HK1096599A - Novel medicament compositions, based on anticholinergically effective compounds and beta-mimetics - Google Patents

Description

Novel pharmaceutical compositions based on anticholinergically effective compounds and beta-mimetics

The present application is a divisional application of an invention patent application having an application date of 2000/5/3, application No. 00807356.2, entitled "novel pharmaceutical composition based on anticholinergic effective compound and β -mimetic".

The invention relates to novel pharmaceutical compositions based on anticholinergic compounds with a long-lasting action and beta-mimetics with a long-lasting action, to a process for their preparation and to their use for the treatment of respiratory diseases.

Background

It is known from the prior art that β -mimetics and anticholinergics can successfully be used as bronchospasmodics for the treatment of obstructive respiratory diseases, such as asthma. Substances with a beta-sympathomimetic action, such as the active substance formoterol (formoterol), are also known from the prior art to have undesirable side effects when administered to humans.

Usually, central effects manifest as discomfort, excitement, insomnia, fear, finger tremor, sweating and headache. Here, inhalation applications do not exclude these side effects, although to a lesser extent than oral or parenteral administration.

The side effects of beta-sympathomimetics as asthma therapeutics are largely more or less strongly correlated with cardiac beta-excitatory effects. It produces tachycardia, palpitation, angina-like symptoms and arrhythmia [ p.t. amomon (Ed.) ], medical Side-effects and Interactions, Wissenschaftliche Verlagsgesellschaft, Stuttgart 1986, s.584 ].

Detailed Description

Surprisingly, it was found that the combined use of a β -sympathomimetic agent with a long-lasting effect and an anticholinergic agent with a long-lasting effect substantially reduces the above-mentioned side effects.

Furthermore, it has surprisingly been found that the bronchospastic action of anticholinergic agents with long-lasting action and β -mimetics with long-lasting action can be increased in a superadditive manner.

The effect of the combined use of the active ingredients according to the invention on both COPD and asthma is therefore substantially increased compared to the single substances and mixtures known from the prior art.

The following active ingredients can be used in the active ingredient mixtures according to the invention as preferred β -mimetics with a long-lasting effect: bambuterol, tolbutadine (bitoleterol), albuterol (carbutarol), clenbuterol (clenbuterol), phenprobuterol (fenoterol), formoterol (formoterol), hexadienerenol (hexoprenalin), albuterol (ibuterol), pirbuterol (pirbuterol), procaterol (procaterol), naloxonol (reproterol), salmeterol (salmeterol), albuterol (sulfonoterol), terbutaline (terbutaline), tollurobuterol (tolbutamol), 4-hydroxy-7- [2- { [2- { [3- (2-phenylethoxy) propyl ] sulfonyl } ethyl ] amino } ethyl ] -2(3H) -benzothiazolone, flubensul (buterol, flutolbutamol), flubuterol (flubuterol), fluterol (fluterol), 4-hydroxy-7- [2- { [2- { [3- (2-phenylethoxy) propyl ] sulfonyl } ethyl ] amino } ethyl ] -2(3H) -benzothiazolone, flutolbutamol, and pharmaceutical compositions containing them,

1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino ] ethanol,

1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl ] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-n-butoxyphenyl) -2-methyl-2-propylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- {4- [3- (4-methoxyphenyl) -1, 2, 4-triazol-3-yl ] -2-methyl-2-butylamino } ethanol,

5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1, 4-benzoxazin-3- (4H) -one,

1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol or

1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol, optionally in the form of its racemate, enantiomers, diastereomers and mixtures thereof, and optionally in the form of its pharmaceutically compatible acid addition salts.

The following active ingredients are used as β -mimetics with a long-lasting effect in the active ingredient combinations according to the invention: formoterol, salmeterol,

4-hydroxy-7- [2- { [2- { [3- (2-phenylethoxy) propyl ] sulfonyl } ethyl ] -amino } ethyl ] -2(3H) benzothiazolone,

1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino ] ethanol,

1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl ] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-n-butoxyphenyl) -2-methyl-2-propylamino ] ethanol or

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- {4- [3- (4-methoxyphenyl) -1, 2, 4-triazol-3-yl ] -2-methyl-2-butylamino } ethanol, optionally in the form of its racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of its pharmaceutically compatible acid addition salts.

The following are preferred for use as beta-mimetics in the pharmaceutical compositions of the present invention: formoterol or salmeterol, optionally in the form of their racemates, enantiomers, diastereomers, and mixtures thereof, and optionally in the form of their pharmaceutically compatible acid addition salts.

The above-mentioned β -mimetics having a prolonged action can be transformed and used in the form of their physiologically and pharmaceutically-compatible salts. The following are conceivable acid addition salts as examples: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, or maleic acid. And mixtures of the above acids may be used.

