RS20050484A - Powdered medicament for inhalation comprising a tiotropium salt and salmeterol xinafoate - Google Patents

Abstract

The invention relates to powdered compositions for inhalation comprising a tiotropium salt and salmeterol xinafoate, a method for production and use thereof for the production of a medicament for treatment of respiratory diseases, in particular for the treatment of COPD (Chronic Obstructive Pulmonary Disease) and asthma.

Description

MEDICINE, IN THE FORM OF POWDER FOR INHALATION,

'' CONTAINING TIOTROPIUM SALT and SALMETEROLXINAFOATE

The invention relates to preparations in the form of a powder for inhalation containing tiotropium salt and salmeterol xinafoate, to the procedure for their preparation as well as to their use for the preparation of a drug for the treatment of respiratory diseases, especially for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.

Basic information about the invention

Tiotropium bromide is known from the European patent application, EP 418 716 Al and has the following chemical structure:

Tiotropium bromide, like other tiotropium salts, is a very effective anticholinergic, with a long-lasting effect, which can be used for the treatment of respiratory diseases, especially COPD (chronic obstructive pulmonary disease) and asthma. Tiotropium refers to the free ammonium cation.

The betamimetic salmeterol is also known from the prior art. It is, for example, suitable for use in asthma therapy.

In WO 00/69468 medicinal combinations, betamimetics with long-term action, with anticholinergics with long-term action are shown, which are characterized by the synergistic effect of both components of the drug. One of the specific drug combinations disclosed in WO 00/69468 is the combination of tiotropium bromide with salmeteroloxy-nafoate.

The active substances, salmeterol and tiotropium, are administered by inhalation. In doing so, suitable inhalation powders can be used.

The suitable way of preparing the previously mentioned preparations, which can be used for inhalative administration of a medicinal substance, is based on various parameters related to the properties of the medicinal substance itself. Without being limited to that, examples of these parameters are stability of the action of the starting material under different environmental conditions, stability during the preparation of the pharmaceutical formulation, as well as stability in the final composition of the medicinal preparation. For the preparation of the aforementioned medicinal preparations, the medicinal substance should be as pure as possible, and its stability during long-term storage must be ensured under different storage conditions. This is absolutely necessary, in order to prevent the use of medicinal preparations in which, in addition to the actual active substance, there are, for example, the products of its decomposition. In such a case, the content of the active substance in the capsule could be lower than what is labeled.

Another critical factor is the even distribution of the drug in the formulation, especially when a low dose of the drug is required. This is especially important when a mixture of active substances is to be used. A further significant aspect, during inhalation application of the active substance used in powder form, is conditioned by the fact that only particles of a certain size reach the lungs during inhalation. The size of such particles that reach the lungs (the fraction that can be inhaled) is in the submicron range. Grinding (so-called micronizing) is also necessary to obtain an effective substance of appropriate particle size. Since as an accompanying phenomenon of grinding (so-called micronization), despite the harsh conditions that are set for the execution of the process, the degradation of the medicinal active substance must be prevented as much as possible, the great stability of the active substance during the grinding process is an absolute necessity. Only a sufficiently high stability of the active substance, during the grinding process, enables the preparation of a homogeneous formulation of the drug, which contains a precisely determined amount of the active substance, which is introduced in a way that is always reproducible.

Another problem that can arise during the grinding process, in order to prepare the desired medicinal formulation, is the loading of the crystal surface with the energy supplied during that process. Under these conditions, it can lead to polymorphic changes, to the transition to an amorphous state or to a change in the crystal lattice. Since the pharmaceutical quality of a medicinal formulation must always have the same crystalline morphology of the active substance, this also places increased demands on the stability and properties of the crystalline active substance.

In addition to the aforementioned requirements, it should generally be taken into account that any change in the state of a medicinal solid substance, which can improve its physical and chemical stability, compared to less stable forms of the same medicinal substance, represents a significant advantage.

The task of this invention is to prepare a medicinal formulation containing tiotropium salt and salmeterol xinafoate, in which both active substances meet the previously mentioned requirements. In particular, a further task of this invention is to prepare a medicinal formulation containing tiotropium salt and salmeterol xinafoate, which is characterized by the highest possible stability of both active substances in the formulation.

The active substances, tiotropium and salmeterol, show particularly high efficiency. In the case of active substances that exhibit particularly high efficiency, only a small amount of the active substance is needed for a single dose, in order to achieve the therapeutically desired effect. In such cases, when preparing inhalation powder, it is necessary to dilute the active substance with suitable auxiliary means (substances). Considering the large share of excipients, the choice of excipients has a decisive effect on the properties of inhalation powder. When choosing an auxiliary agent, the size of its particles (grains) plays a particularly important role. As a rule, the finer the auxiliary agent, the worse its fluidity. In fact, good fluidity is a prerequisite for high dosing accuracy when filling and separating individual doses of the preparation, as well as when preparing capsules (inhalates) for powder inhalation, or dosing a single inhalation performed by the patient when using a multi-dose inhaler. In addition, the particle size of the excipient is of great importance for the behavior (powder) when emptying the capsules in the inhaler, during use. Furthermore, it was shown that the size of the auxiliary agent particles has a significant influence on the share of the active substance in the inhalation powder, which can be taken in (used) by inhalation. Under the share of the active substance that can be taken in by inhalation, or the part that can be inhaled means the particles of inhalable powder that, when inhaled, the inhaled air carries deep into the branched parts of the lungs. The sizes of the particles that are necessary for this lie between 1 and 10 µm, primarily below 6 µm.

The task of the invention is to prepare an inhalation powder containing tiotropium salt and salmeterol xinafoate, which with good dosage accuracy (which refers to the amount of active substance and powder mixture entered, per capsule, during preparation, as well as to the amount of active substance, per capsule, which is separated during the inhalation process and reaches the lungs), and low variability in the batch, enables the application of the active substance with a large possible inhaled share. A further task of the present invention is to prepare an inhalation powder, which contains a salt of tiotropium and salmeterol xinafoate, which ensures good capsule emptying behavior during administration, which should be achieved, e.g. with an inhaler, such as that described for example in WO 94/28958, in a patient, or in vitro, via an impactor or impinger.

Since tiotropium salt in particular, but also salmeterol xinafoate, even in very small doses, exhibit high therapeutic efficiency, further requirements are set for high dosing accuracy of the inhalation powder that is introduced, which contains both of the mentioned active substances. Given the small concentration of the active substance in the inhalation powder, which is required to achieve a therapeutic effect, the homogeneity of the powder mixture and a small deviation in the dispersion behavior between the powder capsule and batch of powder capsules must be ensured to a large extent. The homogeneity of the mixture of powders, as well as small variations in dispersing properties, make a decisive contribution, that the separation of the active substance portion, which can be inhaled, is reproducible with constantly equal amounts, which achieves as little variability as possible.

Therefore, a further task of this invention is to prepare an inhalation powder containing tiotropium salt and salmeterol xinafoate, which is largely characterized by homogeneity and uniform dispersion. A further aim of the present invention is directed to the preparation of an inhalable powder which will enable the use of the active substance portion, which can be inhaled, with as little variability as possible.

