EA010588B1 - 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

The present invention relates to powder preparations for inhalation containing tiotropium salt and salmeterol xinafoate, to a method for their preparation, and also to their use for the manufacture of a medicament for the treatment of respiratory diseases, especially for the treatment of chronic obstructive pulmonary disease (COPD) and asthma

BACKGROUND OF THE INVENTION

Thiotropium bromide is known from EP 418716 A1 and has the following chemical structure:

Tiotropium bromide, as well as other salts of tiotropium, is a highly effective anticholinergic agent with a long-lasting effect, which can be used to treat respiratory diseases, especially for the treatment of chronic obstructive pulmonary disease and asthma. By tiotropium is meant a free ammonium cation.

Betamimetic salmeterol is also known in the art. It is used, for example, in the treatment of asthma.

XVO 00/69468 describes medicinal combinations of long-acting betamimetics and long-acting anticholinergics that exhibit a synergistic effect when using both of these medicinal components. One of the drug combinations specifically described in νθ 00/69468 is a combination of tiotropium bromide and salmeterol xinafoate.

The active substances salmeterol and tiotropium are introduced into the body by inhalation. Suitable inhalation powders may be used for this purpose.

To obtain the above formulations that meet the necessary requirements used for the inhalation of a medicinal active substance into the body, a technology is used based on various parameters, which in turn are associated with the properties of the medicinal active substance itself. As an example of such parameters, it is possible to name, but not limited to, the preservation of its activity by the original substance under the influence of various environmental factors, the stability of the active substance in the process of obtaining the pharmaceutical composition, as well as its stability in the final drug compositions. The medicinal active substance used to obtain the above medicinal compositions should have the highest possible degree of purity and should remain stable during prolonged storage under various environmental conditions. Mandatory compliance with this condition is due to the need to exclude the use of drugs, in which, along with the active substance itself, are present, for example, and its decomposition products. In such a case, the content of the active substance in the drug pre-packaged in capsules may be lower than that specified by the manufacturer.

Further important is the uniform distribution of the active substance in the medicinal composition and, above all, if it is necessary to introduce it into the body in a low dosage. If it is necessary to use a mixture of active substances, their uniform distribution in the medicinal composition becomes especially important. Another aspect that must be taken into account when receiving active substances intended for inhalation administration into the body in the form or in the composition of a powder is that only particles of a certain size are able to enter the respiratory tract and lungs during inhalation. The size of such particles that can penetrate the respiratory tract and lungs (inhalable fraction of the powder) lies in the submicron range. Therefore, to obtain active substances with particles of an appropriate size, such active substances also need to be subjected to grinding or grinding (so-called micronization). Since despite the harsh conditions prevailing in the process of grinding the medicinal active substance, during this process it is necessary to completely eliminate the destruction of the active substance accompanying its milling (respectively micronization), a mandatory requirement that the active substance must satisfy is its high stability, allowing him to maintain their properties during the grinding process. Obtaining a homogeneous drug composition with a constantly reproducible predetermined content of the active substance in it is possible only with a sufficiently high stability of the active substance during its grinding.

Another problem that can be encountered in the process of grinding the active substance upon receipt of the required drug composition is related to the energy supply to the crystals accompanying a similar process and to the application of mechanical load to their surface. The indicated factors under certain conditions can lead to polymorphic changes, to the transformation of the crystalline structure into an amorphous one, or to a change in the crystal lattice. Since it is necessary to ensure that the crystals of the active substance always have the same morphology in order to obtain a pharmaceutical composition of the required pharmaceutical quality, taking into account this aspect, increased requirements should also be made to the stability and properties of the crystalline active substance.

In addition to the above requirements for active substances, in general, the fact that any change in the solid-phase state of a drug, which improves its physical and chemical stability, can achieve significant advantages over forms of the same drug with less stability, should be taken into account.

The present invention was based on the task of proposing a medicinal composition containing tiotropium salt and salmeterol xinafoate, in which both active ingredients contained in it would satisfy the above conditions. Another objective of the present invention was primarily to offer a medicinal composition containing tiotropium salt and salmeterol xinafoate with the highest possible stability of both active substances.

