HRP20030378A2 - Novel medicament compositions based on tiotropiumsalts 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 proposed invention is refers to a new formulation of the drug based on tiotropium salt and salmeterol salt, to the procedure for its preparation as well as to its use in the therapy of respiratory diseases.

Background of the invention

The compound tiotropium bromide is a salt of tiotropium which is known from the European patent application EP 418 716 Al and it has the following chemical structure:

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This compound can also be called by the chemical name (1α,2β,4β,5α,7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo- [3.3.1.0]nonane also has valuable pharmacological properties. The designation tiotropium within the scope of the proposed invention is considered to also mean the free cation.

Tiotropium, as well as its salts, are highly effective anticholinergics and can therefore be used in the treatment of asthma or COPD (chronic obstructive pulmonary disease).

Application of tiotropium salt is primarily by inhalation. In this case, a suitable inhalation powder can be used, which is applied using suitable powder inhalers filled in suitable capsules (inhalates). Alternatively, inhalation administration can also be carried out by the application of a suitable inhalation aerosol. This also includes powder inhalation aerosols, which contain, for example, HFA134a, HFA227 or their mixture as propellant gas. Inhalation application can also be carried out using suitable tiotropium salt solutions.

Description of the invention in detail

It has surprisingly been found that an unexpected beneficial therapeutic effect, particularly a synergistic effect, is observed in the treatment of inflammatory or obstructive diseases of the respiratory tract if one or more tiotropium salts (1) are administered in combination with one or more salmeterol salts (2).

This can significantly limit, for example, the unwanted side effects that are often observed in humans with the application of beta-mimetics, such as balmeterol. The main side effects of beta-mimetics can be mentioned, for example, general restlessness, excitement, loss of sleep, fear, trembling fingers, sweating and headache.

When tiotropium is mentioned within the framework of the proposed invention, then this name refers to the free cation (1'). When salmeterol is mentioned within the scope of the proposed invention, then this name means the free base (2').

The combinations of active substances according to the invention are furthermore characterized by a surprisingly rapid onset of action, as well as a long-lasting effect. This is of great importance for the health of patients, because on the one hand, after the application of the combination, the condition improves quickly, and on the other hand, due to the longer duration of action, one application per day is sufficient.

The aforementioned effects are observed both with simultaneous application in a single formulation of the active substance, and also with the consecutive application of two active substances in separate formulations. According to the invention, the simultaneous application of two active substances in a single formulation is preferred.

One form of the proposed invention relates to a drug containing one or more tiotropium salts (1) and one or more salmeterol salts (2), as needed in the form of their solvates or hydrates. In doing so, the active substances can be contained together in a single application form or in two separate application forms. According to the invention, preference is given to the drug, which contains active substances 1 and 2 in a single form for application.

A further aspect of the proposed invention relates to a drug, which, in addition to therapeutically effective amounts of compounds 1 and 2, also contains a pharmaceutically acceptable carrier. One form of the proposed invention relates to a drug, which, apart from therapeutically effective amounts of compounds 1 and 2, does not contain any pharmaceutically acceptable carrier.

The proposed invention also relates to the use of compounds 1 and 2 for the production of a drug containing a therapeutically effective amount of compounds 1 and 2 for the treatment of inflammatory or obstructive diseases of the respiratory tract, especially asthma or COPD by simultaneous or sequential administration.

The proposed invention also relates to the simultaneous or sequential use of a therapeutically effective dose of a combination of the preceding drugs 1 and 2 for the treatment of inflammatory or obstructive diseases of the respiratory tract, especially asthma or COPD.

Within the scope of the proposed invention, as usable salts of tiotropium 1 are meant compounds that, in addition to tiotropium, contain chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methylsulfonate as an ion of the opposite charge (anion). Within the framework of the proposed invention, preference is given above all to those salts of tiotropium containing methanesulfonate, chloride, bromide or iodide, whereby particular importance is attached to methanesulfonate or bromide. According to the invention, prominent importance is given to tiotropium bromide.

Salts of salmeterol 2 according to the invention mean pharmaceutically acceptable salts, which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid acid, xinaphonic acid or maleic acid, provided that compound 2 cannot be salmeterol xinafoate if compound 1 is tiotropium bromide. If necessary, mixtures of the above-mentioned acids can also be used for the production of salmeterol salts.

According to the invention, preference is given to those salts of salmeterol 2 which are selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate. Next preference is given to those salts of compound 2 which are selected from the hydrochloride and the sulfate, of which particular preference is given to the sulfate. According to the invention, salmeterol x 1/2 H2SO4 has salmeterol.

Combinations of active substances from 1 and 2 according to the invention may contain ingredients 1 and 2 in the form of their enantiomers, mixtures of enantiomers or in the form of racemates.

