CN1473044A - Inhalable formulations of solutions containing tiotrapine salts - 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

Inhalable preparations containing solutions of tiotrapine salts

The present invention relates to propellant-free inhalable formulations of pharmaceutically acceptable salts of diotrapine dissolved in water or in mixtures of water and ethanol, and at least one other active substance, preferably administered by inhalation, and derived therefrom Forms a propellant-free inhalable aerosol. The formulations according to the invention are particularly suitable for administering active substances by inhalation, especially for the treatment of asthma and COPD.

Teochuanping, chemical formula (1α, 2β, 4β, 5α, 7β)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9- Azatricyclo[3.3.1.02,4]nonane, known as Thiotrapine bromide by European Patent Application EP 418 716 A1. The hydrobromide salt of tiotrapine has the following chemical structure:

This compound has valuable pharmacological properties and is known under the name diotrapine bromide. Tiotrapine and its salts are highly potent anticholinergics and may provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease). The monohydrate of tiotrapine bromide also has pharmacological value.

Both compounds are preferred objects of the present invention.

The present invention concerns liquid active substance formulations of these compounds, which can be administered by inhalation; the liquid formulations according to the invention must meet high quality standards.

In order to achieve an optimum distribution of the active substance in the lungs, it is expedient to use a liquid preparation which is administered via a suitable inhaler and does not contain propellant gas. Particularly suitable are those inhalers capable of aerosolizing in seconds the small amount of liquid formulation required for therapeutic purposes in a dose into an aerosol suitable for therapeutic inhalation. Within the scope of the present invention, preferred nebulizers are preferably those capable of nebulizing less than 100 microliters, preferably less than 50 microliters, and most preferably less than 20 microliters of the active substance solution in a single spray to form an average The particle size is an aerosol of less than 20 microns, preferably less than 10 microns, so that the respirable fraction of the aerosol already corresponds to a therapeutically effective amount.

Such devices for the propellant-free administration of metered liquid pharmaceutical compositions for inhalation are described in detail, for example, in International Patent Application WO 91/4468 "Aerosolizing Devices and Methods", and also in WO 97 /12687, see Figures 6a and 6b and accompanying instructions. In this type of nebulizer, a high pressure of up to 500 bar is used to convert a medicinal solution into an aerosol intended for the lungs, which is used via nebulization. Within the scope of this patent description, reference is made in particular to the documents mentioned above in their entirety.

In this type of inhaler, the solution formulation is stored in a reservoir. Basically, the active substance preparations used are sufficiently stable on storage while at the same time enabling their direct administration according to their medical purpose, if possible without any further treatment. Furthermore, it must not contain any ingredients that may interact with the inhaler in such a way as to impair the medicinal quality of the inhaler or the solution or aerosol produced.

For atomizing the solution, special nozzles such as those described in WO 94/07607 or WO 99/16530 are used. Both publications are hereby specifically referenced.

WO 98/27959 discloses a solution formulation for the above-mentioned inhaler, which contains ethylenediaminetetraacetic acid disodium salt (sodium edetate) as an additive. For aqueous formulations intended to be transformed into inhalable aerosol solutions using the above-mentioned inhalers, this patent specification uses a minimum concentration of sodium edetate of 50 mg/100 ml to reduce the incidence of aerosol abnormalities. In the disclosed example, there is a formulation containing tiotrapine bromide. In this formulation, the active substance is dissolved in water. The ratio of sodium edetate is still 50mg/100ml.

Surprisingly, it has now been found that solution formulations of Tiotripine salt in water or in water-ethanol mixtures, in which the proportion of the additive sodium edetate is significantly less than 50 mg/100 ml, compared to the Formulations containing tiotrepine bromide are known in the art which show a reduction in the scattering of the delivered composition. In addition, the spray quality is extremely good. Preference is given to using water as solvent. The aerosols formed have very good properties for administration by inhalation.

Another advantage of the formulations according to the invention is that the pH of the formulations can be lowered due to the absence or reduction of the additive sodium edetate in the active substance solution formulations. A low pH is necessary for the long-term stability of the formulation.

It is therefore an object of the present invention to provide an aqueous active substance formulation containing a pharmaceutically acceptable salt of tiotrapine, which meets the high standards required in order to be able to achieve an optimum nebulization of the solution using the inhaler mentioned above. . The active substance preparation according to the invention must be of sufficiently high pharmaceutical quality, ie it should be pharmaceutically stable over a storage period of several years, preferably one year, more preferably two years.

Another object is to provide propellant-free formulations comprising tiotrapine salt solution which are nebulized under pressure using an inhaler, the composition delivered by the aerosol produced reproducibly falling within the specified range.

Another object is to provide a formulation having a solution of tiotrapine and another active substance which can be administered by inhalation.

According to the present invention, any pharmaceutically acceptable salt of diotrapine can be used in the formulation. When the term Tiotropine salt is used within the scope of the present invention, reference is made to Tiotropine. According to the invention, the free ammonium cation Tetrapine, is the corresponding reference salt form Tetrapine (Tiotropin salt), which contains an anion as a counterion. The diotrapine salts usable within the scope of the present invention preferably contain, in addition to diotrapine, as counterions (anions) chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate and/or Compounds of methylsulfate.

