SK7412003A3 - Novel medicament compositions based on tiotropium salts and on salmeterol salts - Google Patents

Abstract

Drug compositions containing one or more tiotropium salts and one or more salmeterol salts, are new. Drug compositions containing one or more tiotropium salts and one or more salmeterol salts, are new. The salts can be present in the form of enantiomers, enantiomer mixtures or racemates as well as in the form of solvates or hydrates. The compositions may also contain a pharmaceutical adjuvant. ACTIVITY : Antiasthmatic. MECHANISM OF ACTION : Anticholinergic; beta -mimetic.

Description

The present invention relates to pharmaceutical compositions based on tiotropium salt and salmeterol salts and their use in the treatment of respiratory diseases.

BACKGROUND OF THE INVENTION

The compound tiotropium bromide, a tiotropium salt, is known from European patent application EP 418 716 A1 and has the following chemical formula:

This compound can also be designated by its chemical name (1α, 2β, 4β, 5α, 7β) 7 - [(hydroxy-di-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo [ 3.3.1.0 ^2,4 ] nonane bromide and has valuable pharmacological properties. In the present invention, the term tiotropium is understood as a reference to a free cation.

This compound, as well as other tiotropium salts, is a highly effective anticholinergic and may therefore be therapeutically useful for the treatment of asthma or COPD (chronic obstructive pulmonary disease).

The application of tiotropium salts is preferably carried out by inhalation. Here, suitable inhalation powders may be used which are administered filled into suitable capsules (inhalers) by means of appropriate powder inhalers. Alternatively, inhalation may also be accomplished by administration of suitable inhalation aerosols. These also include powdered inhalation aerosols containing, for example, HFA134a, HFA227 as propellant

-Or their mixture. Inhalation administration can further be carried out with suitable tiotropium salt solutions.

SUMMARY OF THE INVENTION

Surprisingly, it has been found that an unexpected advantageous therapeutic effect, in particular a synergistic effect in the treatment of inflammatory or obstructive airways diseases, was observed when one or more salts of tiotropium (1) were used in combination with one or more salmeterol salts (2).

Thus, for example, it is possible to greatly reduce unwanted side effects in humans, which are often observed with β-mimetics such as salmeterol. The central side effect of β-mimetics is, for example, general agitation, arousal, insomnia, fear, tremors, sweating and headaches.

The term tiotropium in the present invention refers to a free cation (I '). Reference to salmeterol is to be understood in the context of the present invention as a reference to the free base (2 ').

Surprisingly, the active compound combinations according to the invention are further characterized by a rapid onset of action as well as a long duration of action. This is of great importance for the patient's satisfaction, since on the one hand, the application is rapidly improved after administration and, on the other hand, once-a-day administration is sufficient due to the long efficacy. The above effects are also observed when co-administered in a single active agent formulation as well as the sequential administration of both active agents in separate formulations. According to the invention, simultaneous application of both active ingredient components in a single formulation is preferred.

Accordingly, the present invention provides a pharmaceutical composition comprising one or more salts of tiotropium (1) and one or more salts of salmeterol (2), optionally in the form of their solvates or hydrates. Here, the active ingredients can be contained either together in a single dosage form or in two separate dosage forms. According to the invention, a pharmaceutical composition comprising active ingredients 1 and 2 in a single dosage form is preferred.

Furthermore, the present invention relates to a pharmaceutical composition comprising, in addition to therapeutically effective amounts of Compound 1 and Compound 2

A pharmaceutically acceptable excipient. One embodiment of the present invention pertains to a pharmaceutical composition which, in addition to therapeutically effective amounts of Compound 1 and Compound 2, contains no pharmaceutically acceptable excipient.

The present invention further relates to the use of Compound 1 and Compound 2 for the manufacture of a pharmaceutical composition comprising therapeutically effective amounts of Compound 1 and Compound 2 for the treatment of inflammatory or obstructive airways diseases, particularly asthma or COPD, by simultaneous or sequential administration.

The present invention is further directed to the simultaneous or sequential use of therapeutically effective doses of a combination of the above pharmaceutical compositions comprising Compound 1 and Compound 2 for the treatment of inflammatory or obstructive airways diseases, particularly asthma or COPD.

The salts of tiotropium 1 useful in the present invention are compounds which contain, in addition to tiotropium, chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methylsulfate as counterion (anion). Within the scope of the present invention, of all tiotropium salts, methanesulfonate, chloride, bromide or iodide are preferred, with methanesulfonate or bromide being of particular importance. According to the invention, tiotropium bromide is of particular importance.

Salmeterol 2 salts according to the invention are pharmaceutically acceptable salts selected from salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, xinafonic acid or maleic acid, provided that compound 2 cannot be salmeterol xinafonan when compound 1 is tiotropium bromide. Alternatively, mixtures of the acids mentioned may also be used to produce the salts of salmeterol.

Salmeterol 2 salts according to the invention are preferably selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate. Particularly preferred are salts of compound 2 selected from hydrochloride and sulfate, of which sulfates are most preferred. According to the invention, salmeterol x ¹ / 2H ₂ SO _{4 is of} particular importance.

In the active compound combinations of the invention consisting of compound 1 and compound 2, the components, compound 1 and compound 2, may be present in the form of their enantiomers, mixtures of enantiomers, or in the form of racemates.