The ratios in which the two active substances 1 and 2 can be used in the combination of active substances according to the invention are variable. Active substances 1 and 2 can, if necessary, be present in the form of their solvates or hydrates. Depending on the choice of the salt of compound 1 or 2, the ratios used in the framework of the proposed invention change due to the different molecular weight of the different forms of the salt. Therefore, the following mass ratios are based on the tiotropium cation 1' as well as on the salmeterol free base 2'. Combinations of active substances 1' and 2' according to the invention can be contained in mass ratios ranging from 1:300 to 30:1, preferably from 1:230 to 20:1, especially preferably from 1:150 to 10:1, furthermore, preferably from 1:50 to 5:1, especially advantageously from 1:3.5 to 2:1. According to the invention, drugs containing combinations of compounds 1' and 2' in a mass ratio in the range of 1:25 to 1:1, preferably in the range of 1:10 to 1:2, particularly advantageous in the range of 1:5 to 1:2.5.

For example, but without the intention of limiting the invention, advantageous combinations of compounds 1 and 2 according to the invention may contain tiotropium 1' and salmeterol 2' in the following mass 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, 1.6:1.

The use of the drug according to the invention, which contains a combination of compounds 1 and 2, is usually performed by administering tiotropium 1' and salmeterol 2' together in a dosage of 0.01 to 10,000 μg, preferably from 0.1 to 2,000 μg, particularly preferably from 1 up to 1000 μg, further preferably from 5 to 500 μg, according to the invention preferably from 10 to 200 μg, preferably from 20 to 100 μg, preferably from 30 to 70 μg per one application.

For example, the combinations of compounds 1 and 2 according to the invention contain such an amount of tiotropium 1' and salmeterol 2' that the total dosage per application is 30 μg, 35 μg, 45 μg, 55 μg, 60 μg, 65 μg, 90 μg, 105 μg, 110 μg, 110 μg, 140 μg or similar. In these dosing ranges, active substances 1' and 2' are contained in the above-mentioned mass ratios.

For example and without intending to limit the scope of the invention, the combinations of compounds 1 and 2 according to the invention can contain such an amount of tiotropium 1' and salmeterol 2' that one application yields 5 μg of compound 1' and 25 μg of compound 2', 5 μg of compound 1 ' and 50 μg of compound 2', 5 μg of compound 1' and 100 μg of compound 2', 5 μg of compound 1' and 200 μg of compound 2', 10 μg of compound 1' and 25 μg of compound 2', 10 μg of compound 1' and 50 μg of compound 2', 10 μg of compound 1' and 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 2', 18 μg of compound 1' and 50 μg of compound 2', 18 μg of compound 1' and 100 μg of compound 2', 18 μg of compound 1' and 200 μg of compound 2', 20 μg of compound 1' and 25 μg of compound 2', 20 μg of compound 1' and 50 μg of compound 2 ', 20 μg of compound 1' and 100 μg of compound 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' and 50 μg of compound 2', 36 μg of compound 1' and 100 μg of compound 2', 36 μg of compound 1' and 200 μg of compound 2', 40 μg of compound 1' and 25 μg of compound 2', 40 μg of compound 1' and 50 μg of compound 2', 40 μg of compound 1' and 100 μg of compound 2' or 40 μg of compound 1' and 200 μg of compound 2'.

If a combination of active substances in which compound 1 is tiotropium bromide and in which compound 2 is salmeterol x 1⁄2 H2SO4 is used as a preferred combination of compounds 1 and 2 according to the invention, then the previous examples of the specified application amounts of active substances 1 and 2 per one application following the appropriate amounts of compounds 1 and 2: 6 μg of compound 1 and 27.9 μg of compound 2, 6 μg of compound 1 and 55.9 μg of compound 2, 6 μg of compound 1 and 111.8 μg of compound 2, 6 μg of compound 1 and 223.6 μg of compound 2, 12 μg of compound 1 and 27.9 μg of compound 2, 12 μg of compound 1 and 55.9 μg of compound 2, 12 μg of compound 1 and 111.8 μg of compound 2, 12 μg of compound 1 and 223.6 μg of compound 2, 21.7 μg of compound 1 and 27.9 μg of compound 2, 21.7 μg of compound 1 and 55.9 μg of compound 2, 21.7 μg of compound 1 and 111.8 μg of compound 2, 21.7 μg of compound 1 and 223.6 μg of compound 2, 24.1 μg of compound 1 and 27.9 μg of compound 2, 24.1 μg of compound 1 and 55.9 μg of compound 2, 24.1 μg of compound 1 and 111.8 μg of compound 2, 24.1 μg of compound 1 and 223.6 μg of compound 2, 43.3 μg of compound 1 and 27.9 μg of compound 2, 43.3 μg of compound 1 and 55.9 μg of compound 2, 43.3 μg of compound 1 and 111 .8 μg of compound 2, 43.3 μg of compound 1 and 223.6 μg of compound 2, 48.1 μg of compound 1 and 27.9 μg of compound 2, 48.1 μg of compound 1 and 55.9 μg of compound 2, 48.1 μg of compound 1 and 111.8 μg of compound 2 or 48.1 μg of compound 1 and 223.6 μg of compound 2.