Within the scope of the present invention, preference is given to using diotrapine bromide as a salt. For diotrapine bromide within the scope of the present invention, reference must always be made to all possible amorphous and crystalline modifications of diotrapine bromide. These may, for example, contain solvent molecules in their crystalline structure. Of all the crystalline modifications of diotranpine bromide, those which also contain water (hydrates) are preferred according to the invention. The use of tioprene bromide monohydrate is particularly preferred within the scope of the present invention.

In the formulations according to the invention, a composition with tiotrapine salt and only one other active substance is preferred.

In the formulations according to the invention, tiotrapine salt is dissolved in a solvent. The solvent may be limited to water only, or it may be a mixture of water and ethanol. Ethanol may be added to the formulation to increase the solubility of additives or other active substances other than the tiotranpine salt (preferably tiotranpine bromide or tiotranpine bromide monohydrate). The relative proportion of ethanol to water is not limited; it may be, for example, 90% by volume. Preferably, the maximum ethanol limit is 70% by volume, especially 60% by volume and most preferably 30% by volume. The remaining volume % is water. The preferred solvent is water without the addition of ethanol.

Based on the proportion of tiochuanpine in the finished pharmaceutical preparation, the concentration of tiochuanpine salt is determined by the therapeutic effect sought. For most diseases to which diotrapine is indicated, the concentration of diotrapine is between 0.0005% and 5% by weight, preferably between 0.001% and 3% by weight.

The pH of the formulations according to the invention is between 2.0 and 4.5, preferably between 2.5 and 3.5, more preferably between 2.7 and 3.3, and particularly preferably between 2.7 and 3.2. Most preferred is a pH with an upper limit of 3.1.

The pH is adjusted by adding a pharmacologically acceptable acid. Examples of preferred inorganic acids for this purpose include: 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 the like. Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which form acid addition salts with the active substances or, in the case of combination preparations, with one of the active substances.

Among organic acids, ascorbic acid, fumaric acid, and citric acid are preferred. Mixtures of the acids mentioned above may also be used if desired, especially if the acid has properties other than its acidifying properties, eg as flavoring agents or antioxidants, eg citric acid or ascorbic acid.

Hydrochloric acid deserves special mention as mineral acid.

A pharmacologically acceptable base can be used to accurately titrate the pH, if desired. Suitable bases include, for example, alkali metal hydroxides and alkali metal carbonates. Preferred alkali metal ions are sodium ions. If bases of this kind are used, care must be taken to ensure that the salts formed, which are included in the finished pharmaceutical formulation, are pharmacologically compatible with the acids mentioned above.

According to the invention, it is not necessary to add ethylenediaminetetraacetic acid (EDTA) or one of its known salts, sodium edetate, to the formulation of the invention as a stabilizer or complexing agent.

Another embodiment contains ethylenediaminetetraacetic acid and/or salts thereof.

In a preferred embodiment with sodium edetate, the content based on sodium edetate is less than 10 mg/100 ml. In this case, one preferred range is from 5 mg/100 ml to less than 10 mg/100 ml, or another is from more than 0 to 5 mg/100 ml.

In another embodiment, the content of sodium edetate is 10 to 30 mg/100 ml, preferably no more than 25 mg/100 ml.

In a preferred embodiment, this additive is omitted entirely.

What has been said about sodium ethylenediaminetetraacetate applies similarly to other equivalent additives which have complexing properties and which can be used instead, such as oxatrilotriacetic acid and its salts.

By complexing agent, within the scope of the present invention preferably is meant a molecule capable of forming complex bonds. Preferably, these compounds should have the effect of complexing cations, most preferably metal cations.

In combination preparations, the other active substances other than tiotrapine salts are in particular selected from antihistamines, antiallergics, leukotriene antagonists and/or steroids. These active substances include:

Regarding steroids: Achotromatone, relaxed fluoropromotomy, octatamone-diopate, relaxed fluorine, alpha flulutramine, Astinida, fluorine test, amino-based gulne Hexanoate, Triamcinolone-Diacetate, Fluodexan, Beclomethasone, Fluocinolone, Beclomethasone, Douglas, Fluticasone, Beclomethasone-17, 2 ]-dipropionate, fluticasone-propionate, beta-methasone valerate, formebolone (Formebolone), beta-methasone adamantanoate, fluformylolone, budesonide, fludroxone butyrochloride Butixocort, Halometasone, clubpicazole-HC, Halopredone-acetate, ciclomethene, hydrogenated loosening, chlorofluoroson, hydrogenated pine -1 7-Butyrate, Copper Clomethasone, Hydrocortisone-Aciboate, Cloprednol, Hydrocortisone-Butyrate Propionate, Cloprednisol, Excormethasone (IComethasone Enbutate), fluoropicine, ciclomethene, and the transligazole, Ruo San Song, Earth Catt, Marbinone, Earth Catt, 6α-nail-11 β-hydroxyl hydroxyl Progesterone, Demetex, Methylprednisone, Dipronone, Methylprednisolone-Acicil