The active substances tiotropium and salmeterol have a particularly high activity. When using active substances with particularly high activity, to achieve the desired therapeutic effect, a single dose of the drug should contain the active substance in only a small amount. In such cases, to obtain an inhalation powder, the active ingredient in its composition must be diluted with auxiliary substances suitable for this purpose. The properties of the inhalation powder due to the high content of excipient in it depend to a large extent on the choice of the appropriate excipient. When choosing an excipient, the size of its particles is of particular importance. Moreover, the smaller the particles of the excipient, the usually worse its mobility (fluidity). However, the good mobility of the powder is, obviously, one of the fundamental factors determining the high accuracy of dosing when packaging the drug and crushing it into single doses, for example, in the manufacture of capsules with inhaled powders (inhalers) or when the patient measures an individual dose of the drug before using the inhaler for powders, the contents of which are designed for repeated administration. In addition, the particle sizes of the excipient have a significant effect on the degree of emptying of the capsules inserted into the inhaler during its use. In addition, the particle size of the auxiliary substance, as it was found, significantly affect the inhalable fraction of the active substance in the portion of the inhalation powder dispensed by the inhaler. By inhalable, respectively, capable of inhalation of the shares of the active substance in the inhalation powder, we mean the content in it of those particles that, when inhaled, penetrate rather deeply with the inhaled air into the branches of the lungs. To achieve this effect, the particle size of the powder should be from 1 to 10 microns, preferably should be less than 6 microns.

In accordance with this, the present invention was also based on the task of obtaining a powder containing tiotropium salt and salmeterol xinafoate, which, when dosed with high accuracy (which relates to the amount of active substance and powder mixture packaged in each capsule for inhalation at the manufacturer, as well as to the dispensed from each capsule upon inhalation and the amount of active substance entering the respiratory tract and lungs) and with a slight variation in parameters between different batches of n products would provide the introduction into the body of the active substance with its high inhalation fraction. Another objective of the present invention was to obtain a salt containing tiotropium and xinafo salmeterol inhalation powder, which would provide a high degree of emptying of the capsules containing it, regardless of whether it is intended, for example, to be introduced into a patient using an inhaler described, for example, in XVO 94/28958, or use ίη νίΐτο with an impactor or impinger.

The fact that mainly salts of tiotropium, but also salmeterol xinafoate, already at extremely low doses, have a high therapeutic effect, imposes other requirements on the inhalation powder used with high dosage accuracy and containing both of these active substances. Due to the low concentration necessary for achieving the desired therapeutic effect, the concentration of active substances in the inhalation powder is important to ensure a high degree of uniformity of the powder mixture and to minimize the variation in dispersion conditions from one batch of capsules with powder to another. At the same time, both the homogeneity of the powder mixture and the minimum dispersion of the dispersion parameters of its particles are decisive factors that ensure the delivery of the inhalable fraction of active substances in constantly high quantities with a high degree of reproducibility and thereby with the minimum possible fluctuations.

In accordance with this, another objective of the present invention was to obtain a salt of tiotropium and xinafo salmeterol inhalation powder, which would have a high degree of

- 2 010588 with the uniformity and uniformity of its dispersed particles. The objective of the invention was also to obtain an inhalation powder, which would provide the possibility of introducing into the body the active substances with extremely small fluctuations in their inhalable fraction.

The degree of emptying of the powder-containing container (i.e., the container from which the active ingredient-containing inhalation powder is dispensed to be introduced into the body by inhalation) plays an important role, although not exclusively, but not least, when inhaled powders are introduced into the body from capsules containing them. When the powder preparation leaves the container containing it only in a small amount due to the small, respectively low degree of its emptying, significant quantities of the active substance containing inhalation powder remain in the container (which can no longer be used by the patient for therapeutic purposes). As a result, it is necessary to increase the dosage of the active substance in the powder mixture so that the amount of active substance in one portion of the inhalation powder dispensed from the container containing it is sufficient to achieve the desired therapeutic effect.

With this in mind, another objective of the present invention was to obtain an inhalation powder containing tiotropium and xinafo salmeterol xinafoate, the properties of which would provide the possibility of efficient emptying of the container containing it.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, it was unexpectedly found that the above problems can be solved using the inventive powder preparations for inhalation (inhalation powders), which contain tiotropium salt 1 and salmeterol xinafoate 2 and which are discussed in more detail below.

According to the present invention, the salts of tiotropium 1. refers to salts formed by the pharmacologically active cation - tiotropium 1 '. In the description of the present invention, when it is specifically a tiotropium cation, the reference 1 'is used to refer to it.

The inhalation powders according to the invention contain tiotropium 1 ′ and salmeterol xinafoate 2 having a melting point of about 124 ° C. mixed with a physiologically harmless excipient.

The aforementioned melting point was determined by differential scanning calorimetry (DSC) using a Meieg E8C 820 instrument, using the 8TLC software package to process the obtained data. Firm Meieg. Data was obtained at a heating rate of 10 K / min.