Although it is not the only (exclusive), nevertheless, especially when applying inhalation powders using capsules containing powder, the procedure of emptying the powder tank (the space from which the inhalation powder containing the active substance for inhalation use is extracted) plays an important role. If the powder formulation is separated (released) in a small amount from the powder tank, just because of the small, or bad emptying behavior, significant amounts of inhalation powder remain in the powder reservoir (e.g. capsule), which has an effective effect, so patients cannot use it therapeutically. The consequence of this is that the dosage of the amount of the active substance in the powder mixture must be increased, so that the extracted amount of the active substance, to achieve the therapeutically desired effect, is large enough.

Therefore, a further task of this invention is to provide a process for preparing inhalation powder, which contains tiotropium salt and salmeterol xinafoate, which is also characterized by very good performance during emptying (capsules).

Detailed description of the invention

Unexpectedly, it was discovered that the initially mentioned task is solved by means of the further described preparation in the form of a powder, based on the invention, for inhalation (inhalation powder), which contains tiotropium salt 1 and salmeterol xinafoate 2.

Within the scope of this invention, tiotropium 1 salts are understood to mean salts that form the pharmacologically effective tiotropium cation 1\ Within this patent application, the use of the designation Explicitly refers to the tiotropium cation.

Inhalation powders, based on the invention, contain tiotropium VI salmeterol xinafoate 2, for which the characteristic melting point is about 124 °C, in a mixture with a physiologically harmless auxiliary agent.

The aforementioned melting point was determined using the DSC method (Differential Scanning Calorimetry), with a Mettler DSC 820 device, and the calculation was performed using the Mettler Software-Package STAR. The data were obtained at a heating rate of 10 K/min.

Primarily, salmeterol xinafoate 2, which is suitable for use in inhalation powders, according to the invention, shows, among others, the following characteristic values, d = 21.5 A; 8.41 A; 5.14 A; 4.35 A; 4.01 A and 3.63 A. More detailed data on the determination of these data, characteristic of powder X-rays, can be found in the experimental part of this invention. The X-ray diagram of salmeterol xinafoate powder, which according to the invention is primarily suitable for use, is shown in Figure 1.

Salmeterol xinafoate 2, which is particularly advantageous for use in inhalation powders according to the invention, has a bulk volume > 0.134 g/cm<3>, preferably > 0.14 g/cm<3>, and particularly preferably > 0.145 g/cm<3>.

In doing so, the bulk volume is determined according to the test method of the European Pharmacopoeia 4

(2002): "apparent density after settling"/ "density of settled product", identical to "tapped density", measured in grams per milliliter, or as "Carr packed bulk density", according to ASTM-Norm (D6393-99, Standard Test Method for Bulk Solids Characterization by Carr Indices), measured in grams per cm<3>. At the same time, bulk volume is a measure of the volume that includes solid, crushed materials, after their filling, under certain conditions (with tapping of the sample).

The special property of salmeterol xinafoate, which is characterized by the aforementioned parameters, refers both to the starting material obtained by the micronization process, and to the use of micronisates of this substance, with the above physical properties, in the preparation of inhalation powder. The previously mentioned parameters are particularly characteristic, both for the product obtained by micronizing, and also for the salmeterol xinafoate used for micronizing.

In inhalation powders, based on the invention, the previously described salmeterol xinafoate 2 is present primarily in an amount of 0.002 to 15%.

According to the invention, inhalation powders containing 0.01 to 10% 2 are preferred. Particularly advantageous inhalation powders contain 2 in an amount of 0.05 to 5%, preferably 0.1 to 3%, particularly preferably 0.125 to 2%, and even more preferably 0.25 to 2%.

Inhalation powders, based on the invention, preferably further contain 0.001 to 5% tiotropiumY_. Based on the invention, inhalation powders containing 0.01 to 3% tiotropiumV_ are advantageous. Particularly advantageous inhalation powders contain tiotropiumV in an amount of 0.02 to 2.5%, preferably 0.03 to 2.5%, and especially preferably 0.04 to 2%.

By tiotropium 1_ is meant the free ammonium cation. If the designation 1 is used within the scope of this invention, it refers to tiotropium in combination with some appropriate counterion. As the opposite ion (anion), chloride, bromide, iodide, methanesulfonate or para-toluenesulfonate come into consideration. Of these anions, bromide is preferred. Therefore, this invention relates primarily to an inhalation powder containing between 0.0012 to 6%, preferably 0.012 to 3.6% tiotropium bromide 1. Based on the invention, inhalation powders containing about 0.024 to 3%, preferably 0.036 to 3%, and particularly preferably 0.048 to 2.4% tiotropium bromide 1 are of particular importance.

Tiotropium bromide, which is primarily found in inhalation powders, based on the invention, can incorporate (into its structure) solvent molecules during crystallization. To prepare, based on the invention, an inhalation powder containing tiotropium, tiotropium bromide hydrate is first introduced. The use of crystalline tiotropium bromide monohydrate, according to WO 0/30928, is especially advantageous. This crystalline thiotropium bromide monohydrate is characterized by an endothermic maximum at 230 + 5 °C, determined by thermal analysis using DSC, at a heating rate of 1OK/min. Furthermore, it is characteristic for him that in the IR spectrum, among other wave numbers, bands appear at 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm"<1>. Finally, this crystalline tiotropium-bromide-monohydrate has, as determined by X-ray structural analysis of the mono-crystal, a simple monoclinic cell with the following dimensions: a = 18.0774 Å, b= 11.9711 Å, c = 9.9321 Å, 0 = 102.691°, V = 2096.96 Å<3>.

Accordingly, this invention primarily relates to inhalation powders containing between 0.00125 to 6.25%, preferably 0.0125 to 3.75%, of crystalline tiotropium bromide monohydrate. Based on the invention, inhalation powders containing about 0.025 to 3.125%, preferably about 0.0375 to 3.125%, and particularly preferably about 0.05 to 2.5% tiotropium bromide monohydrate are of particular importance.

Within the framework of this invention, the stated percentage data refer to mass percentages, unless otherwise specifically stated.

The application of the drug, based on the invention, which contains combinations 1 and 2, is usually carried out so that tiotropium Y_ and salmeterol xinafoate 2 are found together, together administration, in a dose of 5 to 5000 µg, it is advantageous from 10 to 2000 µg, it is particularly advantageous from 15 to 1000 µg, it is even more advantageous from 20 to 500 µg, and according to the invention, primarily from 25 to 250 u.g., it is favorable from 30 to 125 u.g., and especially favorable is 40 to 70 u.g.

For example, without thereby limiting the scope of the invention, combinations 1 and 2, based on the invention, can contain such an amount of tiotropiumVi salmeterol xinafoate 2, that in one administration, for example: 4.5u.g1/i 25u.g 2, 4.5\ igV_i 30^g 2, 4.5ug F i 35ug 2, 4.5u.gri 40u.g 2, 4.5|^gVi 43.5ug 2, 4.5ugVi 50u.g 2, 4.5u.gVi 60u.g 2, 4.5ugVi 70u.g 2, 4.5ugVi 80u.g 2, 4.5ugVi 90|ug 2, 4.5u.gVi 100p.g 2, 4.5ugVi 1 lO^ig 2, lO^g r and 25ug 2, lOugVi 30ug 2, lOugVi 35ug 2, 10ngVi 40ug 2, 10u.g r and 50u£2, lO^ig r and 60u-g2, lOugVi 70ug 2, 10fj.g r and 80ug 2, 10u-gVi 90u-y 2, 10u£Vi lOOug 2, lOugVi HOug 2, 18ugVi 25ug 2, 18ugVi 30|ag 2, 18ugri

35ug 2, 18ug r and 40ug.g 2, 18jag r and 50ug 2, 18ug T and 60ug 2, 18ug r and 70ug 2, 18ug H

and 80ug 2, 18(o.g 1/ and 90ug 2,18ug r and lOOug 2, 18u-gVi llOjag2, 36u-gVi25ug2,36ug r and 30ng 2, 36^gVi 35ug 2, 36ug r and 40ug 2, 36ug V and 50ug 2, 36ugVi 60ug2,36ug r i70fig2, 36figVi 80jxg2,36ugVi 90ug2,36ugVi 100(xg2, 36u-gVi 110ug2.

