KR20040010552A - Inhalable formulation of a solution containing a tiotropium salt - Google Patents

Abstract

The present invention relates to a propellant inhalation formulation of tiotropium bromide or tiotropium bromide monohydrate, dissolved in water or a mixture of water and ethanol, and to a propellant inhalation aerosol produced therefrom.

Description

Inhalable formulation of a solution containing a tiotropium salt

The present invention preferably is a propellant-free inhalable formulation of thiotropium in water or a pharmaceutically acceptable salt of tiotropium dissolved in a mixture of water and ethanol, in combination with one or more other active substances administered by inhalation. And to propellant inhalable aerosols prepared therefrom. The formulations according to the invention are suitable for the administration of the active substance by inhalation, in particular for the treatment of asthma and COPD.

Chemically, (1α, 2β, 4β, 5α, 7β) -7-[(hydroxy-di-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo Tiotropium, represented by [3.3.1.0 ^2,4 ] nonane, is known as tiotropium bromide of EP 418 716 A1. The bromide salt of tiotropium has the structure of formula (I)

The compound, known under the name tiotropium bromide, exhibits effective pharmacological properties. Tiotropium and its salts are very effective anticholinergic agents and can provide therapeutic benefits in the treatment of asthma or COPD (chronic obstructive pulmonary disease). The monohydrate of tiotropium bromide is also pharmacologically valuable. Both compounds are a preferred object of the present invention.

The present invention relates to liquid active substance formulations of such compounds which can be administered by inhalation, wherein the liquid formulations according to the invention meet high quality standards.

In order to optimally distribute the active substance to the lungs, the liquid formulation will need to be administered without a propellant gas using a suitable inhaler. Particularly suitable are inhalers, which can spray a small amount of liquid formulation into aerosols suitable for therapeutic inhalation within a few seconds at dosages necessary for therapeutic purposes. Within the scope of the present invention, preferred nebulizers are sprayed by one operation of less than 100 μl, preferably less than 50 μl, most preferably less than 20 μl of active substance solution, with an average diameter of less than 20 μm, preferably 10 μl. Since less than one can form an aerosol, the inhalable portion of the aerosol corresponds to a therapeutically effective amount.

Devices of this kind in which a metered amount of liquid pharmaceutical composition for inhalation is administered without a propellant is described, for example, in WO 91/14468 and WO 97/12687, entitled “Spraying Devices and Methods”. (See FIGS. 6A and 6B and the accompanying description) in detail. In this type of nebulizer, the pharmaceutical solution is converted to the aerosol used for the lungs by high pressure up to 500 bar. The entire contents of the foregoing documents are incorporated by reference into the scope of this specification.

In this type of nebulizer, the liquid formulation is stored in a reservoir. It is important that the active substance formulations to be used must be sufficiently stable during storage and, depending on their medical purpose, to be directly administrable without any further manipulation. In addition, they should never contain ingredients that can interact with the inhaler or in a way that would damage the pharmaceutical amount of the solution or the aerosol produced.

To spray the solution, special nozzles are used, for example as described in WO 94/07607 or WO 99/16530. Both of these documents are incorporated herein by reference.

WO 98/27959 describes liquid formulations for inhalers as described above which contain the disodium salt of edic acid (sodium edetate) as an additive. In aqueous formulations of solutions to be converted to inhalable aerosols using the inhalers described above, a minimum concentration of 50 mg / 100 ml of sodium edetate is preferred to reduce the occurrence of spray specificity. Among the examples described in this publication there is a formulation containing tiotropium bromide. In such formulations, the active substance is dissolved in water. Likewise, the proportion of sodium edetate is 50 mg / 100 ml.

Surprisingly, formulations of the tiotropium salt solution in water or water-ethanol mixtures with a proportion of the additive sodium edetate of less than 50 mg / 100 ml are compared to formulations containing tiotropium bromide known in the prior art. It has been found that this indicates a decrease in the dispersion of. In addition, the spray quality is also very good. The resulting aerosols exhibit very good properties for administration by inhalation.

Another advantage of such formulations is the fact that the pH of the solution formulation can be lowered due to the absence or drop of additive adetate sodium in the active substance formulation. Low pH levels are essential for the long term stability of the tiotropium salt in the formulation.

It is therefore an object of the present invention to provide an aqueous active substance formulation containing a pharmaceutically acceptable tiotropium salt that meets the high standards required for optimal spraying of solutions using the inhalers described above. The active substance formulations according to the invention must have a sufficiently high pharmaceutical quality. That is, they must be pharmaceutically stable for a storage period of several years, preferably at least one year, more preferably at least two years.

Another object is to provide a propellant formulation of a solution containing a tiotropium salt sprayed under pressure using an inhaler, wherein the composition is carried by an aerosol that is repeatedly produced within a certain range.

Yet another object is to provide a formulation of a solution comprising tiotropium and another active substance which can be administered by inhalation.