From the viewpoint of superadditive bronchospasm effect, the fumarate salt of formoterol (abbreviated as formoterol FU) is a particularly good β -mimetic with long-acting effect. Formoterol active substance can be used here in the form of its enantiomers or diastereomer mixtures or as single enantiomers/diastereomers. In the same preferred sense, salmeterol is also used according to the invention as a β -mimetic with a long-lasting effect; the racemate and the enantiomer can be taken according to the needs; wherein the (R) enantiomer is most preferred and may be used in the form of a pharmaceutically acceptable addition salt thereof, if desired.

For anticholinergic agents with a long-lasting action, essentially all those known from the prior art, such as glycopyrrolate (glycopyrronium bromide) and esters of bicyclic and tricyclic amino alcohols, are suitable, as is known from European publication 0418716 and from International patent application WO 92/16528, which are incorporated herein by reference in their entirety.

Within the scope of the present invention, particular consideration is given to glycopyrrolate as anticholinergic agents with a prolonged action, and the compounds of the formula (I)

Esters of bicyclic and tricyclic amino alcohols

Wherein

A represents a group of the formula (II)

Wherein

Q represents one of the following double bond groups: -CH₂-CH₂-、-CH₂-CH₂-CH₂-, -CH ═ CH-, or

R represents C optionally substituted by halogen-or hydroxy₁-C₄An alkyl group, a carboxyl group,

r' represents C₁-C₄Alkyl, and R' may also combine to form C₄-C₆Alkylene, and

an anion X equivalent which can counteract the positive charge of the N atom, Z represents one of the following two groups

Or

Wherein

Y represents a single bond, an O or S atom or one of the following groups: -CH₂-、-CH₂-CH₂-、-CH＝CH-、-OCH₂-or-SCH₂-；

R¹Represents hydrogen, OH, C₁-C₄Alkoxy or C₁-C₄Alkyl group, which may be desiredSubstituted with hydroxy;

R²represents thienyl, phenyl, furyl, cyclopentyl or cyclohexyl, where these radicals may also be substituted by methyl, and thiophene and phenyl may also be substituted by fluorine or chlorine,

R³represents hydrogen or thienyl or phenyl, which may optionally be substituted by halogen or C₁-C₄Alkyl substitution, optionally in the form of racemates, enantiomers, diastereomers and mixtures thereof.

Within the scope of the present invention, glycopyrrolate is considered as the best anticholinergic agent with long-lasting action and the compounds of formula (I) are considered as esters of bicyclic and tricyclic amino alcohols, wherein A represents a group of the general formula (II)

Wherein

Q represents one of the following double bond groups: -CH ═ CH-, -CH₂-CH₂-, or

R represents methyl, ethyl or propyl, optionally substituted with fluorine or hydroxy,

r' represents methyl, ethyl or propyl, preferably methyl, and

an anion X equivalent which counteracts the positive charge of the N atom, said anion being selected from the group consisting of chlorine, bromine and methanesulfonate, preferably bromine,

z represents one of the following two groups

Or

Wherein

Y represents a single bond or an O atom;

R¹represents hydrogen, OH, methoxy, ethoxy, propoxy, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl or hydroxypropyl;

R²represents thienyl, phenyl or cyclohexyl, where these radicals may be substituted by methyl and thienyl and phenyl may also be substituted by fluorine or chlorine,

R³represents hydrogen, or, thienyl or phenyl, which may optionally be substituted by fluorine, chlorine or methyl, and may optionally be in the form of their racemates, enantiomers, diastereomers and mixtures thereof.

The pharmaceutical compositions of the invention, in which the compounds of the formula (I) are of particular importance as anticholinergic agents with a long-lasting action, are of particular importance

A represents a group of the formula (II)

Wherein

Q represents one of the following double bond groups: -CH ═ CH-, -CH₂-CH₂-, or

R represents methyl or ethyl;

r' represents methyl, and

the equivalent of the monoanionic X ═ bromide is located opposite the positive charge of the N atom, Z represents one of the following diradicals

Or

Wherein

Y represents an O atom;

R¹represents hydrogen, OH or hydroxymethyl;

R²represents thienyl, phenyl or cyclohexyl,

R³represents hydrogen, thienyl or phenyl, and racemates, enantiomers, diastereomers and mixture forms thereof can be used if desired

Of the above compounds, those having a 3-alpha structure are particularly preferred within the scope of the present invention.

The anticholinergic active substances mentioned above can be used as desired in the form of their pure enantiomers, mixtures or racemates.

Particular preference is given to using tiotropium salts, in particular tiotropium bromide [ (1 α, 2 β, 4 β, 5 α, 7 β) -7- [ (hydroxy-2-thienylacetyl) oxy)]-9, 9-dimethyl-3-oxa-9-azonium (azonia) tricyclo [3.3.1.0^2.4]Nonane bromide monohydrate, referred to as tiotropium BR for short]As anticholinergic agents.