When, on the basis of the invention, as an advantageous combination of 1 and 2, the one in which bromide is used as salt 1 is used, then the following amounts of 1 and 2, administered together, correspond to the previous amounts of active substances Y_and 2, given as an example, administered together: 5.4ug 1 and 25|ig 2, 5.4p.g 1 and 30u.g 2, 5.4jag 1 and 35^g 2, 5.4u.gl and 40ug 2, 5.4ug 1 and 50ng 2, 5.4ug 1 and 60ug 2, 5.4ug 1 and 70u-g 2, 5.4ug 1 and 80u-g 2, 5.4u-g 1 and 90ug 2, 5.4^ig 1 and lOOug 2, 5,4|ig 1 i 110u.g 2, 12ug 1 and 25ug 2, 12^g 1 and 30u-g 2, 12ug 1 and 35ug 2, 12^g 1 and 40ug 2, 12ug 1 and 50u.g 2, 12u-g 1 and 60u£ 2, 12|ig 1 and 70u.g 2, 12^<g>li80fig2, 12^gli90ug2, 12ug 1 and lOOug 2, 12ug 1 and 1 lOug 2, 21.7u-g 1 and 25ug 2, 21.7^g 1 and 30^g 2, 21.7|ag I and 35ug 2, 21.7p.g 1 and 40^g 2, 21.7ug 1 and 50ug 2, 21.7ug 1 and 60^ig 2, 21.7ug 1 and 70ug 2, 21.7^g 1 and 80ug 2, 21.7|ag 1 and 90ug 2, 21.7ug 1 and lOO^g 2, 21.7u-g 1 and 1 lOug 2, 43.3^g I and 25(ag 2, 43.3u-g 1 and 30^g 2, 43.3 ug 1 and 35u-g 2, 43.3u-g I and 40ug 2, 43.3^g 1 and 50u.g 2, 43.3u.g I and 60ug 2, 43.3^g I and 70 Mg 2, 43.3|ag 1 and 80ug 2, 43.3|ag 1 and 90u-g 2, 43.3ug 1 and lOOug 2, 43.3^g li llOjag 2.

When, on the basis of the invention, as one of the advantageous combinations 1 and 2, the one in which crystalline tiotropium bromide-monohydrate is used as salt 1 is used, then the previous amounts of active substances 1 and 2, given as an example, applied for one administration, correspond to the following amounts 1 and 2, administered together: 5.6 u.g 1 and 25 u-g 2, 5.6 ug 1 and 30 ug 2, 5.6(ig 1 and 35ug 2, 5.6ug 1 and 40ug 2, 5.6ug 1 and 50ug 2, 5.6p.g 1 and 60ug 2, 5.6jag 1 and 70u.g 2, 5.6^ 1 and 80ug 2, 5.6ug 1 and 90u-g 2, 5.6fig 1 and 100 u.g 2, 5.6u.g 1 and HO^g 2, 12.5ug 1 and 25ug 2, 12.5u.g 1 and 30u-g 2, 12.5|ag 1 and 35^g 2, 12.5ugl and 40ug 2, 12.5u-g 1 and 50^g 2, 12.5|ig 1 and 60ug 2, 12.5ug 1 and 70ug 2, 12.5ug 1 and 80ug 2, 12.5ug 1 and 90ug 2, 12.5ug 1 and 100(ig 2, 12.5ug 1 and 110ug 2, 22.5ug 1 and 25u-g 2, 22.5ug 1 and 30 2, 22.5ug 1 and 35|ug 2, 22.5^g 1 and 40ug 2, 22.5ug 1 and 50|ug 2, 22.5ug 1 and 60ug 2, 22.5ug.g 1 and 70|ig 2, 22.5^g 1 and 80u£ 2, 22.5u-g 1 and 90ug 2, 22.5^g 1 and lOOu-g 2, 22.5u.g 1 and 110u.g 2, 45ug 1 and 25ug 2, 45ug 1 and 30ug 2, 45ug 1 and 35ug 2, 45u-g 1 and 40u.g 2, 45u-g 1 and 50ug 2, 45ug 1 and 60u-g 2, 45^g 1 and 70u-g 2, 45ug 1 and 80ug 2, 45ug 1 and 90^g 2, 45u-g 1 and lOOug 2, 45fj.g 1 and 110u-g2.

As physiologically harmless auxiliaries, which can be used in the preparation of medicines based on the invention, for use in inhalation powder, examples include monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose, trehalose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol) or also salts (e.g. sodium chloride, calcium carbonate). Mono- or disaccharides are primarily suitable for use, with the advantage being the use of lactose or glucose, especially, but not exclusively, in the form of their hydrates. Lactose is particularly advantageous, according to the essence of the invention, for use as an auxiliary agent, and lactose monohydrate is extremely advantageous.

The use of auxiliaries with an average particle size of 10 to 50 µm is particularly advantageous. Meanwhile, the mean particle size, in the meaning used here, means the 50% value of the volume distribution, measured using a laser diffractometer, according to the dry dispersion method. In inhalation powders, which are particularly favorable, it is characteristic for the excipient that the mean particle size is from 12 to 35 μm, and it is particularly favorable from 13 to 30 μm.

The use of auxiliaries whose 10% share is the fine fraction from 0.5 to 6 um is particularly advantageous. At the same time, the 10% share of the fine fraction, in the meaning used here, means the 10% value of the volume distribution, measured with a laser diffractometer. In other words, according to the meaning based on this invention, the 10% value of the proportion of fine particles is below 10% of the amount of particles (in relation to the volume distribution). Furthermore, such inhalation powders are particularly advantageous, in which the 10% share of fine fractions amounts to about 1 to 4 (im, primarily about 1.5 to 3 p.m.

According to the invention, such inhalation powders are further preferred in which the excipient has a specific surface between 0.2 and 1.5 m<2>/g, preferably between 0.3 and 1.0 m<2>/g.

For powder formulations, based on the invention, auxiliaries of higher crystallinity are primarily used. This crystallinity can be estimated from the free enthalpy (enthalpy of dissolution) released during dissolution. In the case of lactose monohydrate, which according to the invention is particularly suitable for introduction as a suitable auxiliary agent, primarily lactose is used, which has a characteristic dissolution enthalpy of > 45 J/g, preferably > 50 J/g, and especially preferably > 52 J/g.

According to the task set on the basis of this invention, the inhalation powders based on the invention are characterized by great homogeneity in terms of the accuracy of individual dosing. It is in the range of < 8%, < 6% is favorable, and < 4% is especially favorable.

