO 91/14468 and WO 97/12687 (see in particular FIGS. 6a and 6b). The nebulizers (devices) described therein are known by the name Respimat®.

This nebulizer (Respimat®) can be effectively utilized to produce an inhalation aerosol of the present invention that includes a combination of active ingredients 1 and 2.
Accordingly, a further aspect of the present invention provides a propellant in combination with a device suitable for administration of a pharmaceutical formulation in the form of an inhalation solution or suspension that does not contain a propellant as described above, preferably Respimat®. The present invention relates to a pharmaceutical preparation containing no inhalation solution or suspension. Preferably, it relates to a propellant-free inhalation solution or suspension, characterized by the combination of active ingredients 1 and 2 according to the invention, in combination with a device known under the name Respimat®. Furthermore, the present invention relates to said inhalation device, preferably Respimat®, characterized in that it contains an inhalation solution or suspension which does not contain the propellant of the present invention as described herein above. Is.
In the present invention, a single-dose inhalation solution containing active ingredients 1 and 2 is preferred. The term “single preparation” also includes a preparation in which two components 1 and 2 are contained in a two-chamber cartridge, as disclosed for example in WO 00/23037. This publication is incorporated herein by reference in its entirety.
Propellant-free inhalation solutions or suspensions according to the invention include concentrates or ready-to-use sterile inhalation solutions or suspensions, as well as the above solutions and suspensions designed for use with Respimat®. It can be in a liquid state. Ready-to-use formulations are obtained from the concentrate, for example by adding isotonic saline. Ready-to-use sterile formulations can be administered using energy-driven fixed or portable nebulizers that generate inhalable aerosols using ultrasound or compressed air according to the Venturi principle or other principles .

Accordingly, another aspect of the present invention provides for the administration of these liquids in the form of concentrates or ready-to-use sterile formulations, inhalable solutions or suspensions containing no propellants as described above. In combination with a suitable device, the device is an energy-driven self-supporting or portable nebulizer that generates inhalable aerosols using ultrasound or compressed air according to the Venturi principle or otherwise It is characterized by that.
The following examples serve to illustrate the invention in more detail without limiting the scope of the invention. The following formulation examples can be obtained in the same manner as known in this field.
Formulation Examples Examples of powder formulations are summarized in the table below. The specified amount is taken as the amount expressed in μg per dose. As an example, each dose could be filled into a capsule used in the inhaler according to FIG.

1) Hydrochloric acid addition salt 2) Maleic acid addition salt 3) Fumaric acid addition salt 4) Monohydrate

An inhaler is shown which is particularly suitable for administering capsules filled with the pharmaceutical composition of the present invention.

Claims (14)

Anticholinergic agent represented by the following formula 1:

(Where
A represents a group selected from:

R and R ¹ represent hydrogen or together represent a single bond, a group selected from —CH ₂ — and —O—,
X ⁻ represents one negatively charged anion, preferably chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate And an anion selected from the group consisting of p-toluenesulfonate)
One or more beta-2 agonists selected from the group consisting of:

These pharmaceutically acceptable acid addition salts may be in the form of enantiomers, mixtures of enantiomers or racemates, solvates and hydrates. A pharmaceutical composition comprising a beta-2 agonist, which may be in the form of a product, and may further contain a pharmaceutically acceptable excipient. In the compound of the formula 1, A represents a group selected from the following:

R and R ¹ represent hydrogen or together represent a group selected from a single bond and —O—;
X ⁻ represents one negatively charged anion, preferably chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate And the anion selected from the group consisting of p-toluenesulfonate. The pharmaceutical composition according to claim 1 or 2, wherein in the compound of the formula 1, A represents the following group.

The pharmaceutical composition according to claim 1 or 2, wherein in the compound of the formula 1, A represents the following group.

The pharmaceutical composition according to claim 1 or 2, wherein in the compound of the formula 1, A represents the following group.

  Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the active ingredients 1 and 2 are present in a single formulation or are contained in two separate formulations. .   Compound 2 is a salt of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid or maleic acid The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is present in the form of   8. A pharmaceutical composition according to any one of claims 1 to 7, characterized in that the compound 2 is present in the form of its R enantiomer. A mass ratio of compound 1 'of the following formula to compound 2 (based on free base) is in the range of about 1:30 to 400: 1, preferably 1:25 to 200: 1. The pharmaceutical composition according to any one of 1 to 4.

  10. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that the pharmaceutical composition is a formulation selected from inhalable powders, propellant-driven metered aerosols and inhalants without propellants. Pharmaceutical composition.   Said pharmaceutical composition together with a suitable pharmaceutically acceptable excipient selected from monosaccharides, disaccharides, oligosaccharides and polysaccharides, polyhydric alcohols, salts or mixtures of these excipients 11. The pharmaceutical composition according to claim 10, which is an inhalable powder containing components 1 and 2.   The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is a propellant-containing inhalation aerosol containing the active ingredients 1 and 2 in a dissolved or dispersed state.   11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is an inhalation liquid containing no propellant and containing water, ethanol or a mixture of water and ethanol as a solvent.   Use of a composition according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of inflammatory or obstructive diseases of the respiratory tract, especially asthma or COPD.

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