With respect to alkyl groups (even components of other groups), unless otherwise defined, branched and straight chain alkyl groups having 1 to 4 carbon atoms are provided. Examples are methyl, ethyl, propyl or butyl. Within this range, all possible isomeric forms of the propyl and butyl radicals mentioned above are included, unless otherwise indicated. For example, propyl includes two isomers, n-propyl and isopropyl, and butyl includes n-butyl, i-butyl, sec-butyl and tert-butyl. The alkyl groups mentioned hereinabove can be indicated, if necessary, by common abbreviations, e.g., Me is methyl, Et is ethyl, etc.

As regards alkoxy groups (and even components of other groups), unless otherwise defined, branched and straight-chain alkyl groups, linked by an oxygen atom, have from 1 to 4 carbon atoms. The following are examples thereof: methoxy, ethoxy, propoxy (═ propyloxy) or butoxy (═ butyloxy). Likewise, all possible isomeric forms of propoxy and butoxy mentioned hereinabove are included within this scope unless otherwise indicated.

Branched and straight-chain alkenyl bridges having from 4 to 6 carbon atoms are used as the alkenyl group. The following are examples thereof: butene, pentene, hexene. Within this range, all possible isomeric forms of butene, pentene, hexene, as indicated above, are included, unless otherwise indicated. Butene as indicated includes the isomers of n-butene, 1-methylpropene, 2-methylpropene, 1-dimethylethylene, 1, 2-dimethylethylene, and the like.

Typically halogen refers to fluorine, chlorine, bromine or iodine.

Within this range, unless otherwise indicated, the anion X is typically referred to as fluorine, chlorine, bromine, iodine, mesylate, fumarate, citrate.

The active substance combinations according to the invention are preferably administered in metered dose aerosol dosage forms-however, any other form or parenteral or oral administration may be used. Metered dose aerosol applications are preferred here, in particular in the treatment of obstructive pulmonary disease or in the treatment of asthma.

In addition to the use of aerosols which are operated by propellant gases, the active substance mixtures according to the invention can also be administered in so-called nebulizers, by means of which the pharmaceutical-active substance solutions can be sprayed out under high pressure to generate a mist of inhalation particles. Such a nebulizer has the advantage that the propellant gas applied can be completely dispersed.

The pharmaceutical agents to be inhaled are usually dissolved in aqueous or alcoholic solutions, where ethanol or water solvent mixtures are also suitable, depending on the solution properties of the active substance.

Sprays of the type described in PCT patent application WO 91/14468 and International patent application PCT/EP96/04351Misters, the contents of which are incorporated herein by reference. The nebulizer described herein, in Respimat^®It is known to make inhalation aerosols by spraying metered dose solutions containing active substances through small nozzles under high pressure to produce particles preferably between 1 and 10, more preferably between 2 and 5 microns in size.

Among these, mixtures containing ethanol as solvent are particularly suitable as solvents for pharmaceutical preparations.

Besides water, other solvent components can be used as required, and other cosolvent can be used, and the medicinal preparation also can contain flavoring agent and other medicinal auxiliary agent. Examples of cosolvents are esters containing hydroxyl groups or other polar groups, such as alcohols, in particular isopropanol, glycols, in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acids. The co-solvents are suitable for increasing the solubility of the auxiliaries and, if desired, the active substances.

Other pharmaceutical adjuvants may be added, such as preservatives, especially benzalkonium chloride. Preferred amounts of preservative, especially benzalkonium chloride, are between 8 and 12 mg per 100 ml of solution.

A complex-forming agent may be added to the active substance mixture to avoid spray abnormalities. Suitable complex forming agents are pharmaceutically acceptable, in particular those which have been approved by the pharmaceutical law. EDTA, nitrilotriacetic acid, citric acid and ascorbic acid, and salts thereof are particularly suitable. Ethylenediaminetetraacetic acid disodium salt is most suitable.

The proportion of the active substance combination dissolved in the final pharmaceutical preparation is between 0.001 and 5%, preferably between 0.005 and 3%, in particular between 0.01 and 2%. The maximum concentration of drug is determined by the solubility in the solvent and the necessary dosage to achieve the desired therapeutic effect.