If in the advantageous combination of compounds 1 and 2 according to the invention, compound 2 represents salmeterol x 1/2 H2SO4, and compound 1 is used, for example, as tiotropium bromide monohydrate, then the above-mentioned examples of the amounts of active substances 1' and 2' that are given with one application corresponds to the following amounts of compounds 1 and 2: 6.2 μg of compound 1 and 27.9 μg of compound 2, 6.2 μg of compound 1 and 55.9 μg of compound 2, 6.2 μg of compound 1 and 111.8 μg of compound 2, 6.2 μg of compound 1 and 223.6 μg of compound 2, 12.5 μg of compound 1 and 27.9 μg of compound 2, 12.5 μg of compound 1 and 55.9 μg of compound 2, 12.5 μg of compound 1 and 111.8 μg of compound 2, 12.5 μg of compound 1 and 223.6 μg of compound 2, 22.5 μg of compound 1 and 27.9 μg of compound 2, 22.5 μg of compound 1 and 55.9 μg of compound 2, 22.5 μg of compound 1 and 111.8 μg of compound 2 22.5 μg of compound 1 and 223.6 μg of compound 2 25 μg of compound 1 and 27.9 μg of compound 2 25 μg of compound 1 and 55.9 μg of compound 2, 25 μg of compound 1 and 111.8 μg of compound 2, 25 μg of compound 1 and 223.6 μg of compound 2, 45 μg of compound 1 and 27.9 μg of compound 2, 45 μg of compound 1 and 55.9 μg of compound 2, 45 μg of compound 1 and 111.8 μg of compound 2, 45 μg of compound 1 and 223.6 μg of compound 2, 50 μg of compound 1 and 27.9 μg of compound 2, 50 μg of compound 1 and 55.9 μg of compound 2, 50 μg of compound 1 and 111.8 μg of compound 2 or 50 μg of compound 1 and 223.6 μg of compound 2.

The application of the combination of active substances 1 and 2 according to the invention is primarily done by inhalation. In doing so, ingredients 1 and 2 must be prepared in a form for application that can be inhaled.

Examples of inhalable application forms include inhalable powders, dosing aerosols with propellant gas or inhalation solutions without propellant gas.

The inhalation powder according to the invention, which contains a combination of active substances 1 and 2, can consist only of the above-mentioned active substances or of a mixture of the above-mentioned active substances with physiologically tolerable excipients. Within the framework of the proposed invention, the term inhalation solution without pressure gas also includes concentrates or sterile inhalation solutions ready for use. According to the invention, the forms for application of the combination can contain active substances 1 and 2 together in one or in two separate forms for application. Application forms which can be used within the scope of the proposed invention will be described in detail in the following part of the description.

A) Inhalation powder containing a combination of active substances 1 and 2

The inhalation powder according to the invention can contain compounds 1 and 2 alone or in admixture with suitable and physiologically unquestionable excipients.

If active substances 1 and 2 are contained in a mixture with physiologically unquestionable excipients, the following physiologically unquestionable auxiliary substances can be used for the preparation of this inhalation powder according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose ), oligo- and polysaccharides (eg dextran), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mutual mixtures of these excipients. Mono- or disaccharides are primarily used, whereby preference is given to the use of lactose or glucose, especially, but not exclusively, in the form of their hydrates. Lactose, preferably lactose monohydrate, is used as a particularly advantageous auxiliary substance in terms of the invention.

For the inhalable powder of the invention, the excipients have a maximum average particle size of up to 250 μm, preferably between 10 and 150 μm, particularly preferably between 15 and 80 μm. If necessary, it may prove meaningful to mix the above excipients with a finer fraction of the excipient with an average particle size of 1 to 9 μm. The latter, smaller excipients are also selected from the above-mentioned group of usable excipients. Then, for the production of the inhalation powder according to the invention, the micronized active substances 1 and 2, preferably with medium particle sizes of 0.5 to 10 μm, especially preferably from 1 to 6 μm, are mixed with a mixture of excipients. Processes for the production of the inhalation powder according to the invention by grinding and micronization as well as the final mixing of the ingredients are known from the state of the art. The inhalation powder according to the invention can be prepared in the form of a single powder mixture, which contains compound 1 as well as compound 2, or in the form of separate inhalation powders, each of which contains only compound 1 and compound 2 and are applied in this way.

The inhalation powder according to the invention can be applied using inhalers known from the state of the art.

The inhalation powder according to the invention, which in addition to compounds 1 and 2 also contains a physiologically unquestionable excipient, can be administered, for example, by means of an inhaler that dispenses a single dose from a container by means of a metering chamber as described in US 4570630A, or by means of another working device, such as the device described in DE 36 25 685 A. According to the invention, an inhalation powder is primarily used, which, in addition to compounds 1 and 2, contains a physiologically unquestionable excipient, primarily filled in capsules (so-called inhalates), which are placed in inhalers such as that described, for example, in WO 94/28958.

If the inhalation powder according to the invention and in terms of the above-mentioned preferred application is to be filled into capsules (inhalates), filling amounts of 1 to 30 mg, preferably 3 to 20 mg, preferably 5 to 10 mg of inhalation powder per capsule are offered. According to the invention, they contain together or in any case the above dosage amounts of compounds 1' and 2' per one application.

B) Inhalation aerosol with propellant gas containing a combination of active substances 1 and 2

The inhalation aerosol containing the propellant gas according to the invention may contain compounds 1 and 2 dissolved in the propellant gas or in dispersed form. Here, compounds 1 and 2 can be in separate forms of application or they can be in one common form of application, whereby both compounds 1 and 2 can be dissolved, both can be dispersed or in any case only one component can be dissolved and the other can be dispersed.

