BG66425B1 - Inhalative solution formulation containing a tiotropium salt - Google Patents

Abstract

The invention relates to a propellant-free inhalation formulation of tiotropium bromide or tiotropium bromide monohydrate, which is dissolved in water or in a mixture consisting of water and ethanol, and to propellant-free inhalable aerosols resulting therefrom.

Description

Field of technology

The present invention relates to an inhalable preparation of a pharmaceutically acceptable salt of tiotropium dissolved in water or a mixture of water and ethanol in combination with at least one preferred inhalable active substance and the resulting inhalable aerosols without working gas. The composition according to the invention is particularly suitable for inhalation administration of the active substance, in particular in indications of asthma and COPD.

BACKGROUND OF THE INVENTION

Tiotropium, (1alpha, 2beta, 4beta, 5alpha, 7beta) -7 [(hydroxy-2-thienylacetyl) oxy] 9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1] nonane. is chemically known from European patent application EP 418 716 A1 as tiotropium bromide. Tiotropium bromide salt has the following chemical structure:

+ Me Me - ^ '

(I)

The compound has valuable pharmacological properties and is known as tiotropium bromide. Tiotropium and its salts are highly effective anticholinergics and may therefore be of therapeutic benefit in the treatment of asthma and COPD (chronic obstructive pulmonary desease). Also interesting is lighthouse tiotropium bromide monohydrate.

Both compounds are a preferred subject of the present invention.

The present invention relates to inhalable liquid preparations of these compounds, wherein the liquid preparations according to the invention must meet high quality standards.

In order to achieve an optimal distribution of the active substance in the lungs, it is preferred to administer a liquid, non-working gas preparation by means of a suitable inhaler. Particularly suitable are inhalers which can convert into aerosols a small amount of liquid preparation is the therapeutically necessary dose within a few seconds into a suitable therapeutically inhalable aerosol. Within the scope of the present invention, aerosol dispensers are preferred in which an amount of less than 100 microl, preferably less than 50 microl, most preferably less than 20 microl solution of active substance, preferably in one course of action, can be converted into aerosols with an average particle size of less than 20 microns, preferably less than 10 microns so that the inhaled amount of aerosols corresponds to a therapeutically effective amount.

Such a device for dispensing a metered amount of liquid medicament for inhalation administration without working gas is described in detail, for example, in International Patent Application WO 1997/014468 "Atomizing Device and Methods" as well as in WO 1997/012687, Figures 6a and 6b and the corresponding description. In such an aerosol device, the drug solution is converted by means of a high pressure of up to 500 bar into aerosol-permeable aerosols. In the present invention, said references are taken with particular emphasis.

In such inhalers, the solutions of the preparations are stored in a tank. It is necessary for the solutions of the preparations used to have sufficient storage stability and at the same time to be prepared in such a way that in accordance with the medical purpose they can be applied without additional manipulation, but directly.

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Furthermore, they must not have constituents which may interact with the inhaler in such a way as to impair the inhaler or the pharmaceutical quality of the solution or the aerosols obtained.

A special nozzle such as that described in WO 1994/007607 or WO 1999/016530 is used to prepare aerosols from the solution. In doing so, both are emphatically taken into account.

WO 1998/027959 discloses solutions of preparations for the inhaler described above, which contain as an additive the disodium salt of edithic acid (sodium edetate). The work favors aqueous solutions of the preparations, which with the help of the inhaler described above must be converted into inhalable aerosols, the minimum concentration of edetate sodium is 50 mg / '100 ml in order to reduce accidental anomalies in the injection. Among the examples presented is a preparation with tiotropium bromide. In this preparation the active substance is dissolved in water. The edetate sodium content is also 50 mg / 100 ml.

Surprisingly, it has now been found that solutions of preparations of tiotropium salts in water or a mixture of water and ethanol, in which the proportion of sodium edetate added is less than 50 mg / 100 ml, have a reduction in the dispersion of tiotropium bromide relative to the prior art. the injected mass. In addition, the quality of the spray is very good. The resulting aerosol has very good properties for inhalation use.

Another advantage of the preparation is that by refusing or reducing the added substance sodium edetate in the preparation, the pH value of the solution of the preparation can be lowered. Low pH values are required for the long-term stability of tiotropium salts in the preparation.

Technical essence of the invention

Therefore, it is an object of the present invention to provide an aqueous active ingredient preparation with a pharmaceutically acceptable tiotropium salt that meets high standards. which are necessary for a solution to be optimally converted into aerosols by means of the above-mentioned inhaler. In this case, the preparations with active substance according to the invention must also have sufficient pharmaceutical quality, i. they must be pharmaceutically stable for a shelf life of several years, preferably at least one year, more preferably two years.