Baconic acid esters, dipronone propionate, mometasone, dexamethasone, mometasone furoate, dexamethasone-21-nicotinate, mycophenolate mofetil, dexamethasone And nicotinate, prunalukast, diflorasone, to Fluentonate-acetate, bisperfluorodinib, Podonika, noresonium, Prometh, fluoropic rice pine, Genqu, Squestqu Seratrodast, Fluclorolone Acetonate, Tiperdan, Hydrocortisone-Pivalate, Trimacinolone Benetonide, Fludroxyprednisolone, Ulobetasol (Ulobetasol)-propionate, fluroxyprednisolone-Hexacetonide, zibaiton, trilosteine,

9-α-chloro-6-α-fluoro-11-β-17-α-dihydroxy-16-α-methyl-3-oxyl-1,4-androsdiene-17-β-carboxylate-17 - methyl propionate,

Particular preference is given to diotrapine bromide or diotrapine bromide-monohydrate and budesonide, 9-desfluracone, beclomethasone dipropionate or fluticasone, and pharmacologically acceptable (possibly others) Salt combination.

A preferred composition comprises tioprepine bromide or tioprene bromide monohydrate and budesonide.

The concentration of steroids, for example budesonide, 9-desfluracone, beclomethasone dipropionate or fluticasone, in the preparations according to the invention is preferably from 0.05% to 10% by weight, preferably up to 5% by weight, preferably up to 5% by weight, more preferably Preferably it is 0.1% by weight to 2.5% by weight, particularly preferably 0.2% by weight to 2.5% by weight. When the formulation is used with the aforementioned inhaler, the steroid concentration is preferably adjusted so that 12.5 to 250 micrograms of steroid are delivered per spray. Particularly preferred are concentrations where the pharmacologically active dose is administered in one or two sprays.

If the combination preparation contains a leukotriene antagonist, it is preferably selected from the group consisting of montelukast, pranthiocarb, zafirlukast, 1-(((R)-(3-(2-( 6,7-Difluoro-2-quinolyl)vinyl)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)-vinyl)phenyl)-3 -(2-(1-Hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-cyclopropane-acetic acid or [2-[[2-(4-tert-butyl-2- Thiazolyl)-5-benzofuryl]oxymethyl]phenyl]acetic acid. Montethiocarb, planthiocarb and/or zafeticarb 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.

The following are mentioned as examples of antihistamines and antiallergics: azelastine, astemizole, benzylamine, carbinoxamine hydrogen fumarate, cetirizine, ciclophen Pyramine (Cexchlorpheniramine), Chlorphenoxyamine, Clemastine, Clemastine Fumarate, Desloratidine, Dimenhydrinate, Dimetindene, Disodium Cromoglycate, Diphenhydramine, Doxylamine, Ebastine, Emedastine, Epinastine, Fexofenadine, Ketotifen , L-carbastine, loratadine, meclizine, mequitazine, mizolastine, nadocromil, antisensitizing and/or promethazine.

Epinatine, nedocromil, disodium cromoglycate, astemizole, mequitazine, carbinoxamine and/or clemastine, and/or their corresponding pharmaceutically acceptable salts are preferred.

The concentration of the antiallergic and/or antihistamine in the combined preparation is preferably 0.05% to 15% by weight, preferably up to 10% by weight, more preferably 0.1% to 10% by weight, most preferably 0.1% by weight % to 7% by weight.

All the active substances mentioned above can optionally be used in the form of their pharmacologically acceptable salts.

The combination formulation is preferably a formulation wherein tiotrapine is present in solution. The other active substance can be dissolved or suspended; this is usually determined by the other active substance and the particular solvent used.

If the other active substance is fragile at low pH, it is preferably formulated as a suspension. The suspension form has the advantage of making the pH more acidic, which favors the stability of the dissolved tiotranpine. The preferred pH range for tiotrapine bromide is between 2.0 and 4.5, preferably between 2.5 and 3.5, most preferably between 2.7 and 3.2.

In the case of steroids, these are preferably used in suspension form, especially fluticasone. This is especially desirable if the solvent used is only water and no ethanol. Steroids can also be formulated into solutions if ethanol is added. However, it has been found that, for example, budesonide is sufficiently stable at a pH of 3.5 if it is dissolved in a mixture of water and ethanol.

With regard to the use of the formulations according to the invention in said inhalers within the scope of the invention, it may be advantageous if all the constituents of the formulation are present in solution.

Also ethanol, other co-solvents and/or other adjuvants may be added to the formulations according to the invention.

Other preferred co-solvents are compounds containing hydroxyl or other polar groups, such as alcohols, especially isopropanol, glycols, especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, glycerol, polyethylene oxide Alcohols and polyoxyethylene fatty acid esters.

The so-called adjuvants and additives, in this connection any pharmacologically acceptable and therapeutically useful substance, which is not the active substance, but can be formulated together with the active substance in a pharmacologically suitable solvent to improve the quality of the preparation of the active substance . Preferably, these substances have no pharmacological effect, or no perceivable or at least no unwanted pharmacological effect with respect to the desired therapy. Adjuvants and additives include, for example, surfactants such as soybean lecithin, oleic acid, sorbitan esters such as sorbitan trioleate, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and/or or preservatives, which prolong the shelf life of the finished pharmaceutical preparation, flavoring agents, vitamins and/or other additives known in the art. Additives also include pharmacologically acceptable salts, such as sodium chloride.