According to the invention, any pharmaceutically acceptable salt of tiotropium can be used in the formulation of the invention. When the term tiotropium salt is used within the scope of the present invention, it is regarded as a reference for tiophorium. According to the invention, the criteria for tiotropium, which is a free ammonium cation, correspond to the criteria for tiotropium in the form of salts (thiotropium salts) containing anions as counter ions. Tiotropium salts which can be used within the scope of the present invention are preferably chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate and / or methylsulfate as counter ions (anions), in addition to tiotropium. It is a compound containing.

Within the scope of the present invention, tiotropium bromide is preferably present as a salt. References to tiotropium bromide within the scope of the present invention must be understood as references to all possible amorphous and crystalline modifications of tiotropium bromide. These may contain, for example, solvent molecules in their crystalline structure. Of all the crystalline modifications of tiotropium bromide, those containing water (hydrates) are also preferred in accordance with the present invention. It is particularly preferred to use tiotropium bromide monohydrate within the scope of the present invention.

Among the formulations according to the invention, combinations of tiotropium salts with one other active substance are preferred.

In the formulations according to the invention, the tiotropium salt is dissolved in a solvent. Such a solvent may be simple water or may be a mixture of water and ethanol. Ethanol may be added to the formulation in order to increase the solubility of the additives or other active materials other than tiotropium salts, preferably tiotropium bromide or tiotropium bromide monohydrate. The relative ratio of ethanol to water is not limited, for example 90% by volume. Preferably, the maximum limit of ethanol is 70% by volume, in particular 60% by volume and most preferably 30% by volume. The remaining volume% consists of water. Preferred solvent is water without the addition of ethanol.

The concentration of tiotropium salt in the final pharmaceutical formulation based on the proportion of tiotropium depends on the desired therapeutic effect. In most diseases responsive to tiotropium, the concentration of tiotropium is from 0.0005 to 5% by weight, preferably from 0.001 to 3% by weight.

The pH of the formulations according to the invention is from 2.0 to 4.5, preferably from 2.5 to 3.5, more preferably from 2.7 to 3.5 and particularly preferably from 2.7 to 3.2. The upper limit of the pH is most preferably 3.1.

pH is adjusted by adding pharmaceutically acceptable acids. Examples of preferred inorganic acids for this purpose are hydrochloric acid, bromic acid, nitric acid, sulfuric acid and / or phosphoric acid.

Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid. Preferred inorganic acids are hydrochloric acid and sulfuric acid. In addition, in the case of an active substance or a combination preparation, an acid which forms an acid addition salt with any of the active substances may be used. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred, and citric acid is particularly preferred. In some cases, mixtures of the above-mentioned acids may also be used, especially in the case of acids exhibiting properties other than their acidifying properties, for example, citric acid or ascorbic acid, which act as a medicament or antioxidant. have. As the inorganic acid, mention may be made in particular of hydrochloric acid.

In some cases, pharmacologically acceptable bases can be used to precisely adjust the pH. Suitable bases are, for example, alkali metal hydroxides and alkali metal carbonates. Preferred alkali ions are sodium. When bases of this kind are used, particular care should be taken to ensure that the resulting salts contained in the final pharmaceutical formulation are pharmacologically compatible with the above-mentioned acids.

According to the present invention, there is no need to add sodium edetate, which is one of their known salts, as the stabilizer or complexing agent to the formulation of the present invention.

Another preferred embodiment contains editic acid and / or salts thereof.

In a preferred embodiment comprising sodium edetate, the content based on sodium edetate is less than 10 mg / 100 ml. In this case, the range of 5 mg / 100 ml-10 mg / 100 ml or 0-5 mg / 100 ml or more is preferable.

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

In a preferred embodiment, such additives are omitted completely.

In addition, the caveats regarding sodium edetate also apply similarly to other comparable additives that exhibit complex properties, for example, such as nitrilotriacetic acid and salts thereof may be used instead.

By complexing agent is meant a molecule that can be introduced into the complex bond within the scope of the present invention. Preferably, such compounds should exhibit the effect of complexing cations, most preferably metal cations.

Other active substances other than tiotropium salts in the formulated formulations are in particular selected from antihistamines, antiallergic agents, leukotriene antagonists and / or steroids.

Such active materials include

steroid:

Alclomethasone, Flunisolid,

Alclomethasone-Dipropionate, Fluorcinolone Acetonide,

Alisactide, Fluorinide,

Amcinononide, fluorocortin,

Aminoglutetimide, fluorocortolone caponate,

Aristocort-diacetate, fluorexic acid,

Beclomethasone, fluorometholone,

Beclomethasone, Douglas, fluticasone,

Beclomethasone-17,21-dipropionate, fluticasone-propionate,

Betamethasone valerate, formmebolone,

Betamethasone adamantatoate, formocortal,

Budesonide, Halsinoid,

Butoxysocort, Halometason,

Carnetsten-HC, halopredone-acetate,

Cyclomethasone, hydrocortisone,

Clobetasol, hydrocortisone-17-butyrate,

Clobetason, hydrocortisone-aselate,

Cloprednol, hydrocortisone-butyrate propionate,

Cloprodnol, icomethasone enbutate,

Fluorocortin butyl, cyclomethasone,

Cortibazole,

Deplazacort,

Deplazacort,

Demetex,

Deprodone, methylprodisolone-acetonate,

Deprodone propionate, mometasone,

Dexamethasone, mometasone fluorate,

Dexamethasone-21-isonicotinate, mycophenolate mofetil,

Dexamethasone isicotinate, franlukast,

Diflorason, Paramethasone-Acetate,

Diflufredate, Prednica Bate,

Endlessone, Promedol,

Fluzazacort,

Fluclolone Acetonide, Tipredan,

Thixocortol-pivalate, trimascinolone bentonide,

Triamcinolone, woolbetasol-propionate,

Triamcinolone-hexaacetonide, zileuton,

Trilostan,

Methyl 9-alpha-chloro-6-alpha-fluoro-10-beta-17-alpha-dihydroxy-16alpha-methyl-3-oxo-1,4-androstadiene-17-beta-carboxylate- 17-propionate.

Tiotropium bromide, or a combination of tritropium bromide-1 hydrate and budesonide, flunisolide, beclomethasone dipropionate, or fluticasone and pharmaceutically acceptable salts thereof (other possible) Particularly preferred.

Preferred combinations include tiotropium bromide or tiotropium bromide monohydrate and budesonide.

The concentration of steroids (eg, budenosides, flunisolide, beclomethasone dipropionate or fluticasone) in the formulations according to the invention is preferably from 0.05 to 10% by weight, preferably up to 5% by weight. More preferably 0.1 to 2.5% by weight, particularly preferably 0.2 to 2.5% by weight. When the formulation is used with the inhaler described above, the concentration of the steroid is adjusted so that preferably 12.5 to 250 μg of steroid is dispensed per spray. Particularly preferred are concentrations in which the pharmacologically active dose is administered in one or two sprays.

If the formulated formulation contains a leukotriene antagonist, it is preferably montelukast, franlukast, zafirlukast, 1-(((R)-(3- (2- (6,7-difluoro-2) -Quinolinyl) ethetyl) phenyl) -3 (2- (2-hydroxy-2-propyl) phenyl) thio) -methylcyclopropane-acetic acid, 1-(((R) -3- (3- ( 2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl)-(E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) Phenyl) propyl) thio) methyl) -cyclopropane-acetic acid or [2-[[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid Is selected from. Montelukast, franlukast and / or zafirlukast are preferred.

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

Examples of antihistamines and antiallergic agents are shown below:

Azelastine,

Asemizol,

Bamifin,

Carbinoxamine hydrogen maleate,

Set Ligin,

Secchlorpheniramine,

Chlorphenoxamine,

Clemastine,

Clemastine hydrogen fumarate,

Desloratidine,

Dimenhydrinate,

Dimethineden,

Disodium chromoglycate,

Diphenylhydramine,

Doxylamine,

Evastin,

Emedastine,

Epineast,

Fexofenadine,

Ketotifen,

Levocavastin,

Loratadine,

Meclozin,

Methagezine,

Mizolastin,

Nedochromil,

Phenyramine and / or promethazine.

Preference is given to efinastin, nedochromyl, disodium chromoglycate, asemizole, mequitazine, carbinoxamine and / or clemastine and / or corresponding pharmaceutically acceptable salts.

In the formulated formulations, the concentration of antiallergic and / or antihistamine is preferably from 0.05 to 15% by weight, preferably up to 10% by weight, more preferably from 0.1 to 10% by weight and most preferably from 0.1 to 7 Weight percent.

In addition, all the active substances mentioned above may optionally be used in the form of their pharmacologically acceptable salts.

The formulated formulation is preferably a formulation in which tiotropium is present in solution. Other active substances can be dissolved or suspended, which is generally determined by the other active substances and in particular the solvent used.

If the additional active substance is capable of being damaged at low pH, it is preferably formulated as a suspension. The advantage of the suspended form is that the pH can be made more acidic, which is for the benefit of the stability of the dissolved tiotropium. The preferred pH range of tiotropium is from 2.0 to 4.5, preferably from 2.5 to 3.5 and most preferably from 2.7 to 3.2.

In the case of steroids, they are preferably used in suspended form, in particular fluticasone. This is especially the case when the solvent used is only water without ethanol. If ethanol is added, the steroid can also be formulated in solution. However, it has been found, for example, that budesonide is sufficiently stable at pH 3.5 when it is dissolved in a mixture of water and ethanol.

In using the formulation according to the invention in an inhaler described within the scope of the invention, it may be advantageous if all the components of the formulation are present in solution.

In addition to ethanol, other cosolvents and / or other auxiliaries may be added to the formulations according to the invention.

Other preferred cosolvents contain hydroxyl groups or other polar groups, for example alcohols, in particular isopropyl alcohol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyoxyethylene alcohol and Polyoxyethylene fatty acid esters.