Another object is to provide solutions, without working gas, of preparations with tiotropium salts which are converted into aerosols by means of a pressurized inhaler, the mass included in the generated aerosol lying reproducibly within a defined range.

A further object is to provide solutions of preparations with tiotropium and an inhalable active substance.

All pharmaceutically acceptable salts of tiotropium can be used for the preparation according to the invention. When the term tiotropium salt is used in the context of the present invention, it is to be understood in connection with tiotropium. Tiotropium having a free ammonium cation corresponds according to the invention to tiotropium in the form of a salt (tiotropium salt) which contains an anion as a counterion. Suitable tiotropium salts within the scope of the present invention are preferably compounds which contain tiotropium with a counterion (anion) chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate and / or methylsulphate.

Within the scope of the present invention, tiotropium bromide is preferred as the salt. In the context of the present invention, tiotropium bromide is always understood to mean all possible amorphous and crystalline modifications of tiotropium bromide. They may, for example, include solvent molecules in the crystal structure. Of all the crystalline modifications of tiotropium bromide according to the invention, those which include water (hydrates) are preferred. Within the scope of the present invention, tiotropium bromide monohydrate is particularly preferred.

In the compositions according to the invention, combinations of the natiotropic salt and only one other active substance are preferred.

In the compositions according to the invention, the tiotropium salts are dissolved in a solvent.

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The solvent may be water alone or a mixture of water and ethanol. Ethanol can be added to the preparation to increase the solubility of the additives or other active substances in parallel with the tiotropium salt, preferably giotropium bromide or tiotropium bromide monohydrate. The relative proportion of ethanol to water is not limited, it is for example 90 Vol. %. Preferably the maximum limit for ethanol is at 70 Vol. %, particularly preferably at 60 Vol. % and most preferably at 30 Vol,%. The remaining volume percentages are filled with water. The preferred solvent is water without the addition of ethanol.

The concentration of tiotropium salt relative to the portion of natiotropium in the finished dosage form depends on the intended therapeutic effect. For most tiotropium-responsive diseases, the tiotropium concentration is between 0.0005 and 5 wt. %, preferably between 0.001 and 3 wt. %.

The pH of the composition according to the invention lies between 2.0 and 4.5, preferably between 2.5 and 3.5, more preferably between 2.7 and 3.5 and particularly preferably between 2.7 and 3.2. The most preferred pH values have an upper limit of 3.1.

The pH is adjusted by adding pharmacologically acceptable acids. Examples of preferred 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. Acids which form acid addition salts with the active substance or, in the case of combined preparations with one of the active substances, may also be used.

Of the organic acids, ascorbic acid, fumaric acid and citric acid, especially citric acid, are preferred. In some cases, mixtures of these acids can also be used, especially in the case of acids which, in addition to their acidic properties, also have other properties, for example as flavoring agents or antioxidants such as citric acid or ascorbic acid. Hydrochloric acid is explicitly mentioned as an inorganic acid.

In some cases, pharmacologically acceptable bases may also be used to accurately titrate the narH-value. Suitable bases are, for example, alkali metal hydroxides and alkali metal carbonates. A preferred alkali ion is sodium. When using such bases, care must be taken that the salts obtained, which are then contained in the finished medicinal product, must also be pharmacologically acceptable with the above acids.

In the present preparation according to the invention there may be no addition of ethylenediaminetetraacetic acid (EDTA) or of any of its known salts, edetate sodium as a stabilizer or complexing agent.

Another preferred embodiment comprises ethylenediaminetetraacetic acid and / or its salts.

In a preferred embodiment with sodium edetate, the sodium edetate content is below 10 mg / 100 ml. In this case, there is a preferred range between 5 mg / 100 ml and less than 10 mg / 100 ml or another one between more than 0 and 5 mg / 100 ml.

In another embodiment, the edetate sodium content is 10 to 30 mg / 100 ml, preferably a maximum of 25 mg / 100 ml.

In a preferred embodiment, this additive is completely absent.

The same as for edetate sodium also applies to other comparable additives which have complexing properties and can be used in its place, such as nitrilotriocetic acid and its salts.

By complexing agents within the scope of the present invention are meant preferably molecules that are capable of participating in complex bonds. By these compounds, cations are preferably present in the complexes, especially preferably metal cations.