The following formulation forms were used as formulation examples:

component (A)	Composition (mg/100 ml)
		Tiotropium bromide	333.3 mg
Formoterol fumarate	333.3 mg
		Benzalkonium chloride	10.0 mg
EDTA	50.0 mg
		HCl(1n)	Adjusted to pH3.4

Component (A)	Composition (mg/100 ml)
		Tiotropium bromide	333.3 mg
Salmeterol, xinafoate)	666.6 mg
		Benzalkonium chloride	10.0 mg
EDTA	50.0 mg
		HCl(1n)	Adjusted to pH3.4

Furthermore, the active substance mixture can also be inhaled in powder form. The preparation of such administration forms is known from the prior art. In addition to the combination of active substances, pharmaceutically-compatible carrier or auxiliary substances-such as microcrystalline lactose-may be included in the present invention. The dosage form for inhalation may be filled into capsules and has the following composition:

component (A)	Measurement of
		Tiotropium bromide hydrate	6 microgram
Formoterol fumarate x 2H2O	6 microgram
		Lactose monohydrate	Adjusting to 25 mg

Results of the experiment

By Respimat^®Bronchospasm-relieving and cardiovascular effects in anesthetized dogs upon inhalation of aqueous solutions containing tiotropium bromide, formoterol fumarate, and combinations thereof.

Materials and methods

The 18 mongrel dogs weighed 27 to 32 kg. The animals were housed in individual or shared cages and fed on a standard diet of granular form, the last feed being about 15 hours before the start of the test, water ad libitum.

After predosing with 2 mg/kg morphine hydrochloride intramuscularly, 30 mg/kg pentobarbital-sodium salt (Nembutal) was slowly injected intravenously^®). Animals were relaxed by intravenous injection of 1.0 mg/kg of succinylcholine.

The animals were ventilated with ambient air and oxygen (4: 1) after intubation with a servo ventilator 900C (Siemens), at a frequency of 15/min and a respiratory volume of 6-8 liters/min. For recording in a respirator, the respiratory flow is measured by means of a pressure tube (flesh No 1) comprising a pressure difference recorder and an amplifier DCB-4C, which is arranged directly in front of the oro-tracheal tube. The catheter was placed inside the trachea and a second (balloon) catheter was placed inside the lung region of the esophagus. Both are connected to a pressure difference recorder and amplifier to measure the transpulmonary pressure. The respiratory mechanics computer (IFD-Muhlheim) measures the pulmonary resistance (R) from the recorded pressure values. Thus, it can be calculated with the computer program VAS-1LA (IFD-Muhlheim):

the heart rate was recorded using an ECG (endpoint derivative) II) and a cardiometer.

After a 30 minute equilibration period, 10 micrograms/kg acetylcholine chloride was injected intravenously to produce short-term bronchospasm, which was repeated 2-3 times over 10 minutes. Aqueous solutions of the test substances tiotropium bromide, formoterol fumarate and combinations thereof were prepared with a BINEB nebulizer (Respimat)^®) And (4) administration. The administration of each composition is about 1 minute apart. With the BINEB system, the priming mechanism occurs at the end of the expiration phase, and the nebulized solution is forced into the tracheobronchial tree during the next inspiration phase by the respiratory pump.

Dosage form

Tiotropium bromide: 3 and 10. mu.g/15. mu.l

Formoterol fumarate: 3 and 10. mu.g/15. mu.l

Tiotropium bromide + formoterol fumarate: 3+3 microgram or 10+10 microgram/15 microliter

Tables 1-6 show the initial values and the values over 180 minutes after treatment with the test substances. The percentage of inhibition of pulmonary resistance by ACh increased with time over 180 minutes.

Results

The results are shown in the table and the figures. Tiotropium bromide, or formoterol fumarate, at 3 and 10 μ g inhibited the increase in bronchial resistance caused by intravenous ACh, and was dose and clear related. At both doses, the maximum bronchospastic effect of formoterol FU occurred rapidly, with the tiotropium BR delayed by about 60 minutes. Formoterol FU has a relatively short shelf life, especially at low doses, but as expected, the tiotropium BR effect persists to the end of the test (180 minutes).

For the composition containing 3 microgram tiotropium bromide +3 microgram formoterol FU, the 90% bronchospasmolytic effect was reached very rapidly and continued almost unchanged until the end of the test. The protective effect of this composition is substantially greater than that of the individual components and also exceeds the sum of the individual effects of 3 microgram tiotropium bromide and 3 microgram formoterol FU. The effect was over 10 microgram tiotropium bromide or 10 microgram formoterol fumarate (see figure 2).

Tiotropium bromide alone, whether at 3 micrograms or 10 micrograms, did not affect heart rate at all. On the other hand, formoterol FU increases the heart rate in a dose-wise manner, which may exceed 90% at high doses. The values at the end of the test still exceeded 80%. Compositions containing 3+3 micrograms or 10+10 micrograms of tiotropium bromide and formoterol fumarate substantially reduced the heart rate boosting effect with an effect of less than 30%.

Evaluation of

The results were found to be entirely surprising, in contrast to the individual substances, i.e. the mixture of anticholinergic agents and β -mimetics:

1. the effect starts rapidly

2. Long action duration

But is mainly composed of

3. Superaddition de-bronchospasm effect, and

4. the frequency of heart rate increases is substantially reduced, especially with high formoterol doses.