In this case, it can be helpful to use a mixture of auxiliaries as the aforesaid auxiliaries, which consist of a mixture of a coarser adjuvant, with an average particle size of 17 to 50 µm, preferably from 20 to 40 µm, and especially advantageously from 25 to 35 µm, and a finer auxiliary agent, with an average particle size of 1 to 8 µm, advantageously from 2 to 7 µm, and especially advantageously from 3 to 6 (im. And here also, the average particle size means the 50% value of the volume distribution measured by laser diffraction, according to the dry dispersion method. If the above-mentioned auxiliary agent mixtures are used, the 10% share of fine particles, in the coarser component of the auxiliary agent, there is about 2 to 5 (im), primarily about 3 to 4 (im), and also in the finer component of the auxiliary agent about 0.5 to 1.5 (im.

Preference is given to inhalation powders in which the proportion of a finer excipient in the overall formulation is 2 to 10%, preferably 3 to 7%, and especially preferably 4 to 6%. When, within the scope of this invention, a mixture of an auxiliary agent is mentioned, it always means a mixture obtained by mixing the previously precisely defined components. Therefore, for example, as a mixture of auxiliary means of coarser and finer parts of the auxiliary means, only such mixtures are understood which were obtained by mixing the coarser component of the auxiliary means with the finer component of the auxiliary means. The coarser and finer portions of the auxiliary agent can consist of chemically the same or chemically different substances, which have already been mentioned as auxiliary agents, whereby it is an advantage that the coarser portion of the auxiliary agent and the finer portion of the auxiliary agent consist of the same chemical compound. If, for example, lactose monohydrate is used as an auxiliary agent, in the case of a specific addition of the auxiliary agent fraction, with the above-mentioned smaller mean particle size, the use of lactose monohydrate is primarily also suitable.

In order to prepare the drug, based on the invention, it is necessary to first prepare salmeterol xinafoate 2, in a form that meets the previous specifications for substance 2. For this, based on the invention, the procedure is primarily as follows.

The free base of salmeterol, which is known from the state of the art, is introduced, together with 1-hydroxy-naphthalene acid, into a solvent mixture consisting of an alcohol and an ether. At least 1 mol of 1-hydroxy-2-naphthalene acid is added to 1 mol of salmeterol, preferably 1 to 1.1 mol of 1-hydroxy-2-naphthalene acid, and 1 mol of 1-hydroxy-2-naphthalene acid is particularly preferred. As an alcohol, based on the invention, a short-chain alcohol comes into consideration, preferably ethanol, n-propanol or iso-propanol, and especially preferably ethanol. Diethylether, methylethylether, tetrahydrofuran, dioxane or tert-butylmethylether are particularly advantageously used as ether based on the invention, with butylmethylether being particularly advantageous according to the invention. The ratio of alcohol to ether (molar ratio), according to the invention, is preferably in the range of about 1:2 to 2:1, particularly preferably in the range of about 1:1.5 to 1.5:1. A ratio of alcohol to ether of 1:1 is particularly favorable.

It is understood that the total amount of solvent is determined according to the batch size. For 1 mole of salmeterol base introduced, approximately 5 to 20 liters are primarily introduced, and it is particularly advantageous to use approximately 7 to 15 liters of solvent. It is particularly advantageous to introduce, per 1 mole of salmeterol introduced, about 9 to 12 liters of solvent, whereby in the said solvent both components, alcohol and ether, can be in the aforementioned volume ratios. After adding all the aforementioned components, the resulting suspension is heated with stirring at a temperature of > 40 °C, preferably > 50 °C, and especially preferably at a temperature of around 55-56 °C. Heating should be carried out until a clear solution is formed. The solution is then filtered, and the filter, in the given case, is washed with a small amount (about 1 to 1.5 liters per 1 mol of salmeterol introduced) of the aforementioned solvent. Then the obtained filtrate is cooled to a temperature of about 30 to 40 °C, preferably about 35-38 °C, and it is stirred at that temperature until the crystallization of salmeterol xinafoate begins.

In a given case, the addition of salmeterol xinafoate, as a crystallization pelzer, may be helpful at that stage. After crystallization begins, the suspension is further cooled with stirring, primarily to a temperature of about -10 °C to about 10 °C, and particularly preferably to a temperature of about 0 °C to about 5 °C. After about 20 to 60 minutes, the crystallization is complete, so the obtained product is separated through a suitable filter and, in the given case, washed with alcohol and/or ether.

The thus obtained salmeterol xinafoate corresponds to the aforementioned specification, which is characteristic for inhalation powders, based on the invention.

Therefore, a further aspect of this invention relates to an inhalation powder which, in addition to tiotropium, also contains salmeterol xinafoate 2, which can be obtained according to the previously described process.

After measuring the starting materials, inhalation powders are prepared, from the auxiliary agent and from the active substance, using procedures known based on the state of the art. Reference can be made here, for example, to publication WO 02/30390. Inhalable powders according to the invention can therefore be obtained, for example, according to the methods described below. In the procedures described below, the mentioned components are introduced in mass parts, as was described in the previously described preparations of inhalation powders.

First, an auxiliary agent and tiotropium salt 1 are introduced into a suitable mixing vessel. The active substance 1 used has an average particle size of 0.5 to 10 µm, preferably from 1 to 6 µm, and especially preferably from 2 to 5 µm. The addition of the active substance 1 and auxiliary agent is primarily done through a sieve or a granulator with a sieve, mesh size from 0.1 to 2 mm, 0.3 to 1 mm is particularly favorable, and 0.3 to 0.6 mm is extremely favorable. In the mixing bowl, the auxiliary agent is introduced first and then the active substance. Primarily, in this mixing process, both components are introduced in portions. It is especially advantageous to introduce both components alternately, by sieving in layers. Even during the addition of the auxiliary agent and active substance 1, mixing of both components, auxiliary agent and substance 1 can be done. Primarily, however, mixing is done only after introducing both ingredients, by sieving in layers.

If a mixture of auxiliaries is used as an auxiliary agent, which consists of a coarser auxiliary agent with an average particle size of 17 to 50 μm, especially preferably from 20 to 35 µm, and a finer auxiliary agent with an average particle size of 1 to 8 µm, preferably from 2 to 7 µm, and especially advantageously from 3 to 6 µm, then the mixture of auxiliary agents is first prepared, by alternating sieving, in layers, both components of the auxiliary agent and finally mixing.

After obtaining the previously described powder mixture containing active substance 1, salmeterol xinafoate 2 is added in the same way. At the same time, substance 2 also has a medium particle size of 0.5 to 10 µm, preferably from 1 to 6 µm, and especially preferably from 2 to 5 µm. The addition of component 2 and the mixture of powders containing component 1 is done primarily through a sieve or a granulation sieve, with a mesh size of 0.1 to 2 mm, 0.3 to 1 mm is particularly favorable, and 0.3 to 0.6 mm is extremely favorable. Primarily, a mixture of powders containing component 1 is applied first, and then substance 2 is introduced into the mixing vessel. In this mixing procedure, it is advantageous to add both components in portions. It is particularly advantageous to introduce both components by alternating sieving in layers. The process of mixing the mixture of powders containing component 1_ with active substance 2 can be carried out during the addition of both components. It is understood that mixing primarily begins only when both ingredients have been sifted in layers.