In addition to the tiotropium salt, the active substances required for a combination preparation are specially selected from the class of antihistamines, antiallergics, leukotriene antagonists and / or

66425 Bl Steroids.

These substances include:

as steroids:

alclometasone, alclometasone dipropionate, alizaktid, amcinonide, aminoglutethimide, Aristocort-diacetate, beclomethasone, beklometazonDouglas, beclomethasone 17,21 dipropionate, betamethasone valerate, betametazonadamantoat, budesonide, butixocort, kanesten-SC tsiklometazon, klobekazol, clobetasone, cloprednol, fluocortin butyl. cortivazole, deflazacort, demethex, deprolone, deprodone propionate, dexamethasone, dexamethasone-21-isonicotinate, dexamethasone isonicotinate, diflorazone, difluprednate, endrizone. fluazakort, fluklorolon acetonide, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, fluokortolonkapronat, fluodeksan, fluorometholone, fluticasone, fluticasone propionate, formebolon, formocortal, halopredone acetate, hydrocortisone, hydrocortisone-17-butyrate, hidrokortizonatseponat, hidrokortizon- butyrate propionate, icomethasone enbutate, cyclomethasone, lotrizone, macipredone. medrizone, meprednisone, methylprednisolone aceponate, mometasone, mometasone furoate, mycophenolate mofetil, pranlukast, paramethasone acetate. prednicarbate, promedrol, seratrodast, tipredan, thixocortol-pivalate, triamcinolone, triamcinolone-hexacetonide, trilostane, trimaquinolone benethonide, ulobetasol-propionate, cilevton. 9-Alpha-chloro-6-alpha-fluoro-11-beta-17-alpha-dihydroxy-16-alpha-methyl-3-oxo-1,4-androstadiene-17-beta-carboxylic acid methyl ester-17-propionate.

Particularly preferred is the combination of tiotropium bromide and tiotropium bromide monohydrate and budesonide, respectively. flunisolide, beclomethasone dipropionate or fluticasone as well as pharmacologically tolerable (in some cases other) salts thereof.

The preferred combination is tiotropium bromide and tiotropium bromide monohydrate and budesonide, respectively.

The concentration of the steroid, for example budesonide. flunisolide, beclomethasone dipropionate or fluticasone in the compositions according to the invention is preferably 0.05 to 10 wt. %, preferably up to 5 wt. %, more preferably 0.1 to 2.5 wt. %, particularly preferably 0.2 to 2.5 wt. %. When administering the preparation with the above inhaler, the steroid concentration is preferably adjusted so that 12.5 to 250 microg steroid is aerosolized upon injection. Particularly preferred are concentrations at which the pharmacologically active dose is administered within one or two injections.

If the combination preparation contains a leukotriene antagonist, it is preferably selected from the group of montelukast, pranlukast, cafirlukast, 1- (I) - (3- (2- (6,7-difluoro-2-quinolinyl) ethenyl) phenyl) - 3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropaneacetic acid, 1- (R) -3- (3- (2- (2- (2,3-dichlorothieno [3,215 b] pyridin-5-yl) ) - ((E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) propylthio) methyl) cyclopropaneacetic acid, [2 - [[2- (4-tert-butyl- 2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid. Montelu20 cast, pranlukast and / or cafirlukast are preferred.

The concentration of the leukotriene antagonist is 0.05 to 10 wt. %, preferably up to 5 wt. %, more preferably 0.1 to 3.5% by weight.

Antihistamines and antiallergics include:

Azelastine, astemizole, bamipin, carbinoxamine hydrogen maleate, cetirizine, cexchloropheniramine, chlorphenoxamine, clemastine, clemas30 tinhydrogen fumarate, desloratidine, dimenhydrinate, dimethindene, disodium chromoglycate, dofenamine, difen meclozine, mekitazine, micolasin, nedocromil, pheniramine and / or promethacin.

Epinastine, nedocromil, disodium cromoglycate, astemicol, mekitacin, carbinoxamine and / or clemastine and / or the corresponding pharmaceutically acceptable salts are preferred.

In a combined preparation, the concentration of antiallergics and / or antihistamines is preferably 0.05 to 15 wt. %, preferably up to 10 wt. %, more preferably 0.1 to 10 wt. %, particularly preferably 0.1 to 7 wt. %.

All these active substances may in some cases also be used in the form of their pharmacologically tolerable salts.

In the case of combined preparations, it is preferred for preparations in which thio

66425 The solution is dissolved. The other active substance may be dissolved or suspended, which is generally determined by the other active substance and the solvent.