Propellant gases that can be used to produce the inhalation aerosol according to the invention are known from the state of 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 chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. At the same time, the above-mentioned propellant gases can be alone or in their mixtures. Particularly favorable propellant gases are halogenated alkane derivatives selected from the group consisting of TG11, TG12, TG134a and TG227. Of the halogenated hydrocarbons mentioned above, according to the invention, TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3-heptafluoropropane) and their mixtures are used primarily.

The inhalation aerosol containing the propellant gas according to the invention may further contain ingredients such as co-solvents, stabilizers, surface-active substances (surfactants), antioxidants, sliding agents as well as an agent for adjusting: pH values. All these ingredients are known from the state of the art.

Inhalation aerosol containing propellant gas according to the invention can contain up to 5 wt. % active substance 1 and/or 2. Aerosols according to the invention contain, for example, 0.002 to 5 wt. %, 0.01 to 3 wt. %, 0.01.5 to 2 wt. %, 0.1 to 2 wt. %, 0.5 to 2 wt. % or 0.5 to 1 wt. % of active substance 1 and/or 2.

If the active substance 1 and/or 2 is present in dispersed form, then this active substance preferably has an average particle size of up to 10 μm, preferably from 0.1 to 5 μm, particularly preferably from 1 to 5 μm.

The aforementioned inhalation aerosol with the pressure gas according to the invention can be applied using inhalers (MDIs = metered dose inhalers) which are known from the state of the art. Accordingly, a further form of the proposed invention is a medicament in the form of the above-described propellant gas aerosol together with an inhaler suitable for single or multiple administration of said aerosol. Furthermore, the proposed invention relates to inhalers which are characterized by the fact that they contain the above-described aerosol with a propellant gas as described above.

The present invention further relates to inserts which are constructed with a suitable valve and which can be used in a suitable inhaler and which contain an inhalation aerosol with a propellant gas according to the invention, as described above. Suitable inserts and methods for filling these inserts with an inhalation aerosol with a pressure gas according to the invention are known from the state of the art.

C) Inhalation solutions without propellant gas containing a combination of active substances 1 and 2 according to the invention

The application of the combination of active substances according to the invention is particularly advantageous in the form of an inhalation solution without propellant gas. As solvents here, aqueous or alcoholic, primarily ethanolic solutions come into consideration. The solvent can be only water or it can be a mixture of water and ethanol. The relative proportion of ethanol to water is not limited, but the maximum limit is preferably up to 70% by volume, especially up to 60% by volume and especially preferably up to 30% by volume. The remaining volume percentages were supplemented with water. The solvent is primarily water without the addition of ethanol. Solutions containing compounds 1 and 2, separately or together, are adjusted with suitable acids to a pH value of from 2 to 7, preferably from 2 to 5, especially preferably from 2.5 to 3.5. According to the invention, inhalation solutions that contain compounds 1 and 2 together and have a pH value of approx. 2.9. To adjust this pH value, acids selected from inorganic or organic acids can be used. Examples of particularly 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 and sulfuric acid. It is also possible to use acids that already form an acid addition salt with the active substance or, in the case of a combined preparation, with one of the active substances. Among the organic acids, ascorbic acid, fumaric acid and citric acid are favorable. If necessary, a mixture of the mentioned acids can also be used, especially in the case of acids that, apart from their acidic properties, also have other properties, e.g. as agents for flavor correction, antioxidants or agents for the formation of complexes, such as citric acid or ascorbic acid.

Hydrochloric acid is especially advantageously used to adjust the pH value according to the invention.

According to the invention, the addition of editic acid (EDTA) or one of its known salts, sodium edetate, as a stabilizer or complex forming agent can be omitted in the proposed formulations.

Other embodiments include that compound(s). In such a preferred embodiment, the sodium edetate content is below 100 mg/100 ml, preferably below 50 mg/ml, particularly preferably below 20 mg/ml.

General advantage: it is given to such inhalation solutions in which the content of sodium edetate is from 0 to 10 mg/l00 ml.

Inhalation solutions without propellant according to the invention may contain co-solvents and/or other excipients.

Favorable co-solvents are those containing hydroxyl groups or other polar groups, for example alcohols, especially isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters.

An auxiliary and additional substance in this sense means any pharmacologically tolerable substance, which is not an active substance, but which together with the active substance (substances) can be formulated in a pharmacologically suitable solvent, thereby qualitatively improving the properties of the formulation of the active substance. These substances do not show any activity or, in terms of the desired therapy, they do not show any noticeable or at least no unwanted pharmacological action. Auxiliary and additional substances include, for example, surface-active substances, such as soy lecithin, oleic acid, sorbitan ester, such as polysorbate, polyvinylpyrrolidone, other stabilizers, complex forming agents, antioxidants and/or preservatives, which enable or extend the shelf life ready-made drug formulations or taste-correcting agents, vitamins and/or other additives known from the state of the art. Additives also include pharmacologically unambiguous salts, such as sodium chloride as an isotonant.

Preferred excipients include antioxidants, such as ascorbic acid, if not already used for pH adjustment, vitamin A, vitamin E, tocopherol and similar vitamins or provitamins that occur in the human body.