The ratios in which both the active compounds Compound 1 and the compound 2 can be used in the active compound combinations according to the invention are variable. The active compounds compound 1 and compound 2 may optionally exist in the form of their solvates or hydrates. Depending on the choice of salt of compound 1 or compound 2, the weight ratios applicable in the present invention vary based on the different molecular weights of the different salt forms. The following weight ratios therefore based on tiotropium cation 1 'as well as salmeterol 2' free base. The active compound combinations according to the invention may contain the compound I 'and the compound 2' in weight ratios from 1: 300 to 30: 1, more preferably from 1: 230 to 20: 1, particularly preferably from 1: 150 to 10: 1, very preferably from 1:50 to 5: 1, most preferably from 1:35 to 2: 1. According to the invention, particularly preferred are pharmaceutical compositions comprising a combination of compound 1 'and compound 2' in a weight ratio of from 1:25 to 1: 1, more preferably from 1:10 to 1: 2, most preferably from 1: 5 to 1: 1 1: 2.5.

By way of example and without limiting the scope of the invention, preferred combinations of compound 1 and compound 2 of the invention may contain tiotropium 1 'and salmeterol 2' in the following weight ratios: 1:40; 1:20; 1: 11.1; 1:10; 1: 5.6; 1: 5; 1: 2.8; 1: 2.5 ;, 1: 1.4; 1: 1.25; 1.44: 1; 1.6: 1st

Administration of a pharmaceutical composition according to the invention comprising a combination of compound 1 and compound 2 is carried out usually by dosing tiotropium 1 'and salmeterol 2' in a combined dose of from 0.01 to 10,000 pg, more preferably from 0.1 to 2000 pg, particularly preferably from 1 to 2,000 pg. up to 1000 pg, particularly preferably from 5 to 500 pg, even more preferably according to the invention from 10 to 200 pg, even more preferably from 20 to 100 pg, most preferably from 30 to 70 pg.

For example, the combinations of Compound 1 and Compound 2 of the invention contain an amount of tiotropium 1 'and salmeterol 2' such that the single dose is 30 pg, 35 pg, 45 pg, 55 pg, 60 pg, 65 pg, 90 pg, 105 pg in a single dose. 110 pg 140

-5pg or the like. In these dosage ranges, the active ingredients 1 'and 2' are contained in the above weight ratios.

By way of example and without limiting the scope of the invention, the combinations of Compound 1 and Compound 2 of the invention may contain such amounts of tiotropium 1 'and salmeterol 2' that 5 µg of Compound 1 'and 25 µg of Compound 2', 5 µg are administered in a single dose. Compound I 'and 50 µg Compound 2', 5 µg Compound I 'and 100 µg Compound 2', 5 µg Compound I 'and 200 µg Compound I', 10 µg Compound I 'and 25 µg Compound I', 10 µg Compound I 'and 50 µg Compound 2 ', 10 µg of compound 1', 100 µg of compound 2 ', 10 µg of compound 1' and 200 µg of compound 2 ', 18 µg of compound 1' and 25 µg of compound 1 ', 18 µg of compound 1' and 50 µg of compound 2 ' and 100 pg of 2 ', 18 pg of 1' and 200 pg of 2 ', 20 pg of 1' and 25 pg of 2 ', 20 pg of 1' and 50 pg of 2 ', 20 pg of 1' and 100 pg of 2 ' , 20 µg of Compound 1 'and 200 µg of Compound 2', 36 µg of Compound 1 'and 25 µg of Compound 2', 36 µg of Compound 1 ' the effects of I 'and 50 µg of 2', 36 µg of I 'and 100 µg of 2', 36 µg of I 'and 200 µg of 2', 40 µg of I 'and 25 µg of 2', 40 µg of I 'and 50 µg of I 2 ', 40 µg of 1' and 100 µg of 2 'or 40 µg of 1' and 200 µg of 2 '.

When a preferred combination is used according to the invention as a combination of active ingredients consisting of compound 1 and compound 2, in which compound 1 is tiotropium bromide and compound 2 is salmeterol x ¹ / 2H ₂ SO 4, the amounts of active ingredients 1 and 2 above. applied in a single dose to the amounts of Compound 1 and Compound 2 administered in a single dose: 6 pg of Compound 1 and 27.9 pg of Compound 2, 6 pg of Compound 1 and 55.9 pg of Compound 2, 6 pg of Compound 1 and 111.8 pg of Compound 2.6 pg of Compound 1 and 223.6 pg of Compound 2, 12 pg of Compound 1 and 27.9 pg of Compound 2, 12 pg of Compound 1 and 55.9 pg of Compound 2, 12 pg of Compound 1 and 111.8 pg of Compound 2, 12 pg of Compound 1 and 223.6 pg of Compound 2, 21.7 pg of Compound 1 and 27.9 pg of Compound 2, 21.7 pg of Compound 1 and 55.9 pg of Compound 2,

21.7 pg of Compound 1 and 111.8 pg of Compound 2, 21.7 pg of Compound 1 and 223.6 pg of Compound 2, 24.1 pg of Compound 1 and 27.9 pg of Compound 2, 24.1 pg of Compound 1 and 55 , 9 pg of compound 2, 24.1 pg of compound 1 and 111.8 pg of compound 2, 24.1 pg of compound 1 a

223.6 pg of compound 2, 43.3 pg of compound 1 and 27.9 pg of compound 2, 43.3 pg of compound 1 and 55.9 pg of compound 2, 43.3 pg of compound 1 and 111.8 pg of compound 2, 43 , 3 pg of Compound 1 and 223.6 pg of Compound 2, 48.1 pg of Compound 1 and 27.9 pg of Compound 2, 48.1 pg of Compound 1 and 55.9 pg of Compound 2, 48.1 pg of Compound 1 and 111, 8 pg of compound 2 or 48.1 pg of compound 1 and 223.6 pg of compound 2.