If the other active substance is a substance sensitive to low pH values, it is preferably prepared as a suspension. The advantage of the suspension is that the pH can be made more acidic, which stabilizes the dissolved tiotropium. The preferred pH range for tiotropium is between 2.0 and 4.5, more preferably 2.5 and 3.5, particularly preferably between 2.7 and 3.2.

In the case of steroids, they are preferably as a suspension, in particular fluticasone. This is especially true when only ethanol-free water is used as the solvent. By adding ethanol, the steroid can also be prepared as a solution.

However, it turned out that, for example, budesonide, when dissolved in a mixture of water and ethanol, is sufficiently stable even at pH values of 3.5.

In view of the administration of the composition according to the invention within the scope of the inhaler described in the present invention, it may be advantageous when all the components of the composition are dissolved.

In addition to ethanol, other co-solvents and / or other excipients may be added to the preparation according to the invention.

Preferred other co-solvents are those which contain hydroxyl groups or other polar groups, for example alcohols - in particular isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohol and polyoxyethylene fatty acid ester.

Excipients in this context means any pharmacologically acceptable and therapeutically meaningful substance which is not an active substance but can be prepared together with the active substance (s) in a pharmacologically appropriate solvent to improve the quality properties of the active substance preparation. . Preferably, these substances either do not have or have in the context of the targeted therapy unworthy of attention or at least no adverse pharmacological action. Excipients and additives include, for example, surfactants such as soy lecithin, oleic acid, sorbitan esters such as sorbitan trioleate, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or preservatives which prolong the duration of preparation of the preparation. , vitamins and / or other supplements known to those skilled in the art. Additives also include pharmacologically safe salts such as sodium chloride.

As a surface active agent or a stabilizing agent slurry are suitable for all pharmacologically acceptable salts thereof, which have a lipophilic hydrocarbon group and one or more functional hydrophilic groups suitable are, in particular C _{5 20} -fatty alcohols, C _{5 0} -fatty acids, esters of C _{5 20} fatty acids, lecithin, glycerides, propylene glycol ester, polyoxyethylene, polysorbate, sorbitan ester and / or carbohydrates. C _5-20 fatty acids, propylene glycol diester and / or triglycerides and / or sorbitans of C _{5 20} fatty acids are preferred, oleic acid and sorbitan mono-, di- or trioleate are particularly preferred. Alternatively, toxicologically and pharmaceutically safe polymers and / or block polymers may also be used as suspension stabilizing agents.

The amount of surfactant may be 1: 1 relative to the weight by weight of the suspended active ingredients, amounts of 0.0001: 1 to 0.5: 1 are preferred, and amounts of 0.0001: 1 to 0.25: 1 are particularly preferred,

Preferred excipients include antioxidants such as ascorbic acid, provided that it is not used to adjust the pH, vitamin A, vitamin E, tocopherol and similar vitamins and provitamins found in the human body.

Preservatives can be used to protect the preparation from contamination by pathogenic strains. Suitable preservatives are those known in the art, in particular benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known in the art.

66425 Bl g, are particularly preferred. 135 g of water. If activated carbon is suspended in water before addition to the tiotropium bromide-containing solution, it is recommended to rinse with the same amount of water. After the addition of the activated carbon at constant temperature, it is stirred for between 5 and 60 minutes, preferably between 10 and 30 minutes, particularly preferably 15 minutes, and the resulting mixture is filtered to remove the activated carbon. The filter is then washed with water. For this purpose, 140 to 400 g, preferably 200 to 320 g, most preferably are used per 1 mol of tiotropium bromide used. 270 g of water.

The filtrate is then slowly cooled, preferably to a temperature of 20-25 ° C. Cooling is preferably carried out at intervals of 1 to 10 ° C for 10 to 30 minutes, preferably 2 to 8 ^° C for 10 to 30 minutes, particularly preferably 3 to 5 ° C for 10 to 20 minutes, most preferably from 3 to 5 ° C for ca. 20 min. In some cases, cooling to 20-25 ° C may be followed by further cooling to below 20 ° C, particularly preferably to 10-15 ° C.

After cooling, it is stirred for between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, particularly preferably about 1 hour for complete crystallization.

The crystals formed are then isolated by filtration or suction of the solvent. If the resulting crystals need to be further washed, it is recommended that water or acetone be used as the washing solvent. Per 1 mol of tiotropium bromide used to wash the resulting tiotropium bromide monohydrate crystals, 0.1 to 1.0 L, preferably 0.2 to 0.5 L, especially preferably about 0.3 L of solvent can be used. In some cases, the rinsing step may be repeated.