The use of a combined preparation may be expected to provide a substantially improved therapeutic effect for both COPD and asthma, with the attendant advantage of minimal cardiac side effects.

Watch (A)

Table 1: 3 μ g of tiotropium bromide by Respimat^®Effect on the frequency of heartbeats of anaesthetised dogs after administration by inhalation, n ═ 6

Heart rate (times/minutes)
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											66.50	63.00	67.00	64.00	61.00	63.00	67.00	63.00	66.00
	87.50	87.00	84.00	82.00	87.00	81.00	89.00	87.00	87.00
											86.50	84.00	84.00	89.00	89.00	89.00	84.00	77.00	86.00
	109.50	115.00	115.00	116.00	120.00	121.00	104.00	105.00	105.00
											110.50	119.00	119.00	118.00	110.00	110.00	111.00	110.00	100.00
	85.50	85.00	87.00	90.00	93.00	97.00	97.00	92.00	96.00
										Mean value of	91.00	92.17	92.67	93.17	93.33	93.50	92.00	89.00	90.00
Standard mean deviation (SD)	6.80	8.63	8.23	8.45	8.35	8.46	6.40	7.14	5.66

3 micrograms tiotropium bromide, change%
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											66.50	-5.26	0.75	-3.76	-8.27	-5.26	0.75	-5.26	-0.75
	87.50	-0.57	-4.00	-6.29	-0.57	-7.43	1.71	-0.57	-0.57
											86.50	-2.89	-2.89	2.89	2.89	2.89	-2.89	-10.98	-0.58
	109.50	5.02	5.02	5.94	9.59	10.50	-5.02	-4.11	-4.11
											110.50	7.69	7.69	6.79	-0.45	-0.45	0.45	-0.45	-9.50
	85.50	-0.58	1.75	5.26	8.77	13.45	13.45	7.0	12.28
										Mean value of	91.00	0.57	1.39	1.81	1.99	2.28	1.41	-2.30	-0.54
Standard mean error	6.80	1.99	1.83	2.25	2.72	3.42	2.62	2.53	2.93

Table 2: 10 micrograms of tiotropium bromide was passed through Respimat^®Effect on the Heart Rate of anaesthetised dogs after inhalation administration, n ═ 6

Heart rate (times/minutes)
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											66.50	79.00	75.00	75.00	77.00	79.00	74.00	75.00	70.00
	87.50	96.00	91.00	88.00	89.00	90.00	85.00	83.00	83.00
											86.50	85.00	80.00	79.00	77.00	76.00	75.00	76.00	87.00
	109.50	104.00	102.00	101.00	101.00	101.00	103.00	103.00	105.00
											110.50	102.00	102.00	102.00	101.00	96.00	101.00	102.00	101.00
	85.50	76.00	75.00	76.00	77.00	74.00	73.00	74.00	74.00
										Mean value of	91.00	90.33	87.50	86.83	87.00	86.00	85.17	85.50	86.67
Standard mean error	6.80	4.89	5.17	5.00	4.82	4.60	5.61	5.53	5.75

10 micrograms tiotropium bromide, variation%
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											66.50	18.80	12.78	12.78	15.79	18.80	11.28	12.78	5.26
	87.50	9.71	4.00	0.57	1.71	2.86	-2.86	-5.14	-5.14
											86.50	-1.73	-7.51	-8.67	-10.98	-12.14	-13.29	-12.14	0.58
	109.50	-5.02	-6.85	-7.76	-7.76	-7.76	-5.94	-5.94	-4.11
											110.50	-7.69	-7.69	-7.69	-8.60	-13.12	-8.60	-7.69	-8.60
	85.50	-11.11	-12.28	-11.11	-9.94	-13.45	-14.62	-13.45	-13.45
										Mean value of	91.00	0.49	-2.93	-3.65	-3.30	-4.14	-5.67	-5.26	-4.24
Standard mean error	6.80	4.68	3.84	3.66	4.25	5.23	3.84	3.86	2.70

Table 3:3 microgram formoterol fumarate by Respimat^®Effect on the Heart Rate of anaesthetised dogs after inhalation administration, n ═ 6

Heart rate (times/minutes)
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											94.50	102.00	105.00	129.00	134.00	138.00	134.00	115.00	108.00
	133.00	123.00	140.00	162.00	165.00	159.00	153.00	147.00	140.00
											60.00	67.00	64.00	100.00	95.00	89.00	86.00	88.00	86.00
	80.50	91.00	95.00	110.00	100.00	95.00	94.00	94.00	96.00
											106.50	129.00	137.00	138.00	141.00	145.00	140.00	130.00	130.00
	92.50	107.00	116.00	125.00	126.00	128.00	128.00	120.00	120.00
										Mean value of	94.50	103.17	109.50	127.33	126.83	125.67	122.50	115.67	113.33
Standard mean error	10.03	9.19	11.59	8.89	10.71	11.44	10.87	9.02	8.39