When, for example, tiotropium bromide monohydrate is used as compound 1 in the combination of compound 1 and compound 2 preferred according to the invention in which compound 2 is salmeterol x ¹ / 2H ₂ SO ₄ , the above amounts of active ingredients 1 'and 2' applied in a single dose Compound 1 and Compound 2 administered in a single dose: 6.2 pg of Compound 1 and 27.9 pg of Compound 2, 6.2 pg of Compound 1 and 55.9 pg of Compound 2, 6.2 pg of Compound 1 and 111.8 pg of Compound 2, 6.2 pg of Compound 1 and 223.6 pg of Compound 2, 12.5 pg of Compound 1 and 27.9 pg of Compound 2, 12.5 pg of Compound 1 and 55.9 pg of Compound 2, 12.5 pg of Compound 1 and

111.8 pg of compound 2, 12.5 pg of compound 1 and 223.6 pg of compound 2, 22.5 pg of compound 1 and 27.9 pg of compound 2, 22.5 pg of compound 1 and 55.9 pg of compound 2, 22 , 5 pg of Compound 1 and 111.8 pg of Compound 2, 22.5 pg of Compound 1 and 223.6 pg of Compound 2, 25 pg of Compound 1 and 27.9 pg of Compound 2, 25 pg of Compound 1 and 55.9 pg of Compound 2 , 25 pg of Compound 1 and 111.8 pg of Compound 2, 25 pg of Compound 1 and 223.6 pg of Compound 2, 45 pg of Compound 1 and 27.9 pg of Compound 2, 45 pg of Compound 1 and 55.9 pg of Compound 2, 45 pg of compound 1 and 111.8 pg of compound 2, 45 pg of compound 1 and 223.6 pg of compound 2, 50 pg of compound 1 and 27.9 pg of compound 2, 50 pg of compound 1 and 55.9 pg of compound 2, 50 pg of compound 1 and 111.8 µg of compound 2 or 50 µg of compound 1 and 223.6 µg of compound

Second

The application of the active compound combination according to the invention composed of compound 1 and compound 2 is preferably carried out by inhalation. For this purpose, it is necessary to prepare components 1 and 2 in a form which can be administered by inhalation. Suitable inhalation dosage forms are inhalable powders, dispensing aerosols containing propellant or propellant-free inhalable solutions. An inhalable powder according to the invention comprising a combination of active substances composed of compound 1 and compound 2 can exist separately from said active substances or from a mixture of said substances with physiologically acceptable excipients. Within the scope of the present invention, propellant-free inhalation solutions also include concentrates or sterile, ready-to-use inhalation solutions. The dosage forms of the invention may comprise a combination of active ingredients composed of compound 1 and compound 2 either together in one or two separate dosage forms. These dosage forms useful in the present invention will be described in detail in the following.

A) Inhalable powders containing the active compound combinations according to the invention composed of compound 1 and compound 2

The inhalable powders of the invention may contain compound 1 and compound 2 either alone or in admixture with suitable physiologically acceptable excipients.

When the active compounds Compound 1 and Compound 2 are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients can be used for the manufacture of these inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose) ), oligosaccharides and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylite), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. The use of monosaccharides or disaccharides is preferred, and the use of lactose or glucose, particularly but not exclusively, in the form of their hydrates is particularly preferred. As a particularly preferred excipient within the meaning of the invention, lactose is most preferably used as an excipient in the form of lactose monohydrate.

The excipients within the inhalable powders of the invention have a maximum mean particle size of up to 250 µm, more preferably from 10 to 150 µm, most preferably from 15 to 80 µm. Alternatively, it may be sensible to admix the finer excipient fraction with a mean particle size of from 1 to 9 µm to the above excipients. The latter finer excipients are also selected from the abovementioned group of useful excipients. Finally, in the manufacture of the inhalable powders according to the invention, the micronized active compounds Compound 1 and Compound 2 are admixed, preferably with a mean particle size of from 0.5 to 10 µm, particularly preferably from 1 to 6 µm. Method for producing inhalable powders according to

The invention of grinding and micronizing as well as the subsequent mixing of the components is known in the art. The inhalable powders according to the invention may exist and be administered either in the form of a single powder mixture containing both Compound 1 and Compound 2, or in the form of separate inhalable powders containing only Compound 1 and Compound 2.

The inhalable powders according to the invention can be administered using inhalers known in the art. The inhalable powders of the invention which, in addition to Compound 1 and Compound 2, further comprise a physiologically acceptable excipient, may, for example, be administered by inhalers which dispense a single dose from a reservoir using a metering chamber as described in US 4570630A or other apparatus, as described in DE 36 25 685 A. However, it is preferable to fill inhalable powders according to the invention containing, in addition to compound 1 and compound 2, physiologically acceptable excipients into capsules (so-called inhalers) which can be administered using inhalers such as described in WO 94/28958 . If the inhalable powders according to the invention are to be filled according to the above-mentioned preferred application in capsules (inhalers), the amount of filling may be from 1 to 30 mg, more preferably from 3 to 20 mg, most preferably from 5 to 10 mg inhalation powder per capsule. According to the invention, these contain, either together or individually, the aforementioned dosages of compound I 'and compound 2' in a single dose.

B) Propellant-containing inhalation aerosols comprising a combination of the active ingredients according to the invention composed of compound 1 and compound 2

The propellant-containing inhalation aerosols according to the invention may comprise compound 1 and compound 2 dissolved in the propellant or in dispersed form. They may contain Compound 1 and Compound 2 in separate dosage forms or together in one dosage form, wherein Compound 1 and Compound 2 may contain both dissolved, both dispersed or only one component dissolved and the other dispersed. Propellants useful in the manufacture of inhalation aerosols according to the invention are known in the art. Suitable propellants are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as

- 9 are chlorinated and / or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above propellants may be used alone or in a mixture thereof. Particularly preferred propellants are halogenated alkane derivatives selected from the group consisting of TG11, TG12, TG134a and TG227. Of the above halogenated hydrocarbons, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof are most preferred according to the invention.

The propellant-containing inhalation aerosols according to the invention may further comprise other components such as cosolvents, stabilizers, surfactants, antioxidants, lubricants as well as pH adjusters. All these components are known in the art.