Adjuvants and excipients herein are any pharmacologically acceptable and therapeutic agents that do not include the active substance but may be formulated in a pharmacologically suitable solvent with the active substance to improve the quality of the active substance formulation. It means a scientifically useful substance. Preferably, such substances do not exhibit any pharmacological effect or measurable pharmacological effect or at least undesirable pharmacological effect within the scope of the desired treatment. Auxiliaries and additives include, for example, soy lecithin, oleic acid, sorbitan esters (eg sorbitan trioleate), surfactants such as polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and / or final Preservatives, flavorings, vitamins and / or other additives known in the art which extend the shelf life of pharmaceutical formulations. In addition, the additives include pharmacologically acceptable salts such as, for example, sodium chloride.

Suitable surfactants or suspension-stabilizers include lipophilic hydrocarbon groups and one or more functional hydrophilic groups, in particular C _5-20 fatty alcohols, C _5-20 fatty acids, C _5-20 fatty acid esters, lecithins, glycerides, propylene glycol There are all pharmacologically acceptable materials having esters, polyoxyethylene, polysorbates, sorbitan esters and / or carbohydrates. Sorbitans of C _5-10 fatty acids, propylene glycol diesters and / or triglycerides and / or C _5-20 fatty acids are preferred, with oleic acid and sorbitan mono, di- or trioleate being particularly preferred. In addition, toxicologically acceptable and pharmaceutically acceptable polymers and / or block polymers may be used as suspension stabilizers.

The amount of surfactant may be 1: 1 or less, based on the weight ratio of the suspended active substance, with an amount of 0.0001: 1 to 0.5: 1 being preferred, with an amount of 0.0001: 1 to 0.25: 1 being particularly preferred.

Preferred excipients are, for example, antioxidants such as ascorbic acid, vitamin A, vitamin E, tocopherol and similar vitamins or provitamins occurring in the human body, if not already used to adjust the pH.

Preservatives may be added to protect the formulation from contamination by pathogenic bacteria. Suitable preservatives are known in the art and in particular benzalkonium chloride or benzoic acid or benzoate (eg sodium benzoate) at concentrations known in the prior art.

Preferred formulations contain only benzalkonium chloride, pH-adjusting acid and sodium adetate, in addition to the solvents water and / or water / ethanol and tiotropium salts. In another preferred embodiment, sodium edetate is omitted. This embodiment may also contain sodium chloride.

As already described several times, tiotropium bromide is described in EP-A-418 716A1, and crystalline tiotropium bromide monohydrate can be obtained using the method described in more detail below.

To prepare the crystalline monohydrate according to the present invention, tiotropium bromide obtained by the method described in EP-418 716A1, for example, is first immersed in water, heated and purified with activated carbon After the activated carbon is removed, the tiotropium bromide monohydrate is slowly crystallized while gradually cooling.

The procedure is preferably as follows:

In a reaction vessel of suitable dimensions, the solvent is mixed with tiotropium bromide obtained by the method described, for example, in EP 418 716A1. 0.4 to 1.5 kg, preferably 0.6 to 1 kg and most preferably about 0.8 kg of water per mole of tiotropium bromide is used as the solvent. The resulting mixture is heated to preferably 50 ° C. or higher, most preferably 60 ° C. or higher with stirring. The maximum temperature that can be selected depends on the boiling point of the solvent used. Preferably, the mixture is heated to the range of 80 to 90 ° C.

To this solution is added activated carbon wetted with anhydrous or water. Preferably, 10 to 50 g, more preferably 15 to 35 g, most preferably about 25 g of activated carbon is added per mole of tiotropium bromide used. If desired, activated carbon is suspended in water prior to addition to the solution containing tiotropium bromide. To suspend activated charcoal, 70 to 200 g, preferably 100 to 160 g, more preferably about 135 g of water is added per mole of tiotropium bromide used. If the activated carbon is previously suspended in water before addition to the solution containing tiotropium bromide, it is preferred to wash once again with the same amount of water. After adding activated carbon, stirring is continued at a constant temperature for 5 to 60 minutes, preferably for 10 to 30 minutes, more preferably for about 15 minutes, and the obtained mixture is filtered to remove activated carbon. Then, the filter is washed with water. At this time, 140 to 400 g, preferably 200 to 320 g, most preferably about 270 g of water is used per mole of tiotropium bromide used. The filtrate is then cooled slowly and preferably to a temperature of 20-25 ° C. Such cooling is preferably 1 to 10 ° C. for every 10 to 30 minutes, preferably 2 to 8 ° C. for every 10 to 30 minutes, more preferably 3 to 5 ° C. for every 10 to 20 minutes, most preferably At a rate of 3-5 ° C. for about every 20 minutes. After cooling is complete, stirring is continued for 20 minutes to 3 hours, preferably 40 minutes to 2 hours, more preferably about 1 hour until crystallization is complete. The crystals obtained are then separated by filtration or suction filtration to remove the solvent. If the obtained crystals need to be washed further, it is recommended to use water or acetone as the washing solvent. To wash the obtained tiotropium bromide monohydrate crystals, 0.1 to 1.0 L, preferably 0.2 to 0.5 L, more preferably about 0.3 L of solvent is added per mole of tiotropium bromide used. If necessary, the washing step can be repeated. The product obtained is dried under vacuum or by circulating heated air until a water content of 2.5 to 4.0% is obtained.