According to an alternative solution, on the basis of the invention, the inhalation powders according to the invention can also be obtained, analogously to the previously described method of operation, by first adding a mixture of powders consisting of an auxiliary agent and substance 2, to which component 1 is then added, in the manner previously described.

According to another alternative solution, on the basis of the invention, inhalation powders according to the invention can also be obtained by first introducing a portion of the auxiliary agent, then the first portion 1 or the first portion 2, then by sieving again the portion of the auxiliary agent is introduced, and then the first portion of the second active component 1 or 2. This order of addition of components, auxiliary agent, substances 1 and 2, is repeated until all the ingredients are added, in the desired quantities. Here, too, it is particularly advantageous to introduce all three components alternately, by sieving in layers. The mixing process can start already during the addition of all three components. It is understood that mixing primarily begins only when all three ingredients have been sifted in layers.

If the active substances 1 and 2, which are used in the above-described procedure, are not already obtained during their chemical preparation in crystalline form, with the above-mentioned particle sizes, they can be converted by grinding into particles whose size meets the above-mentioned parameters

(so-called micronization). Suitable micronization processes are known in the art.

If, based on the invention, a particularly suitable crystalline tiotropium bromide monohydrate is used as the active substance 1, which is shown in WO 02/30928, the following method of operation can be shown to be particularly effective for micronizing such a crystalline modification of the active substance 1. Common mills can be used to carry out this process. At the same time, micronizing is carried out primarily in the absence of moisture, it is particularly advantageous with the addition of a suitable inert gas, such as nitrogen. For this application, mills with the impact of an air jet have proven to be particularly suitable, in which the material is crushed by the collision of particles with each other, as well as by the impact of particles on the walls of the mill container. Based on the invention, it is primarily possible to use nitrogen as the gas used for grinding. The material to be ground is driven by gas, which is used to grind under specific pressures (grinding pressure). Within the scope of this invention, the pressure of the gas used for grinding is usually set to a value between about 2 and about 8 bar, preferably between about 3 and about 7 bar, and particularly preferably between about 3.5 and about 6.5 bar. The introduction of grinding material into the mill with the impact of an air jet is carried out by means of introduction gas, under specific pressures (material introduction pressure). Within the scope of the present invention, the introduction pressure is maintained between about 2 and about 8 bar, preferably between about 3 and about 7 bar, and particularly preferably between about 3.5 and about 6 bar. An inert gas is primarily used as the introduction gas, it is particularly advantageous to also use nitrogen. The feeding of the grinding material (crystalline tiotropium bromide-monohydrate 1) can be done at a speed of about 5-35 g/min, preferably at about 10-30 g/min.

For example, but without limiting the subject matter of the invention, as one possible form of solution for an air jet impact mill, the following device provides: 2-Zoll Microniser, with 0.8 mm grinding ring, Firme Sturtevant Inc., 348 Circuit Street, Hanover, MA 02239, USA. Using this device, the grinding process is performed primarily with the following grinding parameters: grinding pressure: about 4.5-6.5 bar; material introduction pressure: about 4.5-6.5 bar; feeding material for grinding: about 17-21 g/min.

The ground material thus obtained is then further processed, under the specific conditions mentioned below. In doing so, the micronisate is kept at a temperature of 15-40 °C, preferably 20-35 °C, and it is particularly favorable at 25-30 °C, under a relative humidity (r. vi.) of at least 40%. Primarily, the humidity is adjusted to a value of 50-95% r.h. vi., it is favorable at 60-90% r.vl., and especially favorable at 70-80% r.vl. you.

Relative humidity means the quotient of the partial pressure of water vapor and the pressure of water vapor at the observed temperature.

Primarily, based on the previously described grinding process, the resulting micronisate is kept under the above-mentioned spatial conditions for at least 6 hours. Primarily, the micronizate is actually exposed to the mentioned spatial conditions, for about 12 to about 48 hours, preferably about 18 to about 36 hours, and especially preferably about 20 to about 28 hours.

The micronisate of tiotropium bromide 1, which is obtained on the basis of the aforementioned method of operation, has a particle size of between 1.0 pm and 3.5 pm, preferably between 1.1 pm and 3.3 pm, and especially preferably between 1.2 pm and 3.0 pm, and Q(5.g) greater than 60%, preferably greater than 70%, and especially preferably greater than 80%. At the same time, the characteristic (parametric) number Q(5,8) indicates the amount of particles, which is below 5.8 pm, in relation to the volume distribution of individual particles. Within the scope of this invention, particle sizes are determined by laser diffraction (Frauenhofer diffraction). More detailed information on this can be found in the experimental description of the invention.

Also, for the tiotropium micronisate, based on the invention, which is obtained according to the above procedure, specific surface area values in the range between 2 m<2>/g and 5 m<2>/g, especially values between 2.5 m<2>/g and 4.5 m<2>/g, and extremely favorable values, between 3.0 m<2>/g and 4.0 m<2>/g, are characteristic.

One particularly favorable aspect of this invention relates to inhalation powders, based on the invention, which are characterized by containing as component 1 the previously described tiotropium bromide monohydrate micronisate.

For the micronization of salmeterol xinafoate 2, suitable for use according to the invention, the following method of operation is particularly suitable. At the same time, the usual mills are suitable for carrying out the process. At the same time, micronizing is carried out primarily in the absence of moisture, it is particularly advantageous with the use of a suitable inert gas, such as nitrogen. For this application, mills with the impact of an air jet have proven to be particularly suitable, in which the material is crushed by the collision of particles with each other, as well as by the impact of particles on the walls of the mill container. Based on the invention, it is primarily possible to use nitrogen as the gas used for grinding. The material to be ground is driven by gas, which is used to grind under specific pressures (grinding pressure). Within the scope of this invention, the pressure of the gas used for grinding is usually set to a value between about 2 and about 12 bar, preferably between about 5 and about 10 bar, and particularly preferably between about 5 and about 8.5 bar. The introduction of grinding material into the mill with the impact of an air jet is carried out by means of introduction gas, under specific pressures (material introduction pressure). Within the scope of the present invention, the introduction pressure is maintained between about 2 and about 12 bar, preferably between about 5.5 and about 10.5 bar, and particularly preferably between about 5.5 and about 9 bar. An inert gas is primarily used as the introduction gas, it is particularly advantageous to also use nitrogen. The feeding of the grinding material (crystalline salmeterol xinafoate) can be done at a rate of about 5-100 g/min, preferably at about 10-60 g/min.

One particularly advantageous aspect of this invention relates to inhalation powders based on the invention, which are characterized by the content of salmeterol xinafoate 2, which is obtained according to the previously described micronization process.

This invention further relates to the use of inhalation powders, based on the invention, for the preparation of a medicine for the treatment of respiratory diseases, in particular for the treatment of COPD and/or asthma.

Inhalable powders according to the invention can be administered, for example, by means of inhalers that dispense a single dose from a reservoir by means of a measuring chamber (eg by US 4 570 630 A), or by other devices (eg by DE 36 25 685 A). Primarily, inhalation powders, based on the invention, are actually filled into capsules (so-called inhalates), which are suitable for use in inhalers, such as, for example, described in WO 94/28958.

Particularly advantageously, the capsules containing the inhalation powder according to the invention are used in an inhaler, as shown in Figure 2.