The propellant-containing inhalable aerosols according to the invention may contain up to 5% by weight of the propellant. The aerosols according to the invention contain, for example, from 0.002 to 5% by weight, from 0.01 to 3% by weight, from 0.015 to 2% by weight, from 0.1 to 2% by weight. %, from 0.5 to 2 wt. or from 0.5 to 1 wt. of active substance 1 and / or active substance 2.

If the active compounds Compound 1 and / or Compound 2 exist in dispersed form, the mean particle size of the active substance is preferably up to 10 µm, more preferably from 0.1 to 5 µm, most preferably from 1 to 5 µm.

The above-mentioned propellant-containing inhalation aerosols can be administered using metered dose inhalers (MDls) known in the art. Correspondingly, another aspect of the present invention relates to a pharmaceutical composition in the form of the above-described propellant-containing inhalation aerosols in conjunction with one or more inhalers suitable for delivery of such aerosols. Furthermore, the present invention relates to inhalers which are characterized in that they contain the above-described propellant-containing aerosols according to the invention. The present invention further relates to a cartridge which can be used after having been fitted with a suitable valve in a suitable inhaler and which contains the above mentioned propellant-containing aerosols according to the invention. Suitable cartridges and methods for filling these cartridges with propellant-containing inhalation aerosols according to the invention are known in the art.

C) Propellant-free inhalable solutions containing a combination of the active compounds according to the invention composed of compound 1 and compound 2

The application of the active compound combination according to the invention in the form of a propellant-free inhalation solution is particularly preferably carried out. Suitable solvents for this purpose are aqueous or alcoholic solutions, preferably ethanol solutions. The solvent may be exclusively water or a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but a maximum level of up to 70% by volume, more preferably up to 60% by volume, is more preferred. and most preferably up to 30% by volume. Make up the remaining volume percentages with water. A preferred solvent is water without the addition of ethanol. Solutions containing compound 1 and compound 2, separately or together, are adjusted with a suitable acid to a pH of from 2 to 7, more preferably from 2 to 5, particularly preferably from 2.5 to 3.5. Most preferably, the inhalable solutions of the invention together comprising Compound 1 and Compound 2 having a pH of about 2.9. Acids selected from inorganic or organic acids can be used to adjust this pH. Examples of suitable inorganic acids are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids are ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid and others. Preferred inorganic acids are hydrochloric acid, sulfuric acid. It is also possible to use acids which already form an acid addition salt with the active substance or in the case of a combination of the preparations with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. It is also possible to use mixtures of the abovementioned acids, in particular in the case of acids which have, in addition to their acidification properties, other properties, for example as flavorings, antioxidants or complexing agents, such as citric acid or ascorbic acid. According to the invention, it is most preferred to use hydrochloric acid to adjust the pH.

According to the invention, the addition of EDTA or one of their known salts, sodium edetate, as a stabilizer or complexing agent, can be dispensed with in the present formulations. Other embodiments include the following

-11 compounds. In one of these preferred embodiments, the content, based on sodium edetate, is less than 100 mg / 100 ml, more preferably less than 50 mg / 100 ml, most preferably less than 20 mg / 100 ml. Inhalation solutions in which the content of sodium edetate is in the range from 0 to 10 mg / 100 ml are generally preferred.

Co-solvents and / or other excipients may additionally be included in the propellant-free inhalable solutions according to the invention. Preferred co-solvents are those containing hydroxyl groups or other polar groups, for example alcohols, in particular isopropyl alcohol, glycols - especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. In this context, excipients and additives are understood to mean any pharmacologically acceptable substance which is not an active substance but together with the active substance may be formulated in a pharmacologically acceptable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no or, in the context of the therapy outlined, no significant or at least no undesirable pharmacological effect. Adjuvants and additives include, for example, surfactants such as soy, lecithin, oleic acid, sorbitan esters such as polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives that provide or extend the shelf life of the finished pharmaceutical composition, flavorings, vitamins and / or other ingredients known in the art. Additives also include pharmacologically acceptable salts such as sodium chloride as an isotonic agent.

Preferred excipients include antioxidants, such as ascorbic acid, if not already used to adjust the pH, vitamin A, vitamin E, tocopherols, and similar vitamins and provitamins found in the human body. Preservatives may be used to protect the formulation from germ contamination. Suitable preservatives are those known in the art, in particular cetylpyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in concentrations known in the art. The aforementioned preservatives are preferably present in a concentration of up to 50 mg / 100 ml, more preferably from 5 to 20 mg / 100 ml.

Preferred formulations contain, in addition to the water solvent and the active compound combination of Compound 1 and Compound 2, also benzalkonium chloride and sodium edetate. In another preferred embodiment, sodium edetate has been omitted.

Particularly suitable for the administration of propellant-free inhalable solutions according to the invention are those inhalers which are capable of spraying a small amount of a liquid formulation in a therapeutically necessary dose into a therapeutically-inhalable aerosol in a few seconds. Within the scope of the present invention, such atomisers are advantageous which, by means of a single stroke, can be sprayed to form an aerosol having an average particle size of less than 20 µm, more preferably less than 10 µm, of an active substance solution of less than 100 µl, more preferably less than 50 µl. most preferably from 20 to 30 µl in such a way that the inhalable proportion of aerosol already corresponds to a therapeutically effective amount.

Such a device for delivering a propellant-free metered amount of a liquid pharmaceutical composition for inhalation use is extensively described, for example, in International Patent Application WO 91/14468 as well as in WO 97/12687 (especially Figures 6a and 6b). The devices described therein are also known as Respimat®.

This nebulizer (Respimat®) can be advantageously used to form an inhalable aerosol according to the invention comprising a combination of active ingredients composed of compound 1 and compound 2. Based on its cylindrical shape and suitable size of less than 9 to 15 cm in length and 2 to 4 cm width this device can be worn by the patient at any time. The nebulizer sprays a predetermined volume of the pharmaceutical composition using high pressure small nozzles to form inhalable aerosols.