Suitable surfactants or suspension stabilizers include all pharmacologically acceptable substances having a lipophilic hydrocarbon group and one or more functional hydrophilic groups, especially C _5-20 -fatty alcohols, C _5-20 - Fatty acids, C _5-20 -fatty acid esters, lecithin, glycerol esters, propylene glycol esters, polyethylene oxides, polysorbate esters, sorbitan esters and/or carbohydrates. C _5-20 -fatty acids, propylene glycol diesters and/or triglycerides and/or sorbitan esters of C _5-2) -fatty acids are preferred, while oleic acid and sorbitan mono-, Di- or trioleates are particularly preferred. Alternatively, toxicologically and pharmaceutically acceptable polymers and/or block polymers may be used as suspension stabilizers.

The amount of surfactant, based on the weight ratio of the suspended active substance, can be up to 1:1; 0.0001:1 to 0.5:1 is preferred, while 0.0001:1 to 0.25:1 is particularly preferred.

Preferred excipients include antioxidants such as ascorbic acid, provided that it has not been used to adjust pH, vitamin A, vitamin E, tocols and similar vitamins, or provitamins as they occur in the human body.

Preservatives can be added to protect the preparation from contamination by pathogenic bacteria. Suitable preservatives are known from the prior art, especially benzalkonium chloride or benzoic acid or benzoate salts, such as sodium benzoate, in concentrations known from the prior art.

A preferred formulation contains, in addition to the solvent water and/or water/ethanol and tiotripine salt, only benzalkonium chloride, the acid used to adjust the pH, and sodium edetate.

In another preferred embodiment, sodium edetate is omitted. These embodiments may optionally contain sodium chloride.

As already mentioned several times, tiotranpine bromide is described in EP 418 716 A1 and crystalline tiotranpine bromide monohydrate can be obtained using the method described in more detail hereinafter.

In order to prepare the crystalline monohydrates according to the invention, for example the bromide diotrapine obtained by the method disclosed in EP 418 716 A1, it must first be dissolved in water, heated, purified with activated charcoal, after removal of the activated charcoal, Thiotrapine bromide-monohydrate was allowed to crystallize slowly while cooling slowly.

Preferably follow the method below:

In a reaction vessel of suitable size, the solvent is mixed with Thiotrapine bromide, which has been obtained, for example, by the method disclosed in EP 418 716 A1.

0.4 to 1.5 kg, preferably 0.6 to 1 kg, most preferably about 0.8 kg of water is used as solvent for each mole of diotrapine bromide added.

The resulting mixture is heated with stirring, preferably to above 50°C, most preferably to above 60°C. The maximum temperature selectable is determined by the boiling point of the solvent used. Preferably, the mixture is heated to a temperature in the range of 80-90°C.

Activated carbon, dry or wet with water, is added to this solution. Preferably, 10 to 50 grams, more preferably 15 to 35 grams, most preferably about 25 grams of activated carbon is added per mole of thiotrapine bromide used. If desired, suspend activated carbon in water before adding to the solution containing diotrapine bromide. For suspending the activated carbon, 70 to 200 grams, preferably 100 to 160 grams, more preferably about 135 grams of water are used per mole of added thiotrapine bromide. If activated carbon is pre-suspended in water, it is advisable to rinse once more with an equal volume of water before adding to the solution containing diotrapine bromide.

After the activated carbon has been added, stirring is continued at constant temperature for 5 to 60 minutes, preferably at 10 to 30 minutes, more preferably about 15 minutes, and the obtained mixture is filtered to remove the activated carbon. The filter is then rinsed with water. For this purpose 140 to 400 grams, preferably 200 to 320 grams, most preferably about 270 grams of water are used per mole of diotrapine bromide used.

The filtrate is then allowed to cool slowly, preferably to a temperature of 20-25°C. Cooling is preferably carried out at a cooling rate of 1 to 10°C every 10 to 30 minutes, preferably 2 to 8°C every 10 to 30 minutes, more preferably 3 to 5°C every 10 to 20 minutes, most preferably about every 20 min 3 to 5°C. If necessary, after cooling to 20 to 25°C, it can be further cooled to below 20°C, more preferably to 10 to 15°C.

After the cooling is completed, the stirring is continued for 20 minutes to 3 hours, preferably 40 minutes to 2 hours, more preferably about 1 hour until the crystallization is completed.

The crystals obtained are then isolated by removing the solvent by filtration or suction filtration. In case it proves necessary to subject the crystals obtained to another washing step, water or acetone is preferably used as washing solvent. For each mole of added tiomepine bromide, 0.1 to 1.0 liter, preferably 0.2 to 0.5 liter, more preferably about 0.3 liter of solvent may be used to wash the obtained crystal of tiomepine bromide monohydrate. This washing step can be repeated if necessary. The resulting product is dried in vacuo or using circulating heated air until a water content of 2.5-4.0% is obtained.