Preservatives can be used to protect the formulation from germ contamination. Suitable preservatives are substances known from the state of the art, especially cetylpyridinium chloride, benzalkonium chloride or benzoic acid, or benzoates such as sodium benzoate in concentrations known from the state of the art. The aforementioned preservatives are preferably contained in a concentration of up to 50 mg/100 ml, particularly preferably between 5 and 20 mg/100 ml.

In addition to water as a solvent and the combination of active substances 1 and 2, favorable formulations contain only benzalkonium chloride and sodium edetate. In another advantageous embodiment, sodium edetate is omitted.

Inhalers that can atomize a small amount of liquid formulation in a therapeutically necessary dosage in a few seconds into an aerosol that is suitable for inhalation therapy are especially suitable for the application of inhalation solutions without pressure gas according to the invention. Within the framework of the proposed invention, preference is given; such atomizers in which an amount of less than 100 μm, preferably less than 50 μm, can be atomized, especially preferably between 20 and 30 μl of the active substance solution, preferably with one activation into an aerosol with an average particle size of less than 20 μm, preferably less than 10 micrometers , so that the fraction of aerosol that can be inhaled already corresponds to the therapeutically effective amount.

Such an application device without pressure gas for dosing a quantity of liquid medicament for inhalation is described in detail, for example, in International Patent Application WO 91/14468 as well as in WO 97/12687 (especially Figures 6a and 6b). The atomizers (devices) described there are also known as Respimat®.

This atomizer (Respimat®) can be usefully used according to the invention to create an inhalation aerosol containing a combination of active substances 1 and 2. Due to its cylindrical shape and size suitable for handling, it has a length of less than 9 to 15 cm and a width of 2 to 4 cm, this device can always be delivered to patients together. The atomizer expels a defined volume of the drug formulation by applying high pressure through a small nozzle, so that an aerosol that can be inhaled is created.

A preferred atomizer, consisting mainly of an upper housing, a pump housing, a nozzle, a stop member, a spring housing, a spring and a supply tank, is characterized in that the pump housing is secured in the upper housing, and carries a nozzle body at one end thereof , i.e. assembly with nozzle,

- has a hollow piston with a valve body,

- it has a working flange in which a hollow piston is fixed, and it is located in the upper part of the housing,

- has a locking element located in the upper part of the housing,

- has a spring housing in which a spring is located, which spring housing is pivotally seated in the upper part of the housing by means of a pivot bearing,

- has the lower part of the housing, which is pushed onto the spring housing in the direction of the axis.

A hollow piston with a valve body corresponds to the devices described in WO 97/12687. It partially protrudes into the cylinder of the pump housing and is mounted in the cylinder so that it can be moved axially therein. Figures 1-4 are especially taken into account, especially figure 3 and the corresponding description. A hollow piston with a valve body on its high pressure side at the moment of spring release acts with a pressure of 5 to 60 MPa (approx. 50 to 600 bar), preferably 10 to 60 MPa (approx. 100 to 600 bar) on the liquid, i.e. on the metered solution active substances. At the same time, the volume per stroke is preferably from 10 to 50 microliters, especially advantageously from 10 to 20 microliters, especially advantageously 15 microliters.

The valve body is primarily located at the end of the hollow piston facing the nozzle body.

The nozzle in the nozzle body is primarily micro-structured, i.e. it is produced by micro-technique. Micro-structured nozzle bodies are described, for example, in WO-94/07607; as in WO 9:3/16530; therefore, the contents of that document, in particular Figure 1 in WO-94/07607 and its description, are taken into account.

The body of the nozzle consists, for example, of two plates made of glass and/or silicon firmly connected to each other, of which at least one plate has one or more micro-structured channels, which connect the inlet side of the nozzle with the outlet side of the nozzle. On the exit side of the nozzle there is at least one round or non-round opening with a depth of 2 to 10 micrometers and a width of 5 to 15 micrometers, wherein the depth is preferably 4.5 to 6.5 micrometers and the length is 7 to 9 micrometers.

In the event that there are several nozzle openings, these are primarily two openings, then the directions of the jets from the nozzles in the nozzle body can run parallel to each other or they are inclined to each other in the direction of the nozzle openings. In a nozzle body with at least two nozzle openings, the jet directions on the exit side can be inclined to each other at an angle of 20 degrees to 160 degrees, preferably at an angle of 60 to 150 degrees, especially advantageously at an angle of 80 to 100 degrees.

The nozzle openings are arranged preferably at a distance of 10 to 200 micrometers, more preferably at a distance of 10 to 100 micrometers, particularly preferably 30 to 70 micrometers. The best distance is 50 micrometers. Accordingly, the directions of the jets meet in the vicinity of the nozzle opening.

The liquid drug preparation, as already mentioned, comes to the nozzle body with an inlet pressure of 600 bar, preferably 200 to 300 bar, and is sprayed through the nozzle openings into an aerosol that can be inhaled. The preferred size of the aerosol particles is up to 20 micrometers, preferably 3 to 10 micrometers.