A preferred sprayer consists essentially of a good part of the housing, the pump body, the nozzle, the locking tensioning mechanism, the spring housing, the spring and the reservoir, comprising:

- a pump housing which is attached to the top of the housing and is equipped at its end with a nozzle body with a nozzle or nozzle assembly,

- hollow piston with valve body,

- a drive flange in which the hollow piston is mounted and located at the top of the housing,

- locking tensioning mechanism located at the top of the housing,

- a spring housing with a spring inside which is rotatably mounted on the upper part of the housing by means of a rotary bearing,

- a lower part of the housing which is slid in the axial direction onto the spring housing.

The hollow piston with the valve body corresponds to the device disclosed in WO 97/12687. This partially extends into the cylinder of the pump housing and is disposed axially in the cylinder. In particular, reference is made to Figures 1 to 4, in particular to Figure 3 and to the corresponding description. The hollow cylinder with the valve body exerts a pressure of 5 to 60 MPa (approximately 50 to 600 bar), more preferably 10 to 60 MPa (approximately 100 to 600 bar) on its fluid side to measure the active substance solution at the time of the spring application. . Preferred volumes are from 10 to 50 µl, more preferably from 10 to 20 µΙ, most preferably 15 µΙ per stroke.

The valve body is preferably arranged at the end of the hollow piston which faces the nozzle body.

The nozzle is preferably microstructured in the nozzle body, i. made by micro technology. Microstructured nozzles are disclosed, for example, in WO-94/07607; this file is hereby explicitly referred to, in particular Figure 1 and its description.

The nozzle body comprises, for example, two glass and / or silicon plates fixed to one another, of which at least one plate comprises one or more microstructured channels connecting the suction side of the nozzle to the discharge side of the nozzle. On the discharge side of the nozzle there is at least one round or non-round opening with a depth of from 2 to 10 µm and a width of from 5 to 15 µm, a depth of from 4.5 to 6.5 µm and a length of from 7 to 9 µm being preferred.

In the case of a plurality of nozzle orifices, two are preferred, the direction of flow of the nozzles in the nozzle body may be parallel or may be inclined toward one another in the direction of the nozzle opening. In a nozzle body with at least two nozzle orifices on the discharge side, the flow directions may be inclined to each other at an angle of 20 degrees to 160 degrees, preferably an angle of 60 to 150 degrees, most preferably 80 to 100 degrees. The nozzle openings are preferably arranged at a distance of from 10 to 200 µm, more preferably at a distance of from 10 to 100 µm, particularly preferably from 30 to 70 µm.

-14μιτ). The most preferred distance is 50 µm. The flow directions intersect accordingly around the nozzle opening.

The liquid pharmaceutical composition acts on the nozzle body with an inlet pressure of up to 60 MPa (600 bar), more preferably from 20 to 30 MPa (200 to 300 bar) and is sprayed through the nozzle orifices to form an inhalable aerosol. The preferred particle size or droplet size of the aerosol is up to 20 µm, more preferably from 3 to 10 µm.

The locking tensioning mechanism comprises a spring, more preferably a cylindrical coil compression spring, than a mechanical energy storage device. The spring acts on the drive flange as a step element, the movement of which is determined by the position of the locking element. The movement of the drive flange is precisely limited by the upper and lower stops. The spring is preferably clamped via a transmission transmitting force, such as a helical sliding transmission, by an external torque that is generated when the upper housing part is rotated against the spring housing at the lower housing part. In this case, the upper housing part and the drive flange comprise a single or multi-stage wedge gear.

The locking element with the engaging locking surfaces is arranged annularly around the drive flange. It consists, for example, of a radially elastically deformable ring of plastic or metal. The ring is arranged in a plane vertical to the spray axis. When the spring is stretched, the locking surfaces of the locking element are moved into the drive flange path and prevent the spring from loosening. The locking element is triggered by the button. The trigger button is connected or coupled to the locking element. To actuate the locking tensioning mechanism, the trigger button is moved parallel to the plane of the ring, and more preferably to the interior of the atomiser; the deformable ring is deformed in the plane of the ring. The construction details of the locking tensioning mechanism are described in WO 97/20590.

The lower part of the housing is slid in the axial direction over the spring housing and covers the bearing, the spindle drive and the fluid reservoir.

Upon actuation of the sprayer, the upper housing part rotates relative to the lower housing part, the lower housing part carrying the spring housing. In this case, the spring is compressed and tensioned by means of a screw sliding gear and a locking mechanism

-15It will fall freely. The pivot angle is more preferably an integer fraction of 360 degrees, for example 180 degrees. Simultaneously with the spring tension, the drive element in the upper housing part is moved by a predetermined path, the hollow piston being moved back in the pump body cylinder, sucking a portion of the fluid volume from the reservoir into the high pressure space upstream of the nozzle.

Optionally, a plurality of replaceable containers containing the liquid to be sprayed can be inserted into the sprayer in succession. The cartridge comprises an aqueous aerosol formulation according to the invention.

The spraying process is carried out by lightly pressing the start button. In doing so, the locking mechanism releases the path for the drive element. The tensioned spring moves the piston into the cylinder of the pump body. The liquid exits the atomizer nozzle in an atomized form.

Further construction details are published in PCT application WO 97/12683 and WO / 20590, the contents of which are hereby incorporated by reference.

The components of the sprayer are of a material suitable for the function in question. The spray case and, if the function permits, the other parts are preferably made of plastic, for example by injection molding. Physiologically acceptable materials are used for medical purposes.

Figures 1 a / b, which are identical to figures 6a / b in WO 97/12687, disclose a nebulizer (Respimat ®) with which it is possible to advantageously inhale the aqueous aerosol formulations of the invention.