Therefore, according to an aspect of the present invention, also concerning a solution formulation of the above-mentioned type, it is used crystalline tiopranine bromide monohydrate obtainable by the above-mentioned method.

Pharmaceutical preparations according to the invention comprising tiotrapine salts are preferably used in inhalers of the kind described above to generate propellant-free aerosols according to the invention. At this point, we should once again specifically refer to the aforementioned patent documents, which are used here as a reference.

As mentioned at the outset, a further developed embodiment of the preferred inhaler is disclosed in WO 97/12687 and FIG. 6 thereof. This nebuliser ( ^Respimat® ) can advantageously be used to generate an inhalable aerosol according to the invention comprising tiotropine salt as active substance. Due to its cylindrical shape and compact size of less than 9 to 15 cm long and 2 to 4 cm wide, the device can be carried around by the patient. This nebulizer sprays a defined volume of medicinal preparation through a small nozzle under high pressure to produce an inhalable aerosol.

The preferred nebulizer basically comprises an upper housing part, a pump housing, a nozzle, a locking clamp, a spring housing, a spring and a storage container, characterized by

- pump casing, which is fixed in the upper casing part and has a nozzle or nozzle structure at one end

made nozzle body,

- hollow piston with valve body,

- power launch flange, in which the hollow body is fixed, and which is located in the upper shell part,

- locking clamp mechanism, which is located in the upper shell part,

- The spring housing, in which the spring is located, is rotatably mounted to the upper housing by means of a swivel bearing

parts,

- The lower housing part, which is axially fitted on the spring housing.

The hollow piston with valve body corresponds to the device disclosed in WO 97/12687. It partially protrudes into the cylinder of the pump casing and is arranged to move axially within the cylinder. Particular reference is made to Figures 1-4, and especially Figure 3 and relevant parts of the description. When the spring is released, the hollow piston with the valve body applies a pressure of 5 to 60 MPa (approximately 50 to 600 bar), preferably 10 to 60 MPa (approximately 100 to 600 bar) at its high pressure end to the fluid, i.e. the measured volume active substance solution. A volume of 10 to 50 microliters is preferred, a volume of 10 to 20 microliters is more preferred, and a volume of 15 microliters per actuation is particularly preferred.

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

The nozzles in the nozzle body are preferably microstructured, ie produced by microengineering. Microstructured nozzle bodies are disclosed, for example, in WO-94/07607; reference is hereby made to the content of this patent specification, in particular to FIG. 1 of WO-94/07607 and the related description.

The nozzle body comprises, for example, two sheets of glass and/or silicon held together firmly, at least one of which has one or more microstructured channels connecting the nozzle inlet end to the nozzle outlet end. There is at least one circular or non-circular opening at the outlet end of the nozzle, which is 2 to 10 microns deep and 5 to 15 microns wide, preferably 4.5 to 6.5 microns deep and 7 to 9 microns long.

If there are multiple (preferably two) nozzle openings, the spraying directions of the nozzles in the nozzle body may run parallel to each other, or may be obliquely opposite each other in the direction of the nozzle openings. In the case of nozzle bodies having at least two nozzle openings at the outlet end, the spray directions may lie opposite each other at an angle of 20 to 160°, preferably 60 to 150°, most preferably 80 to 100°. The pitch of the array of nozzle openings is preferably 10 to 200 microns, more preferably 10 to 100 microns, most preferably 30 to 70 microns. A pitch of 50 microns is most preferred. The spray directions will thus converge in the region of the nozzle opening.

As already mentioned, the liquid pharmaceutical formulation impinges on the nozzle body with an inlet pressure of up to 600 bar, preferably 200 to 300 bar, and is atomized through the nozzle opening into an inhalable aerosol. The preferred particle size of the aerosol is up to 20 microns, preferably 3 to 10 microns.

The locking clamp mechanism incorporates a spring, preferably a cylindrical helical compression spring, as a store of mechanical energy. The spring acts on the power launching flange as a spring member, the movement of which is determined by the position of the locking member. The travel of the power launch flange is precisely limited by the upper stop pin and the lower stop pin. The spring is preferably tensioned via a booster gear, such as a helical slide gear, by an external torque generated when the upper housing part rotates relative to the spring housing in the lower housing part. In this case, the upper casing part and the power launch flange comprise single or multi-speed scotch gears.

Locking members having engaging locking surfaces are arranged in a ring around the power launch flange. These include, for example, plastic or metal rings, which are radially elastically deformable in nature. The rings are aligned in a plane perpendicular to the nebulizer axis. After the spring is locked, the locking surface of the locking member slides into the path of the power launching flange and prevents the spring from being released. The locking member is activated with a push button. The activation button is connected to the locking member. To activate the locking clamp mechanism, the activation button is moved parallel to the annular plane, preferably into the sprayer, whereby the deformable ring is deformed in the annular plane. Construction details of the locking clamp mechanism are listed in WO 97/20590.

The lower housing part is pushed axially through the spring housing and covers the bearings, the transmission of the spindle and the reservoir for the fluid.