Locking element. includes a spring, preferably a cylindrical coil compression spring, as stored mechanical energy. The spring acts on the working flange as a spring, the movement of which is determined by the position of the locking member. The path of the working flange is exactly bounded by the upper and lower stops. The spring is tensioned via a power transmission gear, such as a screw shift gear, with an external turning moment, which is created by turning the upper part of the housing towards the spring housing. In this case, the upper part of the housing and the working flange contain a single or multi-stage wedge gear.

The locking member with the retractable locking surface is annular to fit the working flange. It consists of a ring that can elastically deform radially inward and is made of plastic or metal. The ring is placed in one plane perpendicular to the axis of the atomizer. After tensioning the spring, the locking surfaces of the locking member move to the path of the working flange and prevent the spring from being unloaded. The locking member is released using a button. The activation button is connected or connected to the locking member. To activate the locking element, the button is moved parallel to the plane of the ring and primarily into the atomizer; in doing so, the ring, which can be deformed, is deformed in the plane of the ring. Details of the construction of the locking element are described in WO 97/20590.

The lower part of the housing moves axially over the spring housing and covers the bearing, spindle drive and fluid reservoir.

To activate the atomizer, the upper part of the housing is rotated towards the lower part of the housing, whereby the lower part of the housing engages the spring housing. In doing so, the spring presses together over the screw displacement gear and is tensioned and the locking element engages automatically. The turning angle is primarily a fraction of a whole number of 360 degrees, eg 180 degrees. At the same time as the spring is tensioned, the working part moves in the upper part of the housing for a predetermined path, the hollow piston is withdrawn; back inside the cylinder in the pump housing, which sucks part of the amount of liquid from the supply tank into the high-pressure space in front of the nozzle.

If necessary, several exchangeable supply containers containing the liquid to be atomized can be pressed into the atomizer and used in succession. The supply container contains the aqueous aerosol preparation according to the invention.

The atomization process is performed by lightly pressing the activation button. In doing so, the locking element clears the way for the working part. A tensioned spring moves the piston into the cylinder of the pump housing. The liquid comes out of the atomizer nozzle in atomized form.

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

Add-on parts of the spray device (atomizer) made of a suitable material that corresponds to its function. The housing of the atomizer and other parts - if this is possible due to the function - are primarily made of plastic, for example by injection molding. Physiologically clear materials are used for medical purposes.

Figures 1la/b, which are identical to Figures 6 a/b from WO 97/12687, show an atomizer (Respimat®) with which aqueous aerosol preparations according to the invention can be inhaled.

Figure 1a shows a longitudinal section through the atomizer with the spring under tension, while Figure 1b shows a longitudinal section through the atomizer with the spring unloaded.

The upper part of the housing (51) contains the pump housing (52), at the end of which there is a holder (53) for the atomizer nozzle. The holder contains the nozzle body (54) and the filter (55). The hollow piston (57), which is fixed in the working flange (56) of the locking element, partially protrudes into the cylinder of the pump housing. The hollow piston carries the valve body (58) at its end. The hollow piston is sealed with a gasket (59). Inside the upper part of the housing there is a stop (60), on which the working flange rests when the spring is tensioned. When the spring is tensioned, then the stop member (62) moves in the upper part of the housing between the stop (61) and the support (63). The activation button (64) is connected to the locking member. The upper part of the housing ends in a spout (65) and it is closed with a protective cap (66) that can be put on.

The spring housing (67) with the compression spring (68) is pivoted by means of a snap-in support (69) and a pivot bearing on the upper part of the housing. The upper part of the housing (70) moves over the spring housing. Inside the spring housing is a replaceable container (71) with a supply of liquid (72) to be sprayed. The container with the supply is closed with a plug (73), through which the hollow piston enters the container with the supply and its end is immersed in the liquid (stock solution of the active substance).

On the surface of the casing of the spring housing there is a spindle (74) for the mechanical dial. At the end of the spindle facing the upper part of the housing there is a drive notch (75). A rider sits on the spindle (76).

The atomizer described above is suitable for atomizing the aerosol preparation according to the invention into an aerosol suitable for inhalation.

If the formulation according to the invention is atomized using the previously described technique (Respimat®), the ejected mass with at least 97%, preferably at least 98% of all inhaler activations (displacements) must correspond to a defined amount with a tolerance area of at most 25%, preferably 20% of that amount . Preferably between 5 and 30 mg of the formulation is ejected per shift as a defined mass, particularly preferably between 5 and 20 mg.

However, the formulation according to the invention can also be atomized with inhalers that are different from the inhaler described above, for example with Jet-Stream inhalers.

Accordingly, a further object of the proposed invention is a drug in the form of the above-described inhalation solution without propellant together with a device suitable for the application of this solution, preferably together with Respimat®. The proposed invention relates primarily to inhalation solutions without propellant gas, which are characterized by a combination of active substances 1 and 2 according to the invention together with a device known as Respimat®. Furthermore, the proposed invention relates to the inhalation device described above, primarily Respimat®, which is characterized by the fact that it contains the inhalation solution described above without the propellant gas according to the invention.