Figure 1a shows a longitudinal section of the atomiser when the spring is tensioned, Figure 1b shows a longitudinal section of the atomizer when the spring is released.

The upper part of the housing 51 comprises a pump body 52, at the end of which a spray nozzle holder 53 is disposed. A nozzle body 54 and a filter 55 are located in the holder. The hollow piston 57 mounted in the drive flange 56 of the locking tensioning mechanism partially extends into the cylinder of the pump body. At its end, the hollow piston has a valve body 58. The hollow piston is sealed by means of a gasket 59. In the upper part of the housing there is a stop 60 on which the drive flange rests when the spring is released. On the drive flange there is a stop 61 on which the drive flange rests when the spring is tensioned. After the spring is stretched, the locking element 62 is moved between the stop 61 and the support 63 on the upper part of the housing. The trigger button 64 is p

-16locking element connected. The upper part of the housing is terminated by a mouthpiece 65 and closed by a push-on protective closure 66.

The spring body 67 with the compression springs 68 is rotatably supported by the latching lugs 69 and the pivot bearing in the upper often housing. A lower part of the housing 70 is inserted through the spring housing. The replaceable fluid container 71 is disposed in the spring housing. The reservoir is closed by a plug 73 through which a hollow piston is inserted into the reservoir extending into the liquid (active substance solution reservoir).

A mechanical counter spindle 74 is provided in the housing of the spring housing. At the end of the spindle facing the top of the housing there is a pinion 75. A slider 76 is disposed on the spindle.

The above-described nebuliser is suitable for spraying an aerosol formulation of the invention into an aerosol suitable for inhalation.

If the formulation of the invention is sprayed using the above-described technique (Respimat®), the plotted amount should correspond to at least 97%, more preferably at least 98% of all actuations of the inhaler (piston strokes) defined amount with a tolerance range of % of this quantity. Preferably, a plurality of from 5 to 30 mg of formulation is plotted per stroke, more preferably from 5 to 20 mg.

However, the formulations of the invention may also be nebulized by means of inhalers other than those described above, for example by means of Jet-Stream inhalers.

Accordingly, the invention further relates to a pharmaceutical composition in the form of the above-described propellant-free inhalation solutions in conjunction with a device suitable for delivering these solutions, more preferably in conjunction with a Respimat ® device. More preferably, the present invention is directed to propellant-free inhalable solutions characterized by a combination of the active ingredients according to the invention composed of compound 1 and compound 2 in conjunction with a device known as Respimat®. Furthermore, the present invention relates to the above-mentioned inhalation devices, more preferably Respimat® devices, characterized in that they contain the propellant-free inhalation solutions described above according to the invention.

The propellant-free inhalable solutions according to the invention may exist as concentrates or sterile ready-to-use inhalation solutions in addition to the solutions described above for use with the Respimat® device. Ready-to-use inhalation solutions can be generated from the concentrates, for example by adding isotonic sodium chloride solution. Sterile ready-to-use inhalation solutions can be applied by means of power-driven stationary or portable nebulizers, which generate inhalable aerosols by ultrasound or by compressed air according to the Venturi principle or other principles.

Correspondingly, a further aspect of the present invention relates to a pharmaceutical composition in the form of the above-described propellant-free inhalable solutions, which exist in the form of concentrates or ready-to-use sterile solutions in connection with the application of these solutions by a suitable device. power-driven stationary or portable nebulizers, which generate inhalable aerosols by ultrasound or by compressed air according to the Venturi principle or other principles.

The following examples serve to broadly illustrate the present invention, but without limiting the scope thereof to the following exemplary embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1 a / b, which are identical to figures 6a / b in WO 97/12687, disclose a nebulizer (Respimat ®) with which it is possible to advantageously inhale the aqueous aerosol formulations of the invention. Figure 1a shows a longitudinal section of the atomiser when the spring is tensioned, Figure 1b shows a longitudinal section of the atomizer when the spring is released.

DETAILED DESCRIPTION OF THE INVENTION

Starting materials Tiotropium bromide

The tiotropium bromide used in the following formulation examples can be obtained by the method described in European patent application EP 418 716 A1.

Crystalline tiotropium bromide monohydrate may also be used to produce the inhalable powder of the invention. This crystalline tiotropium bromide monohydrate can be obtained as follows.

25.7 kg of water and 15.0 kg of tiotropium bromide were mixed in a suitable reaction vessel. The mixture was heated to 80-90 ° C and stirred at a constant temperature until a clear solution was formed. Activated carbon (0.8 kg) moistened with water was soaked in 4.4 kg of water, this mixture was added to a solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained was stirred for a minimum of 15 minutes at 80 to 90 ° C and then filtered through a heated filter in a preheated apparatus with a jacket temperature of 70 ° C. The filter was washed with 8.6 kg of water. The capture in the apparatus was cooled to 20-25 ° C with 3-5 ° C in 20 minutes. Using water cooling, the apparatus was further cooled to 10-15 ° C and the crystallization was completed with at least one hour of additional stirring. The crystallizate was collected by suction drying, the isolated crystal slurry was washed with 9 liters of cold water (10-15 ° C) and cold acetone (10-15 ° C). The obtained crystals were dried at 25 ° C for 2 hours under a stream of nitrogen.

Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory)

The crystalline tiotropium bromide monohydrate so obtained was micronized by known methods to give the active ingredient in the form of a medium particle size which complies with the specification of the invention.

Salmeterol x ¹ / zH 2 SO 4

In the following examples, when referring to salmeterol x ¹ / 2H ₂ SO 4, this was obtained as follows.