The resulting product is dried in vacuo with heated air to a water content of 2.5 to 4%.

Therefore, one aspect of the present invention relates to preparations-solutions of the type described above, in which crystalline tiotropium bromide monohydrate is used, which is prepared according to the method described above.

Preparations with tiotropium salts according to the invention are used. Preferred preparations contain, in addition to the solvent water and / or water / ethanol and tiotropium salt, only benzalkonium chloride, pH-adjusting acid and sodium edetate.

In another preferred embodiment, there is no sodium edetate.

In some cases, these embodiments may also contain sodium chloride.

As repeatedly mentioned, tiotropium bromide is described in EP 418 716 A1, crystalline tiotropium bromide monohydrate can be prepared by a method which will be described in detail below.

In order to obtain the crystalline monohydrate according to the present invention, it is necessary to dissolve the tiotropium bromide, which has been prepared, for example, in accordance with EP 418 716 A1, in water, to heat it, to purify it with activated carbon and after removal. of activated carbon on slow cooling slowly crystallizes tiotropium bromide monohydrate.

Preferably proceed as described below. 25

In a suitably sized reaction vessel, the solvent is mixed with tiotropium bromide, which has been prepared, for example, as prescribed in EP 418716A1.

0.4 to 1.5 kg, preferably 0.6 to 1.0 kg, particularly preferably 0.8 kg of water as solvent are used per 1 mol of tiotropium bromide used.

The resulting mixture is heated with stirring, preferably to more than 50 ° C, especially 35 preferably to more than 60 ° C. The selected maximum temperature is determined by the boiling point of the solvent used water. Preferably the mixture is heated to the range of 8090 ° C. 40

To this solution is added activated carbon, dry or water-wet. Preferably 10 to 50 g, particularly preferably 15 to 35 g, most preferably 25 g of activated carbon are added per 1 mol of tiotropium bromide used. In some cases, the activated carbon is suspended in water before being added to the tiotropium bromide-containing solution. 70 to 200 g, preferably 100 to 160 g, are used per 1 mol of tiotropium bromide used for the activated carbon suspension.

66425 B1 preferably in an inhaler of the type described above to produce aerosols without the use of a working gas according to the invention. Therefore, at this point, the patent documents described at the beginning are emphasized once again, which are thus taken into account.

As described at the outset in WO 1997/012687 and Figures 6, a developed embodiment of the preferred inhaler is set forth. This aerosol device (Respimat®) can be advantageously used for the preparation of inhalable aerosols according to the invention with tiotropium salt as active substance. Due to its cylindrical shape and convenient size of less than 9 to 15 cm in length and 2 to 4 cm in width, this aerosol device can be carried by the patient at any time. This aerosol dispenser dispenses a certain volume of the drug by applying high pressure to small nozzles so that inhalable aerosols are formed.

Essentially the preferred spread.! consists of an upper part of the casing, a pump casing, a nozzle, a fixing spring mechanism, a spring casing, a spring and a tank and is characterized by

- a casing of the pump attached to the upper part of the casing and carrying at one end of the body with the nozzle respectively the nozzle apparatus,

- hollow piston with valve,

- drive flange to which the hollow piston is attached and which is located at the top of the housing.

- a locking spring mechanism located at the top of the housing,

- a housing of the spring with a spring located in it, which is placed in the upper part of the housing rotatably by means of a rotating bearing, - a lower part of the housing, which is inserted into the housing of the spring in the axial direction.

The hollow piston with the valve body corresponds to the devices discussed in WO 1997/012687. It enters partially into the cylinder of the pump housing and is axially movable in the cylinder. In particular, figures 1 -4 are taken into account. especially Figure 3 and the accompanying descriptions. The hollow piston with the valve body at the moment of release of the spring exerts on the high-pressure side a pressure of 5 to 60 MPa (from 50 to 600 bar), preferably 10 to 60 MPa (from 100 to 600 bar) on the liquid and thus a certain amount of solution of the active substance is measured. In this case, volumes of 10 to 50 microl are preferred per injection, especially preferred volumes of 10 to 20 microl, most preferably a volume of 15 microl.

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

The nozzle in its body is preferably microstructured, i. produced by microtechnology. Microstructured nozzle bodies are discussed, for example, in WO 1994/007607 as well as in WO 1999/016530 and their contents are taken into account, in particular figure 1 in WO 1994/007607 and the corresponding description.