Inhalation solution without pressure gas according to the invention, in addition to the solution described above intended for application in Respimat®, can also be provided as a concentrate or as a sterile and ready-to-use solution for inhalation. A ready-to-use inhalation solution can be obtained from the concentrate, for example, by adding an isotonic sodium chloride solution. The sterile and ready-to-use inhalation solution can be applied using a fixed or portable atomizer, which can produce an aerosol for inhalation using ultrasound or compressed air on the Venturi principle or on another principle.

Accordingly, a further form of the proposed invention is a drug in the form of the above-described inhalation solution without propellant gas, which is available as a concentrate or as a sterile and ready-to-use solution, together with a device suitable for the application of this solution, which is characterized in that in the case of that device, it is a fixed or portable atomizer that can produce an aerosol for inhalation using ultrasound or compressed air on the Venturi principle or on another principle.

The following examples serve to further explain the proposed invention, whereby the scope of the invention is in no way limited to the following examples of embodiments.

Starting materials

Tiotropium bromide

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

For the production of inhalation powder according to the invention, crystalline tiotropium bromide monohydrate can also be used. This crystalline tiotropium bromide monohydrate can be obtained according to the procedure described below.

25.7 kg of water is placed in a suitable reaction vessel and 15.0 kg of tiotropium bromide is added. The mixture is heated to 80-90°C and stirred at a constant temperature until a clear solution is obtained. Activated carbon (0.8 kg), moistened with water, is mixed in 4.4 kg of water and this mixture is added to the solution containing tiotropium bromide and supplemented with 4.3 kg of water. The mixture obtained in this way is stirred for at least 15 minutes at 80-90°C and then filtered through a filter into an apparatus whose jacket is preheated to 70°C. The filter is washed with 8.6 kg of water. The contents of the apparatus are cooled to a temperature of 20-25°C at a cooling rate of 3-5°C in 20 minutes. The apparatus is further cooled to 10-15°C by cooling with cold water and crystallization is assisted by stirring for another hour. The crystallisate is isolated by suction, the isolated crystals are washed with 9 l of cold water (10-15°C) and with cold acetone (10-15°C). The obtained crystals are dried for 2 hours at 25°C in a stream of nitrogen.

Yield: 13.4 kg of tiotropium bromide monohydrate (86% of the theoretical).

The thus obtained crystalline tiotropium bromide monohydrate is micronized by a known method so that the active substance is prepared in the form of particles of an average size that corresponds to the description according to the invention.

Salmeterol x 1/2 H2SO4

If Salmeterol x 1/2 H2SO4 is taken into account in the following embodiments, it can be obtained as follows:

A suspension of 2.5 g (4.15 mmol) of salmeterol xinafoate was dissolved in 6 ml of ethanol. A solution of 0.14 ml of 98% sulfuric acid is slowly added to the suspension while stirring. It is heated at 35-40°C until complete dissolution. It is then diluted with 10 ml of diethyl ether and salmeterol sulfate is added to the solution. Salmeterol sulfate is sucked off after 1.5 hours and washed with 20 ml each of cold ethanol, acetone and diethyl ether. 1.5 g (78%) of salmeterol 1/2 sulfate is obtained.

Examples of formulations

A) Inhalation powder

1)

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2)

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3)

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B) Inhalation aerosol with propellant gas

1) Suspension aerosol

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2) Suspension aerosol

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3) Aerosol solution

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C) Inhalation solutions without pressure gas

1) Application solution in Respimat®

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Using the solution in Respimat, 10 μg of compound 1 and 25 μg of compound 2 are dosed.

2) Application solution in Respimat®

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Using the solution in Respimat, 10 μg of compound 1 and 25 μg of compound 2 are dosed.

3) Application solution in Respimat®

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Using α Respimat solution, 20 μg of compound 1 and 25 μg of compound 2 are dosed.

4) Solution for application in Respimat

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Using the solution in Respimat, 20 μg of compound 1 and 25 μg of compound 2 are dosed.

5) Application solution in Respimat®

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Using the solution in Respimat, 10 μg of compound 1 and 100 μg of compound 2 are dosed.

6) Application solution in Respimat®

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Using the solution in Respimat, 0.1 μg of compound 1 and 25 μg of compound 2 are dosed.

7) Application solution in Respimat®

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Using the solution in Respimat, 1 μg of compound 1 and 100 μg of compound 2 are dosed.

8) Application solution in Respimat®

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Using the solution in Respimat, 100 μg of compound 1 and 100 μg of compound 2 are dosed.

9) Concentrated solution

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Claims (34)