For that inhaler, it is characteristic that it consists of a casing 1, which has two windows 2; partition plate 3, in which there are openings for air intake and sieve 5, fixed by means of sieve housing 4; the inhalation chamber 6, attached to the partition plate 3, on which there is, via a spring 8, a movable pusher 9, on which there are two pointed needles 7; an intake 12 which can rotate around a shaft 10, together with a housing 1, a partition plate 3 and a cover 11; as well as opening 13, for the passage of air, which serves to adjust the flow resistance.

This invention also relates to the use of inhalation powders, based on the invention, for the preparation of medicine for the treatment of respiratory diseases, especially for the treatment of COPD and/or asthma, for which it is characteristic to use the previously described inhaler, shown in Figure 2.

For the application of inhalation powders, based on the invention, using capsules containing the powder, it is particularly suitable to use such capsules that are made of material selected from the group of synthetic plastics, especially preferably selected from the group consisting of polyethylenes, polycarbonates, polyesters, polypropylenes and polyethylene terephthalates. Polyethylene, polycarbonate or polyethylene terephthalate are particularly suitable as synthetic plastic materials. If polyethylene is used, as one, based on the invention, of particularly suitable materials for capsules, polyethylene with a density between 900 and 1000 kg/m<3> is primarily suitable, preferably 940-980 kg/m<3>, and especially preferably around 960-970 kg/m<3> (high-density polyethylene).

Synthetic plastic materials suitable for the present invention can be processed in a number of ways using manufacturing processes based on the state of the art. Particularly suitable, for the purposes of the invention, is the melt injection technique, but without the use of means that facilitate removal from the mold. Such a production process is completely defined and is characterized by very good reproducibility.

A further aspect of this invention relates to the aforementioned capsules containing the aforementioned inhalable powder, based on the invention. These capsules can contain about 1 to 20 mg, preferably about 3 to 15 mg, and especially preferably about 4 to 12 mg of inhalation powder. Preferred formulations according to the invention contain 4 to 6 mg of inhalation powder. According to the invention, of the same importance are the inhalation capsules, which in the formulations, based on the invention, contain an amount of 8 to 12 mg, and 9 to 11 mg is particularly advantageous.

Further, this invention relates to an inhalation kit (kit) containing one or more previously described capsules, which are characterized by containing inhalation powder, based on the invention, together with the inhaler according to Figure 2.

This invention also relates to the use of the previously mentioned capsules, which are characterized by containing inhalation powder, based on the invention, for the preparation of a medicine for the treatment of respiratory diseases, especially for the treatment of COPD and/or asthma.

Preparation of filled capsules, which contain inhalation powder based on the invention, is carried out according to procedures known, based on the state of the art, for filling empty capsules with inhalation powders based on the invention.

The following examples serve for a more detailed explanation of this invention, and with them, the scope of the invention is not limited to the following solutions, for the sake of the given example.

Starting materials

I) Auxiliary means:

bark

In the following examples from 1 to 24, lactose monohydrate is used as an auxiliary agent. For example, it can be obtained from the company Borculo Domo Ingredients, Borculo/NL, under the brand name Lactochem Extra Fine Powder. This quality of lactose meets the specification requirements, based on the invention, for particle size and specific surface area. In addition, this quality of lactose meets the aforementioned values for the enthalpy of dissolution of lactose, based on the invention. For example, the following examples use lactose batches that have the following specifications:

a): mean particle size: 17.9 pm; 10% share of fine fraction: 2.3 pm; specific surface: 0.61 m<2>/g; or b) : average particle size: 18.5 pm; 10% share of fine fraction: 2.2 pm; specific surface: 0.83m<2>/g; c) : mean particle size: 21.6 pm; 10% share of fine fraction: 2.5 pm; specific surface: 0.59 m<2>/g; d) : mean particle size: 16.0 pm; 10% share of fine fraction: 2.0 pm; specific surface: 0.79 m<2>/g.

Ibj

In the following examples, 25 to 36, lactose monohydrate (200M) was used as a rougher auxiliary agent. It can, for example, be obtained from the company DMV International 5460 Veghel/NL, under the product name Pharmatose 200M. This lactose is characterized by an average particle size of around 30 to 35 pm. The lactose 200M batches used had, for example, a mean particle size of 31 pm, with a 10% fine fraction of 3.2 pm, or also a mean particle size of 34 pm, with a 10% fine fraction of 3.5 pm.

In the following examples, 25 to 36, lactose monohydrate, with an average particle size of 3-4 pm, was used as a finer auxiliary agent. It can be obtained through the usual procedure (micronization), from commercially available lactose monohydrate, for example, from the previously mentioned lactose 200M. The batches of micronized lactose used had, for example, a mean particle size of 3.7 µm, with a 10% fines fraction of 1.1 µm, or also a mean particle size of 3.2 µm, with a 10% fines fraction of 1.0 µm.

II) Preparation of salmeterol xinafoate, based on the invention:

20 g of salmeterol base and 9.1 g of 1-hydroxy-2-naphthalene acid were suspended in 260 ml of absolute ethanol and 260 ml of tert.-butyl methyl ether. The suspension was heated to 55-56 °C and stirred until a clear solution was obtained. The solution was filtered off, and the filter was washed with 30 ml abs. of ethanol and 30 ml of tert.-butylmethylether. The filtrate was cooled to 38 °C and pelleted with several crystals of salmeterol xinafoate. The solution was stirred for 1 h at 34-37 °C, during which crystallization was initiated. The suspension was cooled to 1-3 °C, so at that temperature, approx. 30 min. The precipitate was suctioned off through a filter and washed with 20 ml of ethanol and 120 ml of tert-butyl methyl ether. The solid was dried at 45 °C in a stream of nitrogen. Yield: 26 g (89.5%).

The crystalline salmeterol xinafoate thus prepared has a bulk volume of 0.27 g/cm<3>.

III) Micronization of salmeterol xinafoate:

Salmeterol xinafoate, obtained according to the previously described procedure, was micronized in an air jet impact mill, Typ MC JETMILL 50, Jetpharma company; Via Sotto Bisio 42 a/c, 6828-Balerna, Switzerland. When using nitrogen as a grinding gas, it was done, for example, with the following grinding parameters:

grinding pressure 7.5 bar, material delivery pressure 8.0 bar.

Feed rate of crystalline salmeterol xinafoate (or flow rate), 40 g/min.

The bulk volume of the micronized salmeterol xinafoate thus obtained was 0.19<g>/cm3.

IV) Micronization of crystalline tiotropium bromide monohydrate:

Crystalline tiotropium bromide monohydrate, which is obtained according to WO 02/30928, is micronised using an air jet microniser (mill), Typ 2-Zoll Microniser, with a grinding ring opening of 0.8 mm, from Sturtevant Inc. 348 Circuit Street, Hanover, MA 02239, USA. When using nitrogen as a gas for comminution (grinding), work is done, for example, with the following comminution (grinding) parameters: grinding pressure: 5.5 bar; material supply pressure: 5.5 bar;

delivery (of crystalline monohydrate), or flow rate: 19 g/min.

The resulting heated material is then placed in multi-row pans, in a layer about 1 cm thick, and exposed to the following (climatic) conditions for 24-24.5 hours:

temperature: 25-30 °C; relative humidity: 70-80%.