When the sprayer is activated, the upper part of the shell rotates relative to the lower part, and the lower part drives the spring shell to accompany it. Simultaneously the spring is compressed and biased by sliding the screw into the gear, and the clamp mechanism is automatically engaged. The rotation angle is preferably an integer part of 360 degrees, eg 180 degrees. Simultaneously, when the spring is tensioned, the power-generating part in the upper casing part is moved by a predetermined amount, and the hollow piston is pulled back to the inside of the cylinder in the pump casing, as a result, a part of the fluid is drawn from the storage container in front of the nozzle. in the high pressure chamber.

If desired, a number of replaceable storage containers containing the fluid to be nebulized may be sequentially inserted into the nebulizer and subsequently used. The storage container contains an aqueous aerosol formulation according to the invention.

The nebulization program is started by lightly pressing the start button. The clamp mechanism then opens the path of the power launch assembly. The piston is pushed into the barrel of the pump casing by a biased spring. The fluid exits the nozzle of the sprayer in the form of a spray.

Further details of the structure are disclosed in PCT applications WO 97/12683 and WO 97/20590, which are hereby incorporated by reference.

The components of the nebulizer (atomizer) are made of materials suitable for their function. The nebulizer housing and other parts (if their function permits) are preferably produced from plastic, for example via injection moulding. For medicinal purposes, physiologically acceptable materials are used.

Figures 1a/b, which are identical to Figures 6a/b of WO 97/12687, show that with a ^Respimat® nebuliser, the aqueous aerosol formulation according to the invention can advantageously be inhaled.

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

The upper housing part 51 contains a pump housing 52, at the end of which is mounted a holder 53 for the sprayer nozzle. The nozzle body 54 and the filter 55 are in the holder. A hollow piston 57 secured in the lock clamp mechanism power launch flange 56 projects partially into the cylinder of the pump housing. The hollow piston has a valve body 58 at its end. The hollow piston is sealed with a gasket 59 . The stop pin 60 is inside the upper housing part, on which the power launch flange is resting when the spring is relaxed. Located on the power launch flange is a stop pin 61 on which the power launch flange rests when the spring is under tension. After tensioning of the spring, the locking member 62 slides between the stop pin 61 in the upper housing part and the carrier 63 . The activation button 64 is connected to the locking member. The upper housing part ends at the mouthpiece 65 and is closed with a removable protective cover 66 .

A spring case 67 with a compression spring 68 is rotatably mounted on the upper case part by means of a snap handle 69 and a rotary bearing. The lower housing part 70 is pushed via a spring housing. Inside the spring housing is a replaceable storage container 71 for the desired atomized fluid 72 . The storage container is closed by a plug 73 through which a hollow piston protrudes into the storage container and whose end is submerged in the fluid (feed of active substance solution).

The main shaft 74 of the mechanical counter is mounted on the outside of the spring case. Located at the end of the main shaft facing the upper housing part is a drive pinion 75 . On the spindle is a slide plate 76 .

The aforementioned nebulizer is suitable for atomizing the aerosol preparation according to the present invention to form an aerosol suitable for inhalation.

If the formulation according to the invention is nebulized using the method described above ( ^Respimat® ), the delivered volume, which is at least 97%, preferably at least 98%, of all actuations (sprays) of the inhaler should correspond to a tolerance not exceeding this volume A limited amount of 25%, preferably 20%. Preferably, 5 to 30 mg, more preferably 5 to 20 mg of formulation is delivered as a defined mass per spray.

The proportion of the delivered mass, the maximum of which is within a tolerance range of not more than 25%, should be less than 1.5%, preferably less than 12%, with respect to the desired mass.

However, the formulations according to the invention can also be nebulized using inhalers other than those mentioned above, for example jet inhalers.

Embodiment 1. the embodiment of synthesizing bromide thiotrapine monohydrate

In a suitable reaction vessel, 15.0 kg of thiotrapine bromide was added to 25.7 kg of water. The mixture was heated to 80-90°C and stirred at constant temperature until a clear solution formed. Water-moistened activated charcoal (0.8 kg) was suspended in 4.4 kg of water, this mixture was added to the solution containing diotrapine bromide and washed with 4.3 kg of water. The mixture thus obtained is stirred at 80-90°C for at least 15 minutes and then filtered through a heated filter into a vessel preheated to an external temperature of 70°C. The filter was rinsed with 8.6 kg of water. The vessel contents were allowed to cool to a temperature of 20-25°C at a rate of 3-5°C every 20 minutes. The vessel was further cooled to 10-15°C with cold water and crystallization was accomplished by stirring for at least another hour. The crystals were isolated using a suction filter drier, and the separated crystal slurry was washed with 9 liters of cold water (10-15°C) and cold acetone (10-15°C). The obtained crystals were dried at 25°C for 2 hours in a nitrogen stream. Yield: 13.4 kg of thiotrapine bromide monohydrate (86% of theory). II. Examples of Formulations