3 microgram formoterol fumarate,% change
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											94.50	7.94	11.11	36.51	41.80	46.03	41.80	21.69	14.29
	133.00	-7.52	5.26	21.80	24.06	19.55	15.04	10.53	5.26
											60.00	11.67	6.67	66.67	54.33	48.33	43.33	46.67	43.33
	80.50	13.04	18.01	36.65	24.44	18.01	16.77	16.77	19.25
											106.50	21.13	28.64	29.58	32.39	36.15	31.46	22.07	22.07
	92.50	15.68	25.41	35.14	36.22	38.38	38.38	29.73	29.73
										Mean value of	94.50	10.32	15.85	37.72	36.17	34.41	31.13	24.58	22.32
Standard mean error	10.03	3.99	3.99	6.24	5.25	5.28	5.10	5.12	5.36

Table 4: 10 microgram formoterol fumarate via Respimat^®Effect on heart rate in anesthetized dogs after inhaled administration, n-6.

Heart rate (times/minutes)
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											94.50	116.00	153.00	155.00	157.00	159.00	163.00	176.00	152.00
	133.00	145.00	136.00	191.00	204.00	207.00	210.00	209.00	205.00
											60.00	109.00	146.00	152.00	153.00	150.00	149.00	146.00	141.00
	80.50	96.00	120.00	144.00	156.00	156.00	140.00	140.00	130.00
											106.50	105.00	120.00	160.00	158.00	150.00	150.00	145.00	145.00
	92.50	122.00	122.00	130.00	135.00	140.00	140.00	135.00	135.00
										Mean value of	94.50	115.50	132.83	155.33	160.50	160.33	158.67	158.50	151.33
Standard mean error	10.03	6.94	5.88	8.32	9.38	9.70	10.83	11.68	11.18

10 microgram formoterol fumarate,% change
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											94.50	22.75	61.90	64.02	66.14	68.25	72.49	86.24	60.85
	133.00	9.02	2.26	43.61	53.38	55.64	57.89	57.14	54.14
											60.00	81.67	143.33	153.33	155.00	150.00	148.33	143.33	135.00
	80.50	19.25	49.07	78.88	93.79	93.79	73.91	73.91	61.49
											106.50	-1.41	12.68	50.23	48.36	40.85	40.85	36.15	36.15
	92.50	31.89	31.89	40.54	45.95	51.35	51.35	45.95	45.95
										Mean value of	94.50	27.20	50.19	71.77	77.10	76.65	74.14	73.79	65.59
Standard mean error	10.03	11.86	20.70	17.32	17.15	16.44	15.70	15.77	14.22

Table 5: 3 micrograms of tiotropium BR +3 micrograms of formoterol FU by Respimat^®Effect on heart rate in anesthetized dogs after inhaled administration, n-6.

Heart rate (times/minutes)
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											107.50	107.00	110.00	112.00	110.00	110.00	110.00	106.00	106.00
	143.00	153.00	162.00	160.00	158.00	154.00	161.00	146.00	145.00
											95.00	106.00	109.00	111.00	121.00	119.00	108.00	114.00	107.00
	95.50	110.00	117.00	129.00	128.00	130.00	129.00	123.00	123.00
											112.00	127.00	120.00	115.00	115.00	104.00	112.00	107.00	96.00
	101.50	100.00	110.00	110.00	112.00	114.00	110.00	101.00	95.00
										Mean value of	109.08	117.17	121.33	122.83	124.00	121.83	121.67	116.17	112.00
Standard mean error	7.31	8.07	8.33	7.69	7.31	7.37	8.47	6.73	7.78

3 microgram tiotropium bromide +3 microgram formoterol fumarate,% change
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											107.50	-0.47	2.33	4.19	2.33	2.33	2.33	-1.40	-1.40
	143.00	6.99	13.29	11.89	10.49	7.69	12.59	2.10	1.40
											95.00	11.58	14.74	16.84	27.37	25.26	13.68	20.00	12.63
	95.50	15.18	22.51	35.08	34.03	36.13	35.08	28.80	28.80
											112.00	13.39	7.14	2.68	2.68	-7.14	0.00	-4.46	-14.29
	101.50	-1.48	8.37	8.37	10.34	12.32	8.37	-0.49	-6.40
										Mean value of	109.08	7.53	11.40	13.17	14.54	12.76	12.01	7.42	3.46
Standard mean error	7.31	2.91	2.87	4.86	5.38	6.41	5.12	5.55	6.23

Table 6: 10 microgram tiotropium bromide +10 microgram formoterol fumarate by Respimat^®Effect on heart rate in anesthetized dogs after inhaled administration, n-4.