A suspension of 2.5 g (4.15 mmol) of salmeterol xinafonane was dissolved in 6 ml in ethanol. While stirring, 0.14 ml of a 98% sulfuric acid solution was added slowly to the suspension. It was heated to 35-40 ° C until completely dissolved. Subsequently, the mixture was diluted with 10 ml of diethylether and the solution was seeded with salmeterol sulfate. The salmeterol sulfate was aspirated after 1.5 hours and washed with 20 ml of cold ethanol, acetone and diethyl ether each time.

1.5 g (78%) of salmeterol ¹ /2-sulfate were obtained.

-19Examples of pharmaceutical compositions

A) Inhalable powder

1)

ingredients pg in one capsule tiotropium bromide 10.8 salmeterol x ¹ / 2H ₂ SO 4 27.9 lactose 4,961.3 together 5000

2)

ingredients pg in one capsule tiotropium bromide 21.7 salmeterol x ¹ / 2H ₂ SO ₄ 55.9 lactose 4,299.4 together 5000

3)

ingredients pg in one capsule tiotropium bromide 22.5 salmeterol x ¹ / 2H ₂ SO ₄ 55.9 lactose 4,921.6 together 5000

B) Propellant-containing inhalation aerosols

1) Aerosol suspensions

ingredients % wt. tiotropium bromide 0,015 salmeterol x ¹ / 2H ₂ SO 4 0,066 soya lecithin 0.2 TG11: TG12 = 2: 3 to 100

2) Aerosol suspensions

ingredients % wt. tiotropium bromide 0,029 salmeterol x ¹ / 2H ₂ SO ₄ 0,033 absolute ethanol 0.5 isopropyl myristate 0.1 TG227 to 100

3) Aerosol solution

ingredients % wt. tiotropium bromide 0,042 salmeterol x ¹ / 2H ₂ SO ₄ 0,047 absolute ethanol 30 water, purified 1.5 citric acid, anhydrous 0,002 TG134a to 100

C) Propellant-free inhalable solutions

1) Solution for use in Respimat®

ingredients mg / 100 ml tiotropium bromide 148.5 salmeterol x% H ₂ SO ₄ 276.7 benzalkonium chloride 10 edetate sodium 10 hydrochloric acid (aq.) and pH 2.9 Water to 100 ml

Use of the solution in the Respimat inhaler resulted in a single dose of 10 µg of Compound 1 and 25 µg of Compound 2.

-21 2) Solution for use in Respimat®

ingredients mg / 100 ml tiotropium bromide 148.5 salmeterol x ¹ / 2H ₂ SO ₄ 276.7 benzalkonium chloride 10 hydrochloric acid (aq.) and pH 2.9 Water to 100 ml

Use of the solution in the Respimat inhaler resulted in a single dose of 10 µg of Compound 1 and 25 µg of Compound 2.

3) Solution for use in Respimat®

ingredients mg / 100 ml tiotropium bromide 297.1 salmeterol x ¹ / 2H ₂ SO ₄ 276.7 benzalkonium chloride 10 edetate sodium 10 hydrochloric acid (aq.) and pH 2.9 Water to 100 ml

Use of the solution in a Respimat inhaler resulted in a single dose of 20 µg of Compound 1 and 25 µg of Compound 2.

4) Solution for use in Respimat®

ingredients mg / 100 ml tiotropium bromide 297.1 salmeterol x / 2H 2 SO 4 276.7 benzalkonium chloride 10 hydrochloric acid (aq.) and pH 2.9 Water to 100 ml

The use of the solution in the Respimat inhaler resulted in a single dose of 20 µg of Compound 1 and 25 µg of Compound 2.

5) Solution for use in Respimat®

ingredients mg / 100 ml tiotropium bromide 148.5 salmeterol x ¹ / 2H ₂ SO 4 1,106.3 benzalkonium chloride 8 edetate sodium 50 hydrochloric acid (aq.) and pH 2.5 Water to 100 ml

Use of the solution in the Respimat inhaler resulted in a single dose of 10 µg of Compound 1 and 100 µg of Compound 2.

6) Solution for use in Respimat®

ingredients mg / 100 ml tiotropium bromide 1.5 salmeterol x ¹ / 2H ₂ SO ₄ 276.7 benzalkonium chloride 8 edetate sodium 10 hydrochloric acid (aq.) and pH 2.5 Water to 100 ml

Use of the solution in the Respimat inhaler resulted in a single dose

0.1 pg of compound 1 and 25 pg of compound 2.

7) Solution for use in Respimat®

ingredients mg / 100 ml tiotropium bromide 14.9 salmeterol x _^1/2 H ₂ SO ₄ 1,106.32

benzalkonium chloride 10 edetate sodium 50 hydrochloric acid (aq.) and pH 3.5 Water to 100 ml

Use of the solution in the Respimat inhaler resulted in a single dose of 1 µg of Compound 1 and 100 µg of Compound 2.

8) Solution for use in Respimat®

ingredients mg / 100 ml tiotropium bromide 1,486.1 salmeterol x ¹ / zH ₂ SO 4 1,106.32 benzalkonium chloride 10 edetate sodium 10 hydrochloric acid (aq.) and pH 3.5 Water to 100 ml

Use of the solution in the Respimat inhaler resulted in a single dose

100 µg of compound 1 and 100 µg of compound 2.