Thus, according to one embodiment, the present invention relates to the formulation of a solution of the above-mentioned type using crystalline tiotropium bromide monohydrate obtainable by the above-described procedure.

Pharmaceutical formulations containing the tiotropium salt according to the invention for the preparation of propellant-free aerosols according to the invention are preferably used in an inhaler of the type described above. Here, the inventors specify the fact that the patent documents published in the prior art are used herein by reference.

As mentioned in the introduction, further developments of preferred inhalers are described in WO 97/12687 and its FIG. 6. Such nebulizers (Respimat ^™ ) can advantageously be used to prepare the inhalable aerosols according to the invention which contain the tiotropium salt as the active substance. Due to the suitable size of the cylindrical shape of less than 9-15 cm in length and 2-4 cm in width, the patient can carry the device anywhere. A limited volume of pharmaceutical formulation is sprayed by the nebulizer through a small nozzle at high pressure to produce an inhalable aerosol.

Preferred nebulizers consist essentially of an upper housing part, a pump housing, a nozzle, a locking clamp, a spring housing, a spring and a storage container, having the following characteristics:

A pump housing fixed to the upper housing part and having a nozzle body at one end with a nozzle or nozzle arrangement,

Hollow piston with valve body,

A power transmission flange fixed in the hollow body and located in the upper housing part;

-Locking clamping device located in the upper housing part,

A spring housing with built-in spring, which is rotatably mounted on the upper housing part by means of a rotating bearing,

Lower housing part mounted on the spring housing in the axial direction.

The hollow piston comprising the valve body corresponds to the device described in WO 97/12687. It is partly arranged to penetrate into the cylinder of the pump housing and move axially within the cylinder. Reference is made to FIGS. 1 to 4, in particular FIG. 3 and related parts of the description. At the moment the spring relaxes, the fluid, measured by the hollow piston having the valve body at its high pressure end, is 5 to 60 MPa (about 500 to 600 bar), preferably 10 to 60 MPa (about 100 to 600 bar) Pressure is applied. A volume of 10 to 50 μl is preferred, a volume of 10 to 20 μl is more preferred, and a volume of 15 μl per operation is particularly preferred.

The valve body is preferably mounted at the distal end of the hollow piston facing the nozzle body.

The nozzle in the nozzle body is preferably microstructured, ie produced by micro engineering. Microstructured nozzle bodies are described in the examples of WO 94/07607 and WO 99/16530, in particular WO 94/07607, the disclosures of which are incorporated herein by reference. Described in the description. Such a nozzle body consists of, for example, two sheets sealed with glass and / or silicone, one or more of which have one or more microstructured channels connecting the nozzle inlet end to the nozzle outlet end. . At the nozzle outlet end there are one or more circular or non-circular openings of 2 to 10 microns in depth, 5 to 15 microns in width, preferably 4.5 to 6.5 microns in depth and 7 to 9 microns in length.

If there are multiple nozzle openings (preferably two), the spraying directions of the nozzles in the nozzle body may operate in parallel to each other, or the directions of the nozzle openings may be inclined to each other. In the case of a nozzle body having two or more nozzle openings at the outlet end, the spraying directions may have an angle of 20 ° to 160 °, preferably 60 to 150 °, most preferably 80 to 100 ° from each other. The nozzle openings are preferably located at intervals of 10 to 200 μ, more preferably at intervals of 10 to 100 μ, even more preferably at intervals of 30 to 70 μ. The interval is most preferably 50 mu. Thus, the spray direction meets in the region of the nozzle opening.

As mentioned above, the liquid pharmaceutical formulation impinges on the nozzle body at an injection pressure of 600 bar or less, preferably 200 to 300 bar, and is sprayed with the inhalable aerosol through the nozzle opening. The preferred particle size of the aerosol is 20 μm or less, preferably 3 to 10 μm.

The locking clamping device contains a spring, preferably a cylindrical helical compression spring, as a reservoir of mechanical energy. This spring acts on the power transmission flange as a spring component, the movement of which is determined by the position of the locking component. The travel distance of the power transmission flange is precisely defined by the upper stop and the lower stop. The spring is preferably compressed by a stepping-up gear (eg helical sliding gear) by the external torque generated when the upper housing portion is compressed against the spring housing in the lower housing portion. In this case, the upper housing portion and the power transmission flange contain a single speed or multi speed spline gear.

The locking components with an engaging locking surface are arranged in an annular arrangement around the power transmission flange. It consists, for example, of rings of plastic or metal which are inherently radially elastically deformable. After locking the spring, the locking surface of the locking component is inserted in the path of the power transmission flange to prevent the spring from loosening. The locking element is operated by the button. The actuation button is connected or coupled to the locking component. To actuate the locking clamping device, the actuation button is moved parallel to the annular face, preferably into the sprayer, whereby the deformable ring is deformed in the annular face. A detailed description of the structure of the locking clamping device is given in WO 97/20590.

The lower housing portion is axially compressed over the spring housing and includes a bearing, a drive for the spindle and a reservoir for the fluid.