In a preferred embodiment, the composition of the inhalation powders of the invention uses salmeterol xinafoate 2, the X-ray powder diffraction of which contains, among others, the following characteristic values b: 21.5, 8.41, 5.14, 4.35, 4.01 and 3, 63 A. Detailed information regarding the determination of these characteristic values by X-ray powder diffractometry is presented in the experimental part of the present description. An X-ray powder diffraction pattern of salmeterol xinafoate, the use of which is preferably according to the present invention, is shown in FIG. one.

In the most preferred embodiment, the salmeterol xinafoate 2 used in the inhalation powders of the invention has a volume after compaction of at least 0.134 g / cm ³ , preferably at least 0.14 g / cm ³ , most preferably at least 0.145 g / cm ³ .

The volume of the powder material after compaction is determined in accordance with the test method according to European Pharmacopoeia 4 (2002): apparent density after settling / density of the settled product (arragep! light tapping (! arreb bep811u) and which is measured in grams per milliliter, respectively, is determined as the bulk density of bulk materials according to the Carr method (Sagg raskeb L1kbepSchu) according to the standard L8TM (Ό 6393-99, 81apbag teTs Me11yub Gog Vi1k 8ο1ί6δ C11agak1ephayup Lu Sagg 1pb1se§), measured in grams per cm ³ . The volume after compaction is in this case a measure of the volume occupied by the solid crushed materials after compaction under certain conditions.

Salmeterol xinafoate, characterized by the parameters described above, is equally suitable for use as a starting material in the micronization process, and for use as a micronized product with the physical properties described above in the process of obtaining an inhalation powder. The product obtained after micronization, as well as the salmeterol xinafoate subjected to micronization, are characterized by the parameters described above.

The content of salmeterol 2 xinafoate described above in the inhalation powders of the invention should preferably be from 0.002 to 15%. Preferred according to the invention are inhalation powders, the content of which component 2 is from 0.01 to 10%. Most preferred are inhalation powders in which the content of component 2 is from 0.05 to 5%, preferably from 0.1 to 3%, most preferably from 0.125 to 2%, particularly preferably from 0.25 to 2%.

In a further preferred embodiment, the inventive inhalation powders

- 3 010588 contain tiotropium 1 'in an amount of from 0.001 to 5%. Inhalation powders containing tiotropium 1 ′ in an amount of from 0.01 to 3% are preferred according to the invention. Most preferred are inhalation powders with a tiotropium content of 1 'in an amount of from 0.02 to 2.5%, preferably from 0.03 to 2.5%, particularly preferably from 0.04 to 2%.

By tiotropium 1 'is meant a free ammonium cation. Under used in the present description, the designation 1 means tiotropium in combination with the corresponding counterion. Such a counterion (anion) is preferably chloride, bromide, iodide, methanesulfonate or laura-toluenesulfonate. Of these anions, bromide is preferred. Accordingly, the invention preferably provides inhalation powders containing tiotropium bromide 1 in an amount of from 0.0012 to 6%, preferably from 0.012 to 3.6%. Of particular interest according to the invention are inhalation powders containing tiotropium bromide 1 in an amount of from about 0.024 to 3%, preferably from 0.036 to 3%, most preferably from about 0.048 to 2.4%.

Tiotropium bromide, which is preferably used in the inhalation powders of the invention, may contain molecules of the solvent used to crystallize it. To obtain the inventive tiotropium-containing inhalation powders, it is preferable to use tiotropium bromide hydrates. Most preferably, crystalline tiotropium bromide monohydrate known from \ ¥ O 02/30928 is used. This crystalline tiotropium bromide monohydrate is distinguished by the presence of an endothermic maximum at a temperature of 230 ± 5 ° C, which manifests itself during its thermal analysis by DSC at a heating rate of 10 K / min. In addition, such crystalline tiotropium bromide monohydrate is characterized by the presence in its IR spectrum of bands corresponding to wave numbers 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm ^-1 . Such crystalline tiotropium bromide monohydrate according to the data of X-ray diffraction analysis of single crystals further has a simple monoclinic cell of the following sizes: a = 18.0774 A, b = 11.9711 A, c = 9.9321 A, β = 102.691 °, V = 2096.96 A ³ .

Accordingly, the invention preferably provides inhalation powders containing crystalline tiotropium bromide monohydrate in an amount of from 0.00125 to 6.25%, preferably from 0.0125 to 3.75%. According to the invention, inhalation powders with a content of tiotropium bromide monohydrate of from about 0.025 to 3.125%, preferably from about 0.0375 to 3.125%, most preferably from about 0.05 to 2.5%, are of particular interest.

In accordance with the present invention, the percentages given above in all cases, unless specifically indicated otherwise, are percent by weight (wt.%).