100 g of medicinal preparation contains: example The amount of bromide thiotropin, based on thiotropin: The amount of bromide tiopranine monohydrate, based on tiopranine: benzalkonium chloride amount Sodium edetate amount pH value, adjusted with HCl (1N) 1 0.099 grams --- 10 mg 25 mg 3.0 2 0.006 grams --- 10 mg 25 mg 3.0 3 0.099 grams --- 10 mg 10 mg 3.0 4 0.006 grams --- 10mg 10mg 3.0 5 --- 0.099 grams 10 mg 25 mg 3.0 6 --- 0.006 grams 10 mg 25 mg 3.0 7 --- 0.099 grams 10 mg 10 mg 3.0 8 --- 0.006 grams 10 mg 10 mg 3.0

The remainder is water or water/ethanol and one of the above-mentioned active substances in amounts known in the prior art. Examples 9 to 12: Budesonide

Examples 1 to 8 may additionally contain:

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

Example 9b: budesonide: 0.3 g, pH adjusted by HCl: 3.5;

Example 9c: budesonide: 0.3 g, pH adjusted by HCl: 40;

Embodiment 10: Similar to Embodiment 9a to 9c, wherein budesonide: 0.6 grams,

Embodiment 11: Similar to Embodiment 9a to 9c, wherein budesonide: 1.3 grams,

Embodiment 12: Similar to Embodiments 9a to 9c, wherein budesonide: 2.0 grams.

In Examples 9 to 12, the steroid was present in the formulation in suspension. Sorbitan trioleate can be used as a surfactant. Examples 13 to 15

Similar to Examples 9 to 12. The benzalkonium chloride was replaced by sodium benzoate. Examples 16 to 19

Similar to Examples 9 to 12. Instead of hydrochloric acid, only citric acid was used to adjust the pH. Examples 20 to 30

Components and consumption are similar to Examples 9 to 19. Instead of water, a mixture of water (10% by volume) and ethanol (90% by volume) was used. Budesonide is present in solution. other examples

Similar to the above Examples 9 to 30, the same amount of 9-desflufluidozone, beclomethasone dipropionate or fluticasone was used instead of budesonide. In the case of fluticasone, it is preferred to add lecithin instead of sorbitan trioleate in the case of suspension formulations. If water alone is the solvent used, the steroid is formulated as a suspension. In the case of water and ethanol mixtures, the steroid may be in solution. Example 31

Epinatine: 0.2 grams

EDTA: 25 mg

Thiotrapine bromide monohydrate: 29 mg,

0.1N hydrochloric acid to adjust the pH to 3.0,

water to 100ml

Claims (41)