When the compressor is operated, the upper part of the housing rotates with respect to the lower part, the lower part comprising its spring housing. On the other hand, when the spring is compressed and deflected by the helical sliding gear, the clamping device is automatically engaged. The rotation angle is preferably an entire portion of 360 °, for example 180 °. As the spring is compressed, the power transmission component in the upper housing portion moves by a predetermined amount and the hollow piston is pulled back inside the cylinder in the pump housing, resulting in a portion of the fluid from the reservoir being drawn into the high pressure chamber in front of the nozzle. .

If desired, multiple replaceable reservoirs containing the fluid to be sprayed may be inserted into the sprayer in succession. Such storage containers contain an aqueous aerosol formulation according to the invention.

The spraying method is initiated by lightly pressing the actuation button. The path for the power transmission component is then opened by the clamping device. This biased spring compresses the piston into the cylinder in the pump housing. The fluid is injected from the nozzle of the nebulizer in the form of a nebulizer.

Further details regarding the structure are described in PCT applications WO 97/12683 and WO 97/20590, which are incorporated herein by reference.

The components of the nebulizer (injector) are made of materials suitable for their function. The housing and other components of the nebulizer (if operated) are preferably made of plastic, for example by injection molding. In the medical field, physiologically acceptable substances are used.

1A / B, identical to FIG. 6A / B of WO 97/12687, shows a Respite ^™ nebulizer with which an aqueous aerosol formulation according to the invention can be advantageously inhaled.

FIG. 1A shows a cross sectional view of the nebulizer with the spring compressed, and FIG. 1B shows a cross sectional view of the nebulizer with the spring relaxed.

The upper housing portion 51 contains a pump housing 52, on one end of which is mounted a holder 53 for the spray nozzle. The nozzle body 54 and the filter 55 are located in the holder. The hollow piston 57 fixed in the power transmission flange 56 of the locking clamping device partially protrudes into the cylinder of the pump housing. At its end, the hollow piston has a valve body 58. The hollow piston is sealed by the gasket 59. Inside the upper housing part there is a stop 61 where the power transmission flange is stopped when the spring is relaxed. In the power transmission flange, a stop 61 is located where the power transmission flange is stopped when the spring is extended. When the spring is extended, the locking component 62 flows between the stop 61 and the support 63 in the upper housing portion. The actuation button 64 is connected with the locking component. The upper housing portion terminates at the mouthpiece 65 and is closed by a movable protective cap 66.

The spring housing 67 including the compression spring 68 is rotatably mounted to the upper housing portion by a snap-fit lug 69 and a rotating bearing. The lower housing portion 70 is compressed above the spring housing. Inside the spring housing is a replaceable storage container 71 for the fluid 72 to be sprayed. This storage container is sealed by a stopper 73 through which a hollow piston protrudes into the storage container, the end of the piston being immersed in the fluid (supply of active substance solution).

A mechanical counter spindle 74 is mounted on the outside of the spring housing. A drive gear 75 is located at the distal end of the spindle facing the upper housing portion. On the spindle a slider 76 is located.

The nebulizer described above is suitable for spraying an aerosol formulation according to the invention for forming an aerosol suitable for inhalation.

When the formulations according to the invention are sprayed using the method described above, the amount emitted in at least 97%, preferably at least 98% of the total operation (puff) of the inhaler is not more than 25%, preferably 20% Must correspond to a finite amount with a margin of error. Preferably, 5 to 30 mg, more preferably 5 to 20 mg of the formulation is delivered in a defined amount per puff.

The proportion of conveyed amount outside the margin of error of 25% or less relative to the desired amount should be less than 1.5%, preferably less than 1.2%.

However, the formulations according to the invention may also be sprayed using a nebulizer other than those described above (eg a jet-stream nebulizer).

I. Synthesis Examples of Tiotropium Bromide Monohydrate

15.0 kg of tiotropium bromide is added to 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 ° C. and stirred at a constant temperature until a clear solution is formed. Activated carbon wetted with water (0.8 kg) is suspended in 4.4 kg of water, and the mixture is added to a solution containing tiotropium bromide and washed with 4.3 kg of water. The mixture thus obtained is stirred at a temperature of 80-90 ° C. for at least 15 minutes and then filtered through a heated filter with a preheated device having an external temperature of 70 ° C. The filter is washed with 8.6 kg of water. The contents of the device are cooled to a temperature of 20-25 ° C. at a rate of 3-5 ° C. every 20 minutes. The apparatus is further cooled to 10-15 [deg.] C. with cold water and stirred for an additional 1 hour or more to complete the crystallization. The crystals are separated using a suction filtration dryer, and the separated crystal slurry is washed with 9 L of water (10 to 15 DEG C) and cold acetone (10 to 15 DEG C). The obtained crystals are dried at 25 ° C. for 2 hours under a stream of nitrogen. Yield: 13.4 kg tiotropium bromide monohydrate (86% of calculated value).