The nozzle body consists, for example, of two fixedly connected glass and / or silicon plates, at least one of which has one or more microstructured channels connecting the inlet to the outlet side of the nozzle. On the outlet side of the nozzle there is at least one round or non-round hole with a depth of 2 to 10 microns and a width of 5 to 15 microns, the depth being preferably 4.5 to 6.5 microns and the length 7 to 9 microns.

In the case of multiple nozzle openings, two are preferred, the jet directions of the nozzles may be parallel to each other or inclined relative to each other in the direction of the nozzle opening. With a nozzle body with at least two openings on the outlet side, the jet directions can be inclined relative to each other at an angle of 20 degrees to 160 degrees, preferably an angle of 60 to 150 degrees, especially 80 to 100 degrees.

The nozzle openings are preferably arranged at a distance of 10 to 200 microns, preferably at a distance of 10 to 100 microns, particularly preferably 30 to 70 microns. Most preferably 50 microns. Accordingly, the jet directions meet in the vicinity of the nozzle openings.

The liquid drug falls as already mentioned with an initial pressure of up to 600 bar, preferably 200 to 300 bar, on the nozzle body and through the nozzle holes

66425 Bl disintegrates in inhalable aerosols. Preferred aerosol particle sizes are at up to 20 microns, preferably 3 to 10 microns.

The locking spring mechanism comprises a spring, preferably a cylindrical, helical, compression spring, as a mechanical energy accumulator. The spring acts on the drive flange as a transition part, the movement of which is determined by the location of the fixing element. The path of the drive flange is precisely limited by an upper and lower stop. The spring is preferably tensioned by a force-transmitting gear, for example a helical-sliding gear, from an external torque which occurs when the upper part of the housing rotates relative to the spring housing in the lower part of the housing. In this case, the upper part of the housing and the drive flange comprise a single- or multi-way wedge gear.

The locking unit with movable locking surfaces is arranged in an annular manner around the drive flange. It consists of, for example, a radial, resiliently reshaped, plastic or metal ring. The ring is placed in a surface perpendicular to the axis of the sprinkler. After the spring pressure, the locking surfaces of the locking unit move towards the path of the drive flange and prevent the spring from stretching. The locking unit is activated by means of a button. The button is connected and purchased with the locking unit. To actuate the locking spring unit, the button moves parallel to the surface of the ring, preferably to the sprayer, whereby the shape-changing ring is deformed. The design details of the locking spring mechanism are set out in WO 1997/020590.

The lower part of the housing moves in an axial direction on the spring housing and closes the bearing, the spindle drive and the fluid reservoir.

When the sprayer is actuated, the upper part of the housing rotates relative to the lower part of the housing, whereby the lower part of the housing takes over the housing of the spring. In this case, the spring is compressed and tensioned by means of a screw-sliding gear and the locking device is automatically extended forward. The angle of rotation is preferably an even number part of 360 degrees for example 180 degrees. Simultaneously with the tension of the spring, the drive in the upper 5 part of the housing is displaced by a predetermined path, the hollow piston is returned to the cylinder in the pump housing, by which a certain amount of liquid is sucked from the tank into the high pressure space in front of the nozzle.

In the sprinkler, in some cases, more replaceable tanks containing the spray liquid can be inserted and used one after the other. According to the invention, the tank contains the aqueous aerosol preparation.

The spray process is triggered by lightly pressing the release button. In this case, the locking mechanism clears the way for the actuating part. The tensioned spring 20 inserts the piston into the cylinder of the pump housing. The liquid flows out of the nozzle of the sprayer in aerosol form.

Further design details are discussed in PCT applications WO 1997/012683 and

WO 1997/020590 and thus their content is taken into account.

The components of the sprayer (aerosol device) are made of a material suitable for the function. The housing of the spray gun and - as far as the function allows - also other parts are preferably made of plastic produced, for example, by the injection molding method. Physiologically reliable materials are used for medical purposes.

Figures I a / b, which are identical to figures 6 a / b of WO 1997/012687, show the aerosol device (Respimat®) with which the aqueous aerosol preparations according to the invention can be advantageously inhaled.

Figure 1a shows a longitudinal section of the nozzle with the spring extended, Figure 1b shows a longitudinal section of the nozzle with the spring released.

The upper part of the housing 51 comprises a housing 45 of the pump 52, at the end of which is the holder 53 for the spray nozzle. In the holder is the body of the nozzle 54 and a filter 55. Attached to the drive flange 56 of the fixing spring mechanism hollow piston50 lo 57 partially enters the cylinder of the casing of

66425 Bl pump. At its end, the hollow piston carries the valve body 58. The hollow piston is sealed by means of a seal 59. In the upper part of the housing there is a clamp 60, on which the drive flange rests when the spring is released. 5 After tensioning the spring, the locking unit 62 is inserted between the lock 61 and a support 63 in the upper part of the housing. The actuating button 64 is connected to the locking unit. The upper part of the housing ends in a mouthpiece 65 and is closed with a protective cap 66.