1. A liquid propellant-free pharmaceutical preparation comprising at least two combinable active substances, comprising · Teochuanping salt, as one of the active substances, its concentration is 0.0005 based on Tiouchuanping Between wt% and 5 wt%, another active substance selected from antiallergics, antihistamines, steroids and/or leukotriene antagonists agent, water or a water/ethanol mixture as a solvent in which at least the salt of Tiotrapine is dissolved, acid, passed to achieve a pH between 2.0 and 4.5, Pharmacologically acceptable preservatives, · In addition to preservatives, optional pharmacologically acceptable complexing agents and/or stabilizers, and/ Or pharmacologically acceptable co-solvents, and/or other pharmacologically acceptable adjuvants and added agent. 2. The pharmaceutical preparation according to claim 1, wherein Tiouchuanping salt is a salt formed from HBr, HCl, HI, monomethylsulfate, methanesulfonic acid and/or p-toluenesulfonic acid . 3. The pharmaceutical preparation according to claim 1, characterized in that the active substance is tiotrapine bromide. 4. The pharmaceutical preparation according to claim 1, characterized in that the active substance is tiotrapine bromide monohydrate. 5. Pharmaceutical formulation according to any one of claims 1 to 4, characterized in that the solvent is water. 6. Pharmaceutical formulation according to any one of claims 1 to 4, characterized in that the solvent is a water-ethanol mixture with preferably up to 70% by volume of ethanol, more preferably up to 70% by volume of ethanol, and Most preferred is up to 30% ethanol by volume. 7. The pharmaceutical preparation according to any one of claims 1 to 6, characterized in that it does not contain complexing agents. 8. Pharmaceutical formulation according to any one of claims 1 to 7, characterized in that it contains no stabilizers. 9. The pharmaceutical preparation according to any one of claims 1 to 6, characterized in that EDTA is present in an amount greater than 0 up to 25 mg/100 ml, preferably 5 to less than 10 mg/100 ml ml. 10. The pharmaceutical preparation according to claim 9, characterized in that EDTA is sodium EDTA. 11. Pharmaceutical preparation according to any one of claims 1 to 10, characterized in that the pH value is between 2.5 and 3.5, preferably between 2.7 and 3.3, and most preferably between 2.7 and 3.0 . 12. Pharmaceutical formulation according to any one of claims 1 to 11, characterized in that the concentration of tiotrapine is between 0.0005% and 5% by weight, preferably up to 3% by weight. 13. Pharmaceutical preparation according to any one of claims 1 to 12, characterized in that the preparation contains benzalkonium chloride as preservative. 14. Pharmaceutical formulation according to any one of claims 1 to 6 and 9 to 13, characterized in that, in addition to preservatives, co-solvents and/or pharmacologically acceptable adjuvants and additives are used. 15. The pharmaceutical preparation according to claim 14, characterized in that the preparation contains an antioxidant as an adjuvant. 16. Pharmaceutical formulation according to any one of claims 1 to 15, characterized in that, apart from preservatives, no co-solvents and/or pharmacologically acceptable adjuvants and additives are used. 17. The pharmaceutical preparation according to any one of the preceding claims, characterized in that the concentration of tiotrapine is 0.001% to 3% by weight, preferably 0.0005% to 0.5% by weight, more preferably 0.0005% by weight to 0.25% by weight, and most preferably from 0.001% to 0.1% by weight. 18. Pharmaceutical formulation according to any one of the preceding claims, characterized in that all components are dissolved in a solvent. 19. Pharmaceutical formulation according to any one of the preceding claims, characterized in that the other active substance is suspended in a solvent. 20. Pharmaceutical preparation according to any one of the preceding claims, characterized in that the other active substance is a steroid. 21. Pharmaceutical preparation according to claim 20, characterized in that the concentration of the steroid is 0.005% to 5% by weight, preferably 0.1 to 2.5% by weight. 22. The pharmaceutical preparation according to any one of claims 20 or 21, characterized in that the steroid is budesonide, beclomethasone dipropionate, fluticasone and/or 9-desflurouzone. 23. Pharmaceutical formulation according to any one of claims 1 to 19, characterized in that the other active substance is an antiallergic and/or antihistamine. 24. Pharmaceutical preparation according to claim 23, characterized in that the concentration of antiallergic and/or antihistamine is 0.05% by weight to 15% by weight, preferably up to 10% by weight, more preferably 0.1% by weight to 10% by weight, particularly preferably 0.1% to 7% by weight. 25. according to the pharmaceutical preparation described in any one in claim 23 or 24, it is characterized in that another kind of active substance is in the form of epinatine, nadocromil, disodium cromoglycate, astemizole, mequitazine , carbinoxamine and/or clemastine and/or its corresponding pharmaceutically acceptable salts. 26. Pharmaceutical formulation according to any one of claims 1 to 19, characterized in that the other active substance is a leukotriene antagonist. 27. Pharmaceutical preparation according to claim 26, characterized in that the leukotriene antagonist concentration is 0.05% to 10% by weight, preferably to 5% by weight, more preferably 0.1% to 3.5% by weight. 28. The pharmaceutical preparation according to any one of claims 26 or 27, characterized in that the leukotriene antagonist is montthiocarb acid, pranthiocarb, zafetiacar, 1-(((R)-( 3-(2-(6,7-difluoro-2-quinolyl)vinyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methyl ring Propane-acetic acid, 1-(((R)-3-(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-vinyl) Phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetic acid, [2-[[2-(4-tert-butyl yl-2-thiazolyl)-5-benzofuryl]oxymethyl]phenyl]acetic acid. 29. The pharmaceutical preparation according to claim 1, which contains water, a surfactant, 0.1% by weight of diotrapine bromide, selected from the group consisting of antiallergics, antihistamines, steroids and/or leukotriene antagonists Another active substance, 0.01% by weight benzalkonium chloride, 0.05% by weight sodium edetate, the pH of this preparation was adjusted to 3.0 with hydrochloric acid or citric acid. 30. The pharmaceutical formulation according to any one of claims 1 to 29 for use as a pharmaceutical composition for administration by inhalation. 31. Use of a pharmaceutical formulation according to any one of claims 1 to 29 in an inhaler according to WO 91/14468 or as described in Figures 6a and 6b of WO 97/12687 atomization. 32. Use of a medicinal preparation according to any one of claims 1 to 29 for nebulization in an inhaler by applying a pressure of 100 to 600 bar through the nozzle to make a defined amount of medicinal The formulation is nebulized to form an inhalable aerosol, the nozzle having at least one nozzle opening having a depth of 2 to 10 microns and a width of 5 to 15 microns. 33. Use according to claim 32, characterized in that the at least one nozzle has at least two nozzle openings, which are inclined to each other in the direction of the nozzle openings at an angle of 20° to 160°. 34. Use according to claim 32 or 33, characterized in that the defined volume is between 10 and 50 microliters. 35. Use according to any one of claims 31 to 34, characterized in that the inhaler is 9 to 15 cm long and 2 to 4 cm wide. 36. Use according to any one of claims 31 to 35, characterized in that at least 97% of all actuations of the inhaler deliver a mass of formulation between 5 and 30 mg with a tolerance of 25% scope. 37. Use according to any one of claims 31 to 36, characterized in that the mass of the formulation delivered in at least 97% of all actuations of the inhaler is between 5 and 30 mg with a tolerance of 20% scope. 38. Use according to any one of claims 36 or 37, characterized in that the mass delivered is achieved at least 98% of all actuations of the inhaler. 39. Use of a pharmaceutical preparation according to any one of claims 1 to 29 as a medicament, in particular for the treatment of asthma and/or COPD. 40. 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. 41. A process for the preparation of a pharmaceutical formulation according to any one of claims 1 to 29 by mixing the individual ingredients.

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