Measurement methods:

I) X-ray structural analysis of salmeterol xinafoate:

Measuring device and settings:

The powder X-ray pattern, within the scope of this invention, was recorded with a BRUKER D8 ADVAN-CED diffractometer, equipped with a spot-sensitive detector (=OED) and a Cu-anode, as a source of X-ray radiation (CuKa-radiation, X =1.5418 A, 40 kV, 40 mA).

Figure 1 shows the obtained radiogram of powder, salmeterol xinafot based on the invention. The following Table 1 shows the data obtained from that spectroscopic analysis:

In the previous table, the value "20 [°]" indicates the deflection (diffraction) angle, in degrees, and the value "d[A]", the specified grating distance, in A.

II) Determination of the particle size of micronized tiotropium monohydrate:

Measuring device and settings:

Work with the device according to the manufacturer's instructions.

Measuring device: laser diffraction spectrometer (HELOS), Svmpatec (particle size determination based on Fraunhofer

diffraction)

dispersion unit: RODOS dry dispersion device,

with suction funnel Svmpatec

sample amount: 200 mg ± 150 mg

sample feeding: vibration channel, Vibri, Fa. Svmpatec frequency vibr. channels: increases to 100%

sample feeding takes: 15 to 25 s (in the case of working with 200 mg)

focal length: 100 mm (measuring range: 0.9 -175 pm)

measurement/waiting time: approx. 15 s (in case of work with 200 mg)

cycle time: 20 ms

start/stop, at: 1 % on channel 28

dispersing gas: air under pressure

pressure: 3 bar

vacuum: maximum

calculation method: HRLD

Sample preparation/ product management:

On a sheet of cardboard, measure approx. 200 mg of the test substance. All larger agglomerates are broken with the second sheet of cardboard. Then the powder is sprinkled in the first half of the vibrating channel (starting from approx. 1 cm from the outer edge).

After starting the measurement, the frequency of the vibration channel is changed in such a way that the introduction of the sample takes place as continuously as possible. However, the amount of product should not be too large in order to achieve sufficient dispersion.

III) Determination of lactose particle size:

Measuring device and settings:

Work with the device according to the manufacturer's instructions.

Measuring device: laser diffraction spectrometer (HELOS), Svmpatec (particle size determination based on Fraunhofer

diffraction)

dispersion unit: RODOS dry dispersion device,

with suction funnel Svmpatec

sample amount: 200 mg + 100 mg

sample feeding: vibration channel, Vibri type, Svmpatec frequency vibr. channels: increases to 100%

focal length: 200 mm (measuring range: 1.8 - 350 u.m)

measurement/waiting time: approx. 10 s (in case of work with 200 mg)

cycle time: 10 ms

start/stop, at: 1% on channel 28

dispersing gas: air under pressure

pressure: 3 bar

vacuum: maximum

calculation method: HRLD

Sample preparation/ product management:

On a sheet of cardboard, measure approx. 200 mg of the test substance. All larger agglomerates are broken with the second sheet of cardboard. The powder is transferred into the vibrating channel. Adjust the distance from 1.2 to 1.4 mm between the vibrating channel and the funnel. After starting the measurement, the vibration channel amplitude setting is increased as continuously as possible towards 100% at the end of the measurement.

IV) Determination of the specific surface area of micronized tiotropium bromide micronisate (BET method; 1 point)

Working principle:

The specific surface area is determined by exposing the powder sample to a nitrogen/helium atmosphere at different pressures. By cooling the sample, nitrogen molecules condense on the surface of the particles. The amount of condensed nitrogen is determined based on the change in the thermal conductivity of the nitrogen/helium mixture, and the surface area of the sample is determined based on the area occupied by (adsorbed) nitrogen. Based on these values and the measured mass of the sample, the specific surface area is calculated.

Measuring device and settings:

measuring device: Monosorb, manufacturer Quantachrome drying device: Monotektor, manufacturer Quantachrome gas for measuring and drying: nitrogen (5.0) / helium (4.6) 70/30, prod. Messer Griesheim adsorbate: 30% nitrogen in helium

coolant: liquid nitrogen

measuring cell: with capillary tube, prod. W. Pabisch GmbH & Co.KG calibration syringe: 1000 ul, prod. Precision Sampling Corp.

analytical balance: R 160 P, manufacturer Sartorius

Calculation of specific surface area:

The measuring device shows the measured values in [m<2>], so they are calculated according to the measured mass (dry mass) in [cm<2>/gl:

V) Determination of the heat of dissolution of lactose (enthalpy of dissolution) Ec: The determination of the enthalpy of dissolution was performed using a solution calorimeter 2225 Precision Solution Calorimeter, Thermometric.

The heat of dissolution is calculated based on the temperature change, which occurs during the dissolution process, and based on the calculated system conditioned temperature change, based on the baseline. Before and after breaking the ampoule, electrical calibration was always performed using a built-in thermal resistance of exactly known conductivity. In doing so, a known amount of heat was communicated to the system, during a precisely determined period of time, and a temperature jump was achieved.

Device and settings:

solution calorimeter: 2225 Precision Solution Calorimeter, Thermometric reaction cell: 100 ml

thermistor resistance: 30.0 kQ (at 25 °C)

mixer speed: 500 rpm

thermostat: thermostat, 2277 Thermal Activity Monitor TAM,

Thermometric company

temperature: 25 °C + 0.0001 °C (within 24 h)

measuring ampoule: breakable ampoule 1 ml, Thermometric seal: silicone stopper and beeswax, Thermometric scale: 40 to 50 mg

solvent: water, chemically pure

solvent volume: 100 ml

bath temperature: 25 °C

heat release: high

starting temperature: -40 mK (± 10 mK) temperature-offset interface: 2280-002 TAM accessorv interface 50 Hz,

Thermometric company

software: SolCal V 1.1 for WINDOWS

calculation: automatic calculation with Meniipunkt CALCULATION/ANALYSE EXPERIMENT. (baseline dynamics; calibration after breaking the ampoule).

Electrical calibration:

Electrical calibration was performed during the measurement, once before and once after breaking the ampoule. The calibration after breaking the ampoule was taken for the calculation.

Preparation of formulations with powder, based on the invention:

I) Equipment

For example, the following machines and devices can be used for the preparation of inhalation powders: Mixing vessel, or powder mixer: Turbulamischer 2L, Typ 2C; prod. Willy A.

Bachofen AG, CH-4500 Basel

Hand sieve: mesh width 0.135 mm

Filling empty inhalation capsules with inhalation powder containing tiotropium can be done manually or mechanically. The following devices can be used.

Capsule filling machine:

MG2, Typ G100, Manufacturer MG2 S.r.l, 1-40065 Pian di Macina di Pianoro (BO), Italy

Example 1:

Powder mixture:

295.43 g of excipient, 0.61 g of micronized tiotropium bromide monohydrate and 3.96 g of micronized salmeterol xinafoate were taken to prepare the powder mixture. In 300 g of inhalation powder prepared in this way, the active substances are 0.2% V and 1.32% 2.

Through a 0.135 mm mesh hand sieve, ca. 40-45 g of excipient. Then, tiotropium bromide-monohydrate 1, in portions of approx. 90-110 mg, and an auxiliary agent, in portions of about 40-50 g. The addition of auxiliary agent and active substance 1 was performed in 7, respectively. 6 layers.