The housing of the spring 67 with a compression spring 68 is pivotally connected to the upper part of the housing by means of locking lugs 69 and a support bearing. The lower part of the housing 70 is put on the spring housing 15. In the spring housing there is a replaceable tank 71 for the sprayed liquid 72. The tank is closed with a cap 73, through which the hollow piston passes into the tank and is immersed 20 with its end in the liquid (stock of the active substance solution).

The spindle 74 for the mechanical counter is located in the wall of the spring housing. At the end of the spindle, which faces the upper part 25 of the casing, is the drive gear 75. On the spindle stands a guide 76.

The above-described aerosol device is suitable for dispersing aerosol preparations according to the invention to aerosols suitable for inhalation.

If the preparation according to the invention is sprayed by the technique described above (Respimat®). the ejected mass of at least 97%, preferably at least 98% of all inhaler operations must correspond to a certain amount with a tolerance range of a maximum of 25%, preferably 20% of this mass. Preferably, between 5 and 30 mg of the preparation are consumed as a defined mass, especially preferably between 5 and 20 mg.

The part of the ejected mass which lies outside the tolerance limits of a maximum of 25% for the desired mass must be below 1.5%, preferably below 1.2%.

However, the composition according to the invention can also be dispensed by means of inhalers other than those described above, for example by means of Jet-Stream inhalers.

Examples of the invention

I. Example of synthesis of tiotropium bromide monohydrate

Add 15.0 kg of tiotropium bromide to 25.7 kg of water in a suitable reaction vessel. The mixture was heated to 80-90 ° C and stirred at the same temperature until a clear solution formed. Suspend activated carbon (0.8 kg), water moist, in 4.4 kg of water, add this mixture to the tiotropium bromide-containing solution and rinse with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 minutes at 80-90 ° C and then filtered through a heated filter into a housing preheated to 70 ° C. Wash the filter with 8.6 kg of water. The apparatus is cooled by 3-5 ° C for 20 minutes to a temperature of 20-25 ° C. Cooling is continued with cold water to 10-15 ° C and crystallization is completed by at least one hour of stirring. The crystallizate was isolated using a suction dryer, the isolated crystal slurry was washed with 9 L of cold water (10-15 ° C) and cold acetone (10-15 ° C). The resulting crystals were dried at 25 ° C for 2 hours under a stream of nitrogen.

Yield: 13.4 kgTnoTponHeB bromide monohydrate (86% of theory)

II. Examples of preparations

100 g of medicinal product contain:

66425 Bl

Example Amount of tiotropium bromide relative to tiotropium: Amount of tiotropium bromide monohydrate relative to tiotropium: Amount of Benzalkonium chloride Amount of sodium edetate pH-value adjusted cHCldN) 1 0.099 α _ 10 mq 25 mq 3.0 2 0.006 q - 10 mq 25 mq 3.0 3 0.099 q - 10 mq 10 mq 3.0 4 0.006 q 10 mq 10 mq 3.0 5 - 0.099 q 10 mq 25 mq 3.0 6 - 0.006 α 10 mq 25 mq 3.0 7 in » 0.099 q lOmq 10 mq 3.0 8 - 0.006 g 10mg 10 mg 3.0

The remaining component is water or ethanol and one of the above-mentioned active substances in an amount known in the art.

Examples 9 to 12: Budesonide

Each of Examples 1 to 8 may further comprise:

Example 9a: Budesonide: 0.3 g, pH value adjusted with HCl: 3.0, solvent water only, no ethanol;

Example 9b: Budesonide: 0.3 g, pH adjusted with HCl: 3.5;

Example 9c: Budesonide: 0.3 g, pH adjusted with HCl: 4.0;

Example 10: analogously to Examples 9a to 9c with Budesonide: 0.6 g;

Example 11: analogously to Example 9a to 9c with Budesonide: 1.3 g.

Example 12: analogous to examples 9a to 9c with budesonide: 2.0 g.

In Examples 9 to 12, the steroid in the formulation is in the form of a suspension. Sorbitan trioleate can be used as a surfactant.

Examples 13 to 15

Analogous to Examples 9 to 12. Benzalkonium chloride is replaced by sodium benzoate.

Examples 16 to 19

Analogous to Examples 9 to 12. Citric acid is preferably used instead of hydrochloric acid to adjust the pH.