9) Concentrated solution

ingredients mg / 100 ml tiotropium bromide 1,486.1 salmeterol x ¹ / 2H ₂ SO ₄ 11,063.2 benzalkonium chloride 20 edetate sodium 100 hydrochloric acid (aq.) and pH 3.5 Water to 100 ml

7? zooj

Claims (34)

Pharmaceutical composition, characterized in that it contains one or more salts of tiotropium 1 in combination with one or more salts of salmeterol 2, optionally in the form of their enantiomers, mixtures of enantiomers or in the form of racemates, optionally in the form of solvates or hydrates, and optionally together with a pharmaceutically acceptable excipient. Pharmaceutical composition, characterized in that the active compounds Compound 1 and Compound 2 are contained either together in one dosage form or in two separate dosage forms. Pharmaceutical composition according to any one of claims 1 or 2, characterized in that compound 1 is in the form of chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methylsulfate, preferably in the form of bromide. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that compound 2 is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, xinafonic acid and maleic acid, provided that compound 2 cannot be salmeterol xinafonan when compound 1 is tiotropium bromide. Pharmaceutical composition according to claim 4, characterized in that compound 2 is a salt selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate, hydrochloride and sulfate are particularly preferred. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the weight ratios of tiotropium 1 'to salmeterol 2 are in the range of 1: 300 to 30: 1, more preferably of 1: 230 to 20: 1. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that the amount of active compound combination comprising compound 1 'and compound 2' per single application is from 0.01 to 1000 pg, more preferably from 0.1 to 200 pg. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that it is in a form for inhalation. Pharmaceutical composition according to claim 8, characterized in that the form for inhalation administration is selected from the group comprising inhalable powder, a propellant-containing dispensing aerosol and a propellant-free inhalation solution. Pharmaceutical composition according to claim 9, characterized in that it is in the form of an inhalable powder which, together with the compound 1 and compound 2, contains suitable physiologically acceptable excipients selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols. , salts, or mixtures of these excipients. Pharmaceutical composition in the form of an inhalable powder according to claim 10, characterized in that the excipient has a maximum mean particle size of up to 250 µm, preferably of 10 to 150 µm. Pharmaceutical composition, characterized in that it is in the form of a capsule containing the inhalable powder according to claim 10 or 11. Pharmaceutical composition according to claim 9, characterized in that the inhalation powder contains only active substance 1 and active substance 2. 14. A pharmaceutical composition according to claim 9, wherein the form for inhalation is a propellant-containing inhalation aerosol containing Compound 1 and Compound 2 in dissolved or dispersed form. A propellant-containing inhalable aerosol formulation according to claim 14, characterized in that it contains hydrocarbons such as n-propane, n-butane or isobutane or halogenated hydrocarbons such as chlorinated and / or fluorinated derivatives of methane, ethane as propellant. , propane, butane, cyclopropane or cyclobutane. Propellant-containing inhalable aerosol pharmaceutical composition according to claim 15, characterized in that it contains TG11, TG12, TG134a, TG227 or mixtures thereof as propellant, more preferably TG134a, TG227 or a mixture thereof. 17. A propellant-containing inhalable aerosol formulation according to any one of claims 14, 15 or 16, which may contain one or more components selected from the group consisting of cosolvents, stabilizers, surfactants, antioxidants, lubricants. and means for adjusting the pH. A pharmaceutical composition in the form of a propellant-containing inhalation aerosol according to any one of claims 14 to 17, characterized in that it can contain up to 5 wt. and / or active substance 2 '. Pharmaceutical composition according to claim 9, characterized in that the form for administration by inhalation is a propellant-free inhalable solution containing water, ethanol or a mixture of water and ethanol as solvent. A pharmaceutical composition in the form of an inhalation solution according to claim 19, characterized in that the pH of the solution is from 2 to 7, preferably from 2 to 5. A pharmaceutical composition in the form of an inhalation solution according to claim 20, characterized in that the pH is adjusted with an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and propionic acid or mixtures thereof. A pharmaceutical composition in the form of an inhalation solution according to any one of claims 19 to 21, characterized in that it optionally further comprises further cosolvents and / or auxiliaries. Pharmaceutical composition in the form of an inhalable solution according to claim 22, characterized in that it contains components which contain hydroxyl groups or other polar groups, such as alcohols, in particular isopropyl alcohol, glycols, in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. Pharmaceutical composition in the form of an inhalation solution according to any one of claims 22 or 23, characterized in that it contains surfactants, stabilizers, complexing agents, antioxidants and / or preservatives, flavoring agents, pharmacologically acceptable salts and / or vitamins as adjuvants. Pharmaceutical composition in the form of an inhalable solution according to claim 24, characterized in that it contains as the complexing agent editic acid or editic acid salt, preferably sodium edetate. Pharmaceutical composition in the form of an inhalation solution according to any one of claims 24 or 25, characterized in that it contains as antioxidants compounds selected from the group consisting of ascorbic acid, vitamin A, vitamin E and tocopherols. Pharmaceutical composition in the form of an inhalation solution according to any one of claims 24, 25 or 26, characterized in that as The preservatives include compounds selected from cetylpyridinium chloride, benzalkonium chloride, benzoic acid and benzoates. A pharmaceutical composition in the form of an inhalation solution according to any one of claims 22 to 27, characterized in that it contains benzalkonium chloride and sodium edetate in addition to the active compounds of compound 1 and compound 2 and the solvent. A pharmaceutical composition in the form of an inhalation solution according to any one of claims 22 to 27, characterized in that it contains benzalkonium chloride in addition to the active compounds of compound 1 and compound 2 and the solvent. A pharmaceutical composition in the form of an inhalation solution according to any one of claims 19 to 29, which is in the form of a concentrate or sterile ready-to-use inhalation solution. Use of a pharmaceutical composition in the form of an inhalation solution according to any one of claims 19 to 29 for nebulization by means of an inhaler according to WO 91/14468 or a similar inhaler as shown in Figures 6a and 6b in WO 97/12687. Use of a pharmaceutical composition in the form of an inhalation solution according to claim 30 for nebulisation in a stationary or portable energy-driven nebulizer that generates inhalable aerosols by ultrasound or compressed air according to the Venturi principle or other principles. A pharmaceutical composition according to any one of claims 1 to 30 for use in the treatment of respiratory diseases. The pharmaceutical composition of claim 33, wherein the airways disease is asthma or COPD.