Then the ingredients, introduced by sieving, were mixed (mixing: 900 rpm). The final mixture was sieved through a hand sieve twice more, and then mixed again (mixing: 900 rpm).

Then through a hand sieve, with 0.315 mm mesh, ca. 40-45 g of the powder mixture, which is obtained according to the above method, containing the active substance 1. Then, by sieving in layers, salmeterol xinafoate 2 was introduced alternately, in portions of approx. 650-670 mg, and the powder mixture, which contains the active substance 1, in portions of about 40-45 g. The addition of the powder mixture, which contains active substance 1, and active substance 2, was performed in 7, respectively. 6 layers. Then the ingredients introduced by sieving were mixed (mixing: 900 rpm). The final mixture was passed through a manual sieve twice more and finally mixed again (mixing: 900 rpm).

According to the method of operation described for example 1, the following inhalation powders can be obtained, from which the following inhalation capsules are obtained after filling the appropriate capsules made of synthetic plastic material:

Example 2:

Example 3:

Example 4:

Example 5:

Example 6:

Example 7:

Example 8:

Example 9:

Example 10:

Example 11:

Example 12:

Example 13:

Powder mixture:

295.43 g of excipient, 0.61 g of micronized tiotropium bromide monohydrate and 3.96 g of micronized salmeterol xinafoate were taken to prepare the powder mixture. In 300 g of inhalation powder prepared in this way, the share of active substances amounts to 0.2%VI1.32% 2.

Through a 0.135 mm mesh hand sieve, ca. 20-23 g of excipient. Then, tiotropium bromide-monohydrate1, in portions of approx. 90-110 mg, excipient, in portions of about 20-23 g and salmeterol xinafoate 2, in portions of ca. 650-670 mg. This mode of operation was repeated 6 times. Then the last portion of adjuvant of about 20-23 g was added.

Then the ingredients, introduced by sieving (6 layers 1 and 2 each, as well as 13 layers of auxiliary agent) were mixed (mixing: 900 rpm). The final mixture was sieved through a hand sieve twice more, and then mixed again (mixing: 900 rpm).

According to the method of operation described in example 13, such inhalation powders can be obtained, from which after filling the appropriate capsules made of synthetic plastic material, the following inhalation capsules are obtained:

Example 14:

Example 15:

Example 16:

Example 17:

Example 18:

Example 19:

Example 20:

Example 21:

Example22:

Example23:

Example 24:

Example25:

Powder mixture:

295.43 g of excipient, 0.61 g of micronized tiotropium bromide monohydrate and 3.96 g of micronized salmeterol xinafoate were taken to prepare the powder mixture. In 300 g of inhalation powder prepared in this way, the active substances are 0.2% V and 1.32% 2.

A mixture of 280.43 g of lactose monohydrate, mentioned under item 1b, with 15 g of micronized lactose monohydrate, medium-sized particles of about 3-4 pm, mentioned under item 1b, was used as an auxiliary agent.

In the drug formulation prepared in this way, the share of the auxiliary agent fraction with a smaller average particle size was 5%.

Through a 0.135 mm mesh hand sieve, ca. 29-33 g of rougher auxiliary means. Then, alternately, by sieving in layers, approx. 1.5-2 g of a finer auxiliary agent. This procedure was repeated 8 times. Then the last portion of 29-33 g of coarser excipient was added. Then the ingredients introduced by sieving (9 layers of adjuvant with coarser mean particle size and 8 layers of micronized adjuvant) were mixed (stirring: 900 rpm).

Then the adjuvant mixture thus obtained was used to prepare the final mixture, in the manner according to example 13. Then the ingredients introduced by sieving (6 layers 1 and 2 each, as well as 13 layers of the adjuvant mixture) were mixed (mixing: 900 rpm). The final mixture was sieved twice more through a hand sieve and then mixed again (mixing: 900 rpm).

According to the method of operation described in example 25, such inhalation powders can be obtained, from which, after filling the corresponding capsules made of synthetic plastic material, the following inhalation capsules are obtained. In the following examples, the label lactose-monohydrate (3-4 µm) was used for micronized lactose, and the label lactose-monohydrate for coarser lactose:

Example 26:

Example27:

Example 28:

Example 29:

Example 30:

Example 31:

Example 32:

Example 33:

Example 34:

Example 35:

Example 36:

Claims (16)

1) Inhalation powder, which contains tiotropiumVi salmeterol xinafoate 2, which has a characteristic melting point of about 124 °C, in a mixture with a physiologically harmless auxiliary agent. 2) Inhalation powder according to claim 1, characterized in that it is tiotropium Y in combination with a counter ion selected from the group consisting of chloride, bromide, iodide, methanesulfonate and para-toluenesulfonate. 3) Inhalation powder, according to claim 1 or 2, wherein salmeterol xinafoate 2, which is suitable for use, in the roentgenogram of the powder contains, among others, characteristic values d = 21.5 A; 8.41 A; 5.14 A; 4.35 A; 4.01 A and 3.63 A. 4) An inhalation powder according to claim 1, 2 or 3, wherein the salmeterol xinafoate 2, which is suitable for use, has a bulk volume of > 0.134 g/cm<3>, preferably of > 0.14 g/cm3. 5) Inhalation powder according to one of claims 1 to 4, characterized in that salmeterol xinafoate 2 is present in an amount of 0.002 to 15%. 6) Inhalation powder according to one of claims 1 to 5, characterized in that tiotropium Y is present in an amount of 0.001 to 5%. 7) Inhalation powder, according to one of claims 1 to 6, characterized in that tiotropium and salmeterol xinafoate 2 are present together in a dose of 5 to 5000 u.g. 8) Inhalation powder, according to one of claims 1 to 7, characterized in that the physiologically harmless auxiliary agent is selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols or also salts. 9) Inhalation powder, according to one of claims 1 to 8, characterized in that the physiologically harmless auxiliary agent is selected from the group consisting of glucose, arabinose, lactose, sucrose, maltose and trehalose, in the given case, in the form of their hydrates. 10) Use of inhalation powder, according to one of the claims 1 to 9, for the preparation of a medicine for the treatment of respiratory diseases. 11) A capsule containing inhalation powder, according to one of claims 1 to 10. 12) Capsule, according to claim 11, characterized in that it contains 1 to 20 mg, preferably about 3 to 15 mg of inhalation powder. 13) Capsule, according to claim 12, characterized in that it contains 4 to 6 mg of inhalation powder. 14) Capsule according to claim 12, characterized in that it contains 8 to 12 mg of inhalation powder. 15) An inhalation kit (kit) consisting of a capsule according to any of claims 11 to 14 and an inhaler, which can be used for the use (application) of inhalation powder from capsules containing the powder. 16) Inhalation accessory, according to claim 15, characterized by the fact that the inhaler is characterized by the fact that it consists of a casing 1, which has two windows 2; partition plate 3, in which there are openings for air intake and sieve 5, fixed by means of sieve housing 4; the inhalation chamber 6, attached to the partition plate 3, on which there is, via a spring 8, a movable pusher 9, on which there are two pointed needles 7; an intake 12 which can rotate around a shaft 10, together with a housing 1, a partition plate 3 and a cover 11; as well as opening 13, for the passage of air, which serves to adjust the flow resistance.