Examples 20 to 30

The components and amounts are analogous to Examples 9 to 19. A mixture of water (10 Vol%) and ethanol (90 Vol%) is used instead of water. Budesonide is dissolved.

Other examples

In analogy to Examples 9 to 30 above, the same amount of flunisolide, beclomethasone dipropionate or fluticasone was used instead of budesonide. In the case of fluticasone, lecithin is preferably added to the suspension preparation instead of sorbitan trioleate. Steroids are prepared as a suspension in the case where only water is used as a solvent. In the case of a mixture of water and ethanol, the steroid can be dissolved.

Example 31

Epinastine: 0.2 g EDTA: 25 mg

Tiotropium bromide monohydrate: 29 mg, 0.1 η hydrochloric acid to adjust the pH value to 3.0,

Water ad 100 ml.

Claims (21)

1. A liquid, propellant-free, pharmaceutical preparation consisting of at least two active substances containing 66425 Bl - tiotropium salt as one of the active substances in a concentration relative to tiotropium between 0.0005 and 5 wt. %, - another active substance which is a steroid, - water as solvent in which the ponetiotropium salt is dissolved, - acid to reach a pH between 2.0 and 3.1, - pharmacologically tolerable preservative, - ethylenediaminetetraacetic acid salt in an amount greater than 0 to 10 mg / 100 ml, optionally a stabilizer and / or pharmacologically acceptable co-solvent and / or other pharmacologically acceptable excipients or additives other than the preservative. 15 Pharmaceutical preparation according to Claim 1, characterized in that the tiotropium salt is a salt selected from bromide, chloride, iodide, methanesulfonate and p-toluenesulfonate. Pharmaceutical preparation according to Claim 1 or 2, characterized in that the active substance is tiotropium bromide. Pharmaceutical preparation according to Claim 1 or 2, characterized in that the active substance is tiotropium bromide monohydrate. Pharmaceutical preparation according to Claim I or 2, characterized in that it is free of stabilizer. Pharmaceutical preparation according to Claim 1 or 2, characterized in that the salt of ethylenediaminetetraacetic acid is from 5 to less than 10 mg / 100 ml. Pharmaceutical preparation according to Claim I or 2, characterized in that the salt 35 of ethylenediaminetetraacetic acid is sodium edetate. Pharmaceutical preparation according to Claim 1 or 2, characterized in that the pH value is between 2.5 and 3.0. 40 Pharmaceutical preparation according to Claim 1 or 2, characterized in that the concentration of tiotropium is between 0.0005 and 5 wt. %. Pharmaceutical preparation according to Claim 1 or 2, characterized in that the preparation contains benzalkonium chloride as a preservative. Pharmaceutical preparation according to Claim 1 or 2, characterized in that in addition to a preservative, pharmacologically 1 o acceptable excipients and additives, Pharmaceutical preparation according to Claim 1 or 2, characterized in that the preparation contains an antioxidant selected from ascorbic acid, vitamin A, vitamin E or tocopherol as an excipient. Pharmaceutical preparation according to Claim 1 or 2, characterized in that no co-solvents and / or pharmacologically acceptable excipients are used in addition to the preservative. Pharmaceutical preparation according to Claim 1 or 2, characterized in that the concentration of tiotropium is between 0.001 and 3 wt. %. Pharmaceutical preparation according to Claim 1 or 2, characterized in that all the components are dissolved in the solvent. Pharmaceutical preparation according to Claim 1 or 2, characterized in that the other active substance is suspended in the solvent. Pharmaceutical preparation according to Claim 1 or 2, characterized in that the other active substance is one of the steroids in a concentration of 0.05 to 5% by weight. %. Pharmaceutical preparation according to Claim 17, characterized in that the steroid is budesonide, beclomethasone dipropionate, fluticasone or flunisolide. Pharmaceutical preparation according to Claim 1 or 2, comprising water, surfactant, 0.1 wt. % tiotropium bromide, another active substance in a concentration of 0.05 to 5 wt. %, which is a steroid selected from budesonide, beclomethasone dipropionate, fluticasone or flunisolide, 0.01 wt. % benzalkonium chloride, 0.05 wt. % edetate sodium, where the preparation is adjusted to pH 3.0 with hydrochloric or citric acid. Pharmaceutical preparation according to one of Claims 1 to 19 for use as a medicament for inhalation administration. Use of a pharmaceutical preparation according to one of claims 1 to 20 for the preparation of a medicament for the treatment of asthma and / or COPD.