Heart rate (times/minutes)
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											107.50	107.00	107.00	114.00	117.00	117.00	117.00	116.00	119.00
	143.00	150.00	154.00	171.00	180.00	182.00	181.00	168.00	168.00
											95.00	107.00	107.00	116.00	124.00	127.00	125.00	122.00	126.00
	95.50	116.00	117.00	120.00	127.00	129.00	130.00	120.00	123.00
										Mean value of	110.25	120.00	121.25	130.25	137.00	138.75	138.25	131.50	134.00
Standard mean error	11.29	10.22	11.17	13.64	14.49	14.65	14.50	12.23	11.42

10 microgram tiotropium bromide +10 microgram formoterol fumarate,% change
											Control group	Minutes after application
		1	5	10	20	30	60	120	180
											107.50	-0.47	-0.47	6.05	8.84	8.84	8.84	7.91	10.70
	143.00	4.90	7.69	19.58	25.87	27.27	26.57	17.48	17.48
											95.00	12.36	12.36	22.11	30.53	33.68	31.58	28.42	32.63
	95.50	21.47	22.51	25.65	32.98	35.08	36.13	25.65	28.80
										Mean value of	110.25	9.63	10.59	18.35	24.56	26.22	25.78	19.87	22.40
Standard mean error	11.29	4.77	4.80	4.29	5.44	6.04	5.97	4.61	5.06

Drawings

Figure 1 shows the effect of 3 microgram formoterol fumarate, 3 microgram tiotropium bromide and 3 microgram tiotropium bromide +3 microgram formoterol fumarate composition on bronchial resistance in anesthetized dogs, with n being 6.

Figure 2 shows the effect of 10 microgram formoterol fumarate, 10 microgram tiotropium bromide and 3 microgram tiotropium bromide +3 microgram formoterol fumarate composition on bronchial resistance in anesthetized dogs, with n ═ 6.

Claims (15)

1. A pharmaceutical composition characterized by comprising an anticholinergic agent having a long-acting action and a beta-mimetic agent having a long-acting action.

2. A pharmaceutical composition according to claim 1, characterized in that the anticholinergic agent with a long-lasting action is selected from glycopyrrolate or the esters of bicyclic and tricyclic amino alcohols of formula (I)

Wherein

A represents a group of the formula (II)

Wherein

Q represents one of the following double bond groups: -CH₂-CH₂-、-CH₂-CH₂-CH₂-, -CH ═ CH-, or

R represents C optionally substituted by halogen-or hydroxy₁-C₄An alkyl group, a carboxyl group,

r' represents C₁-C₄Alkyl, and R' may also combine to form C₄-C₆Alkenyl, and

an anionic X equivalent which counteracts the positive charge of the N atom,

z represents one of the following two groups

Or

Wherein

Y represents a single bond, an O or S atom or one of the following groups: -CH₂-、-CH₂-CH₂-、-CH＝CH-、-OCH₂-or-SCH₂-；

R¹Represents hydrogen, OH, C₁-C₄Alkoxy or C₁-C₄Alkyl, which may be optionally substituted with hydroxy;

R²represents thienyl, phenyl, furyl, cyclopentyl or cyclohexyl, where these radicals may also be substituted by methyl, and thiophene and phenyl may also be substituted by fluorine or chlorine,

R³represents hydrogen or thienyl or phenyl, which may optionally be substituted by halogen or C₁-C₄Alkyl radical takingInstead of the first generation,

optionally in the form of their racemates, enantiomers, diastereomers and mixtures thereof.

3. A pharmaceutical composition according to claim 1 or 2, characterized in that the anticholinergic agent with a long-lasting effect is selected from glycopyrrolate or bicyclic and tricyclic amino alcohols of the formula (I), wherein

A represents a group of the formula (II)

Wherein

Q represents one of the following double bond groups: -CH ═ CH-, -CH₂-CH₂-, or

R represents methyl, ethyl or propyl; may be optionally substituted with fluorine or hydroxyl,

r' represents methyl, ethyl or propyl, preferably methyl, and

an anionic X equivalent capable of counteracting the positive charge of the N atom, selected from chlorine, bromine and the salts of methanesulfonic acid, preferably bromine,

z represents one of the following two groups

Or

Wherein

Y represents a single bond or an O atom;

R¹represents hydrogen, OH, methoxy, ethoxy, propoxy, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl or hydroxypropyl;

R²represents thienyl, phenyl or cyclohexyl, where these radicals may be substituted by methyl and thienyl and phenyl may also be substituted by fluorine or chlorine,

R³represents hydrogen, or thienyl or phenyl, which may optionally be substituted by fluorine, chlorine or methyl,

it can be used in the form of its racemate, enantiomer, diastereomer and mixture thereof.