II. Examples of Formulations

Ingredients of 100 g of pharmaceutical preparation:

Example Amount of tiotropium bromide based on tiotropium The amount of tiotropium bromide monohydrate based on tiotropium Amount of benzalkonium chloride Amount of sodium edetate PH adjusted with HCl (1N) One 0.099g --- 10mg 25mg 3.0 2 0.006g --- 10mg 25mg 3.0 3 0.099g --- 10mg 10mg 3.0 4 0.006g --- 10mg 10mg 3.0 5 --- 0.099g 10mg 25mg 3.0 6 --- 0.006g 10mg 25mg 3.0 7 --- 0.099g 10mg 10mg 3.0 8 --- 0.006g 10mg 10mg 3.0

The remainder is water or water / ethanol in an amount known in the prior art and one of the active substances described above.

Examples 9-12: budesonide

Each of Examples 1-8 may further contain:

Example 9a: 0.3 g of budesonide, pH 3.0 adjusted with HCl, without solvent water, ethanol,

Example 9b: 0.3 g of budesonide, pH 3.5 adjusted with HCl.

Example 9c: 0.3 g of budesonide, pH 4.0 adjusted with HCl.

Example 10 Budesonide is 0.6 g, similar to Examples 9a-9c

Example 11: Budesonide is 1.3 g, similar to Examples 9a-9c

Example 12 Budesonide is 2.0 g, similar to Examples 9a-9c

In Examples 9 to 12 the steroids are in dosage form in suspension. Sorbitan trioleate can be used as the surfactant.

Examples 13-15

Similar to Examples 9-12. Benzaconium chloride is replaced by sodium benzoate.

Examples 16-19

Similar to Examples 9-12. Instead of hydrochloric acid, citric acid is used alone to adjust the pH.

Examples 20-30

Ingredients and amounts are similar to Examples 9-19. Instead of water, a mixture of water (10% by volume) and ethanol (90% by volume) is used. Budesonide is present in solution.

Other Example

Similar to Examples 9-30 described above, small amounts of flunisolide, beclomethasone dipropionate or fluticasone are used in place of budesonide. For fluticasone, for suspension formulations, lecithin is added instead of sorbitan trioleate. If the solvent used is water, the steroid is formed as a suspension. In the case of a mixture of water and ethanol, the steroid may be present in solution.

Example 31

Epineast: 0.2 g

EDTA: 25 mg

Tiotropium bromide monohydrate: 29 mg

PH was adjusted to 3.0 with 0.1 N hydrochloric acid.

Add 100 ml of water.

Claims (41)