1. Medicine, characterized by the fact that it contains one or more salts of tiotropium (1) in combination with one or more salts of salmeterol (2), as necessary in the form of their enantiomers, a mixture of enantiomers or in the form of a racemate, as necessary in the form of a solvate or hydrate , as well as, if necessary, together with a pharmaceutically acceptable carrier. 2. Medicine according to claim 1, characterized in that the active substances, 1 and 2 are found together in one single form for application or are found in two separate forms for application. 3. Medicine according to any claim 1 or 2, characterized in that compound 1 is present in the form of chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methyl sulfate, preferably in the form of bromide. 4. The drug according to any of claims 1 to 3, characterized in that the compound 2 is selected from salts of hydrochloric acid, hydrobromic acid:, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid acid, xinaphonic acid or maleic acid, provided that compound 2 cannot be salmeterol-xinafoate if compound 1 is tiotropium bromide. 5. The drug according to claim 4, characterized in that the compound 2 is selected from hydrochloride, hydrobromide, sulfate, phosphate and methanesulfonate salts, preferably from hydrochloride and sulfate. 6. The drug according to any claim 1 to 5, characterized in that the mass ratios of tiotropium 1' to salmeterol 2' are in the range from 1:300 to 30:1, preferably from 1:230 to 20:1. 7. The drug according to any of claims 1 to 6, characterized in that a single dosage application of the combination of active substances 1' and 2' corresponds to an amount of 0.01 to 1000 μg, preferably from 0.1 to 200 μg. 8. The drug according to any one of claims 1 to 7, characterized in that it is available in a form suitable for application by inhalation. 9. Medicine according to claim 8, characterized in that the form for application is selected from the group consisting of inhalation powder, aerosol for dosing with propellant gas and inhalation solutions without propellant gas. 10. Medicine according to claim 9, characterized in that it is an inhalation powder containing compounds 1 and 2 in a mixture together with suitable physiologically unquestionable excipients selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols, salts or mixtures thereof auxiliary substances. 11. Inhalation powder according to claim 10, characterized in that the excipient has a maximum average particle size of 250 μm, preferably between 10 and 150 μm. 12. Capsule, characterized in that it contains inhalation powder according to claim 10 or 11. 13. The drug according to claim 9, characterized by the fact that it is an inhalation powder containing only active substances 1 and 2 as ingredients. 14. The drug according to claim 9, characterized in that it is an inhalation aerosol containing propellant gas and compounds 1 and 2 in dissolved or dispersed form. 15. Inhalation aerosol containing propellant gas according to claim 14, characterized in that as propellant gas it contains hydrocarbons r.-propane, n-butane or isobutane or halogenated hydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. 16. Inhalation aerosol containing propellant gas according to claim 15, characterized in that the propellant gas is TG11, TG12, TG134a, TG227 or their mixture, preferably TG134a, TG227 or their mixture. 17. Inhalation aerosol containing propellant gas according to claim 14, 15 or 16, characterized by the fact that it contains, if necessary, one or more further ingredients selected from the group consisting of co-solvents, stabilizers, surface-active agents (surfactants), antioxidants, sliding agents and agents for adjusting the pH value. 18. Inhalation aerosol containing propellant according to claims 14 to 17, characterized in that it can contain up to 5 wt. % of active substance 1' and/or 2'. 19. Medicine according to claim 9, characterized in that it is an inhalation solution without pressure gas which contains water, ethanol or a mixture of water and ethanol as a solvent. 20. Inhalation solution according to claim 19, characterized in that the pH of the solution is 2-7, preferably 2-5. 21. Inhalation solution according to claim 20, characterized in that the pH value is adjusted using 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 a mixture thereof. 22. Inhalation solution according to any of claims 19 to 21, characterized in that it contains, if necessary, further co-solvents and/or auxiliary substances. 23. Inhalation solution according to claim 22, characterized in that it contains as co-solvents ingredients containing hydroxyl groups or other polar groups, for example alcohols - especially isopropyl alcohol, glycols - especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol , polyoxyethylene alcohols and polyoxyethylene fatty acid esters. 24. Inhalation solution according to any claim 22 or 23, characterized in that it contains surface-active substances, stabilizers, complex-forming agents, antioxidants and/or preservatives, taste-correcting agents, pharmacologically unmistakable salts and/or vitamins as excipients . 25. Inhalation solution according to claim 24, characterized in that it contains editic acid or one of its salts, preferably sodium edetate, as a complex forming agent. 26. Inhalation solution according to claim 24 or 25, characterized in that it contains, as antioxidants, compounds selected from the group consisting of ascorbic acid, vitamin A, vitamin E and tocopherol. 27. Inhalation solution according to claim 24, 25 or 26, characterized in that it contains as a preservative a compound selected from cetylpyridinium chloride, benzalkonium chloride, benzoic acid and benzoate. 28. Inhalation solution according to any of claims 22 to 27, characterized in that, in addition to active substances 1 and 2 and solvent, it also contains only bezalkonium chloride and sodium edetate. 29. Inhalation solution according to any of claims 22 to 27, characterized in that it contains only benzalkonium chloride in addition to active substances 1 and 2 and solvent. 30. Inhalation solution according to any of claims 19 to 29, characterized in that it is a concentrate or sterile inhalation solution ready for use. 31. The use of an inhalation solution according to any one of claims 19 to 29, characterized in that it is used for atomization in an inhaler according to WO 91/14468 or in an inhaler as shown in Figures 6a and 6b in WO 97/12687. 32. The use of an inhalation solution according to claim 30, indicated by the fact that it is used for atomization in a stationary atomizer that requires energy for operation or in a portable atomizer, which produces an aerosol for inhalation using ultrasound or compressed air on the Venturi principle or on other principles. 33. Use of the formulation according to any one of claims 1 to 30, characterized in that it is used for the production of a medicine for the treatment of respiratory diseases. 34. The use according to claim 33, characterized in that it is used for the production of a medicine for the treatment of asthma or COPD.