4. Pharmaceutical composition according to claim 1 or 2, characterized in that the anticholinergic agent with a long-lasting effect is selected from the group of esters of bicyclic and tricyclic amino alcohols of formula (I), wherein

A represents a group of the formula (II)

Wherein

Q represents one of the following double bond groups: -CH ═ CH-, -CH₂-CH₂-, or

R represents methyl or ethyl;

r' represents methyl, and

the monoanionic X ═ bromide equivalent to counteract the positive charge of the N atom, Z represents one of the following diradicals

Or

Wherein

Y represents an O atom;

R¹represents hydrogen, OH or hydroxymethyl;

R²represents thienyl, phenyl or cyclohexyl,

R³represents hydrogen, thienyl or phenyl,

the racemates, enantiomers, diastereomers and mixtures thereof may be used as desired.

5. A pharmaceutical composition according to claim 1, 2, 3 or 4, characterized in that the anticholinergic agent with a long-lasting effect is a salt selected from tiotropium.

6. A pharmaceutical composition according to claim 1, 2, 3 or 5, characterized in that the anticholinergic effect with a long-lasting effect is tiotropium bromide.

7. A pharmaceutical composition according to any one of claims 1 to 6, characterized in that the β -mimetic with long-acting action is selected from the group consisting of bambuterol, tolbutadine (bitolterol), albuterol (carbbuterol), clenbuterol (clenbuterol), fenoterol (fenoterol), formoterol (formoterol), hexadephrine (hexopralin), albuterol (tributerol), pirbuterol (pirbuterol), procaterol (procaterol), procaterol (reproterol), salmeterol (salmeterol), albuterol (sulfonoterol), terbutaline (terbutalin), tolbutamide (tolbutaterol), 4-hydroxy-7- [2- { [2- { [3- (2-phenylethoxy) propyl ] sulfonyl } ethyl ] amino } ethyl ] -2(3H) -benzothiazolone,

1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino ] ethanol,

1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl ] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-n-butoxyphenyl) -2-methyl-2-propylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- {4- [3- (4-methoxyphenyl) -1, 2, 4-triazol-3-yl ] -2-methyl-2-butylamino } ethanol,

5-hydroxy-8- (1-hydroxy-2-isopropylaminobutyl) -2H-1, 4-benzoxazin-3- (4H) -one,

1- (4-amino-3-chloro-5-trifluoromethylphenyl) -2-tert-butylamino) ethanol and

1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol,

optionally racemates, enantiomers, diastereomers and mixtures thereof, and optionally pharmaceutically compatible acid addition salts thereof.

8. A pharmaceutical composition according to any one of claims 1 to 6, characterized in that the long-acting β -mimetic is selected from formoterol, salmeterol,

4-hydroxy-7- [2- { [2- { [3- (2-phenylethoxy) propyl ] sulfonyl } ethyl ] -amino } ethyl ] -2(3H) -benzothiazolone,

1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino ] ethanol,

1- [3- (4-methoxybenzyl-amino) -4-hydroxyphenyl ] -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-N, N-dimethylaminophenyl) -2-methyl-2-propylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-methoxyphenyl) -2-methyl-2-propylamino ] ethanol,

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- [3- (4-n-butoxyphenyl) -2-methyl-2-propylamino ] ethanol, and

1- [ 2H-5-hydroxy-3-oxo-4H-1, 4-benzoxazin-8-yl ] -2- {4- [3- (4-methoxyphenyl) -1, 2, 4-triazol-3-yl ] -2-methyl-2-butylamino } ethanol,

optionally in the form of their racemates, enantiomers, diastereomers and mixtures thereof, and optionally in the form of their pharmaceutically compatible acid addition salts.

9. A pharmaceutical composition according to claims 1 to 8, characterized in that the β -mimetic with long-acting action is selected from formoterol and salmeterol, optionally in the form of its racemate, enantiomers, diastereomers and mixtures thereof, and optionally in the form of its pharmaceutically compatible acid addition salts.

A pharmaceutical composition according to any one of claims 1 to 8, characterized in that the anticholinergic agent with a long-acting action is tiotropium bromide and the β -mimetic with a long-acting action is formoterol fumarate.

11. A pharmaceutical composition according to any one of claims 1 to 9, characterised in that the anticholinergic agent with a long-acting action is tiotropium bromide and the β -mimetic with a long-acting action is salmeterol.

12. Pharmaceutical composition according to one of claims 1 to 11, characterized in that it is an inhalable-administered pharmaceutical composition.

13. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 12, characterized in that it is prepared by mixing an anticholinergic agent with a long-acting action and a β -mimetic with a long-acting action, if desired with further auxiliaries and/or carrier substances, according to methods known per se.

14. A pharmaceutical composition according to any one of claims 1 to 13 for the preparation of a medicament for the treatment of respiratory diseases.

15. A pharmaceutical composition according to claim 14 for the manufacture of a medicament for the treatment of asthma or COPD.