Tiotropium salt as one of the active substances, at a concentration of 0.0005 to 5% by weight, based on thiotropium, Another active substance selected from the group consisting of antiallergic, antihistamine, steroid and / or leukotriene antagonists, As a solvent, water or water / ethanol mixture in which at least tiotropium salt is dissolved, acid to bring the pH to 2.0-4.5, Pharmacologically acceptable preservatives, In addition to the preservatives, two or more blendable active substances containing any pharmacologically acceptable complexing agent and / or stabilizer and / or pharmacologically acceptable cosolvent and / or other pharmacologically acceptable auxiliaries and additives Liquid, propellant-free pharmaceutical preparation (liquid). The pharmaceutical formulation of claim 1 wherein the tiotropium salt is a salt with HBr, HCl, HI, monomethylsulfuric acid ester, methanesulfonic acid and / or p-toluenesulfonic acid. The pharmaceutical formulation of claim 1 wherein the active substance is tiotropium bromide. A pharmaceutical formulation according to claim 1 wherein the active substance is tiotropium bromide monohydrate. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the solvent is water. The pharmaceutical composition according to any one of claims 1 to 4, wherein the solvent is a water-ethanol mixture having ethanol up to 90% by volume, more preferably up to 70% by volume and most preferably up to 30% by volume. Formulation. The pharmaceutical formulation according to any one of claims 1 to 6, which contains no complexing agent. 8. A pharmaceutical formulation according to any of claims 1 to 7, characterized in that it contains no stabilizer. The pharmaceutical preparation according to any one of claims 1 to 6, wherein the edetic acid salt is present in an amount of 0 to 25 mg / 100 ml, preferably in an amount of at least 5 mg / ml and less than 10 mg / ml. . 10. The pharmaceutical formulation of claim 9 wherein the edit acid salt is sodium edetate. The pharmaceutical formulation according to any one of the preceding claims, wherein the pH is 2.5 to 3.5, preferably 2.7 to 3.3, most preferably 2.7 to 3.0. The pharmaceutical formulation according to any one of claims 1 to 11, wherein the concentration of tiotropium is 0.0005 to 5% by weight, preferably 3% by weight or less. The pharmaceutical preparation according to any one of claims 1 to 12, which contains benzalkonium chloride as a preservative. The pharmaceutical preparation according to any one of claims 1 to 6 and 9 to 13, characterized in that, in addition to a preservative, co-solvents and / or pharmaceutically acceptable auxiliaries and additives are used. The pharmaceutical formulation according to claim 14, which contains an antioxidant as an adjuvant. The pharmaceutical formulation of claim 1, wherein no co-solvent and / or pharmacologically acceptable auxiliaries and additives are used other than a preservative. The concentration of tiotropium according to claim 1, wherein the concentration of tiotropium is 0.001 to 3% by weight, preferably 0.0005 to 0.5% by weight, more preferably 0.0005 to 0.25% by weight, most preferably 0.001. To 0.1% by weight of the pharmaceutical formulation. The pharmaceutical formulation according to any one of claims 1 to 17, wherein all components are dissolved in a solvent. The pharmaceutical formulation according to any one of claims 1 to 18, wherein the additional active substance is in suspension in the solvent. The pharmaceutical formulation according to any one of claims 1 to 19, wherein the further active substance is a steroid. The pharmaceutical preparation according to claim 20, wherein the concentration of the steroid is 0.05 to 5% by weight, preferably 0.1 to 2.5% by weight. The pharmaceutical formulation according to claim 20 or 21, wherein the steroid is budesonide, beclomethasone dipropionate, fluticasone and / or flunisoleide. The pharmaceutical formulation according to any one of claims 1 to 19, wherein the further active substance is an antiallergic and / or antihistamine. The method according to claim 23, wherein the concentration of antiallergic and / or antihistamine is 0.05 to 15% by weight, preferably 10% by weight or less, more preferably 0.1 to 10% by weight, particularly preferably 0.1 to 7% by weight. Pharmaceutical formulations characterized in that. 25. The method according to claim 23 or 24, wherein the further active substance is epinastine, nedochromyl, disodium chromoglycate, asemizole, mequitazine, carbinoxamine and / or clemastine and / or their A pharmaceutical formulation characterized in that the corresponding pharmacologically acceptable salt. 20. The pharmaceutical formulation of claim 1, wherein the additional active agent is a leukotriene antagonist. The pharmaceutical preparation according to claim 26, wherein the concentration of the leukotriene antagonist is from 0.05 to 10% by weight, preferably from 5% by weight, more preferably from 0.1 to 3.5% by weight. The method of claim 26 or 27, wherein the leukotriene antagonist is montelukast, franlukast, zafirlukast, 1-(((R)-(3- (2- (6,7-difluoro-2-qui) Nolinyl) ethetyl) phenyl) -3- (2- (2-hydroxy-2-propyl) phenyl) thio) methylcyclopropane-acetic acid, 1-(((R) -3- (3- (2- (2,3-dichlorothieno [3,2-b] pyridin-5-yl)-(E) -ethenyl) phenyl) -3- (2- (1-hydroxy-1-methylethyl) phenyl) Propyl) thio) methyl) cyclopropane-acetic acid or [2-[[2- (4-tert-butyl-2-thiazolyl) -5-benzofuranyl] oxymethyl] phenyl] acetic acid Formulation. 2. Another active material according to claim 1, another active substance selected from the group consisting of water, surfactant, tiotropium bromide, anti-allergic agent, antihistamine, steroid and / or leukotriene antagonist, 0.01 wt% of benzalkonium chloride, A pharmaceutical formulation containing 0.05% by weight sodium edetate, wherein the pH is adjusted to 3.0 with hydrochloric or citric acid. 30. A pharmaceutical formulation according to any one of claims 1 to 29 for use as a pharmaceutical composition for administration by inhalation. A drug according to any one of claims 1 to 29 for spraying in an inhaler according to WO 91/14468 or in the inhaler described in FIGS. 6A and 6B of WO 97/12687. Use of pharmaceutical preparations. Spraying a limited amount of pharmaceutical formulation in an atomizer that is sprayed by applying a pressure of 100 to 600 bar through a nozzle having one or more nozzle openings having a depth of 2 to 10 microns and a width of 5 to 15 microns to form an inhalable aerosol. Use of a pharmaceutical formulation according to any one of claims 1 to 29. 33. The use of claim 32, wherein the one or more nozzle openings are two or more nozzle openings inclined at an angle of 20 ° to 160 ° from each other in the direction of the nozzle opening. 34. Use according to claim 32 or 33, characterized in that the limited amount is from 10 to 50 microns. 35. The use according to any one of claims 31 to 34, wherein the inhaler is 9-15 cm in length and 2-4 cm in width. 36. The use according to any one of claims 31 to 35, wherein the amount of the formulation delivered in at least 97% of the total inhaler working amount is 5 to 30 mg with a margin of error of 25%. 37. The use according to any one of claims 31 to 36, wherein the amount of formulation delivered in at least 97% of the total inhaler working amount is 5 to 30 mg with an error range of 20%. 38. Use according to claim 36 or 37, characterized in that the amount delivered is at least 98% of the total working amount of the inhaler. Use of a pharmaceutical preparation according to any one of claims 1 to 29 as a drug, in particular as a drug for the treatment of asthma and / or COPD. A method of treating asthma and / or COPD using a pharmaceutical preparation according to any one of claims 1 to 29 in particular in an inhaler according to any one of claims 31 to 38. 30. A method for preparing a pharmaceutical formulation according to any one of claims 1 to 29 by mixing the individual components.