Usually, when using the drugs of the invention containing combinations of active ingredients 1 and 2, tiotropium 1 ′ and salmeterol xinafoate 2 are co-administered in a dosage amounting to 5 to 5000 μg, preferably 10 to 2000 μg per dose, more preferably from 15 to 1000 μg, preferably from 20 to 500 μg, according to the invention, preferably from 25 to 250 μg, more preferably from 30 to 125 μg, most preferably 40 to 70 μg.

The combinations of active substances 1 and 2 according to the invention may contain tiotropium 1 'and salmeterol xinafoate 2', for example, in such quantities (but not limited to them), so as to ensure the introduction of 4.5 μg of component 1 'and 25 into the body at one time μg component 2, 4.5 μg component 1 'and 30 μg component 2, 4.5 μg component 1', and 35 μg component 2, 4.5 μg component 1 'and 40 μg component 2, 4.5 μg component 1 'and 43.5 μg component 2, 4.5 μg component 1' and 50 μg component 2, 4.5 μg component 1 'and 60 μg component 2, 4.5 μg component 1' and 70 μg component and 2, 4.5 μg of component 1 'and 80 μg of component 2, 4.5 μg of component 1' and 90 μg of component 2, 4.5 μg of component 1 ', and 100 μg of component 2, 4.5 μg of component 1' and 110 μg of component 2, 10 μg of component 1 'and 25 μg of component 2, 10 μg of component 1, and 30 μg of component 2, 10 μg of component 1, and 35 μg of component 2, 10 μg of component 1, and 40 μg of component 2 10 μg of component 1 'and 50 μg of component 2, 10 μg of component 1' and 60 μg of component 2, 10 μg of component 1 and 70 μg of component 2, 10 μg of component 1 and 80 μg of component 2, 10 μg of component 1 ' and 90 μg component 2, 10 μg component 1 'and 100 μg compone That 2, 10 μg component 1 'and 110 μg component 2, 18 μg component 1', and 25 μg component 2, 18 μg component 1 ', and 30 μg component 2, 18 μg component 1' and 35 μg component 2, 18 μg of component 1 'and 40 μg of component 2, 18 μg of component 1' and 50 μg of component 2, 18 μg of component 1 'and 60 μg of component 2.18 μg of component 1' and 70 μg of component 2, 18 μg of component 1 'and 80 μg component 2, 18 μg component 1 ', and 90 μg component 2, 18 μg component 1' and 100 μg component 2, 18 μg component 1 'and 110 μg component 2, 36 μg component 1' and 25 μg component 2, 36 μg component 1 'and 30 μg component that 2, 36 μg component 1 'and 35 μg component 2, 36 μg component 1', and 40 μg component 2, 36 μg component 1 'and 50 μg component 2, 36 μg component 1' and 60 μg component 2, 36 μg component 1 'and 70 μg component 2, 36 μg component 1' and 80 μg component 2, 36 μg component 1 'and 90 μg component 2, 36 μg component 1' and 100 μg component 2, 36 μg component 1 'and 110 μg component 2.

- 4 010588

If, as a preferred combination of active substances 1 and 2 according to the invention, a combination is used in which salt 1 is bromide, then the amounts of active substances 1 'and 2 given above as an example correspond to the following amounts of active substances 1 and 2 based on one dose: 5.4 μg of component 1 and 25 μg of component 2, 5.4 μg of component 1 and 30 μg of component 2, 5.4 μg of component 1 and 35 μg of component 2, 5.4 μg of component 1 and 40 μg component 2, 5.4 μg component 1 and 50 μg component 2, 5.4 μg component 1, and 60 μg of component 2, 5.4 μg of component 1, and 70 μg of component 2, 5.4 μg of component 1, and 80 μg of component 2, 5.4 μg of component 1, and 90 μg of component 2, 5.4 μg component 1 and 100 μg component 2, 5.4 μg component 1 and 110 μg component 2, 12 μg component 1 and 25 μg component 2, 12 μg component 1 and 30 μg component 2, 12 μg component 1, and 35 μg component 2, 12 μg component 1 and 40 μg component 2, 12 μg component 1, and 50 μg component 2, 12 μg component 1 and 60 μg component 2, 12 μg component 1 and 70 μg component 2, 12 μg component 1 and 80 μg component 2, 12 mcg comp onenta 1 and 90 μg component 2, 12 μg component 1 and 100 μg component 2, 12 μg component 1 and 110 μg component 2, 21.7 μg component 1 and 25 μg component 2, 21.7 μg component 1 and 30 μg component 2, 21.7 μg component 1, and 35 μg component 2, 21.7 μg component 1 and 40 μg component 2, 21.7 μg component 1 and 50 μg component 2, 21.7 μg component 1, and 60 μg component 2, 21.7 μg component 1, and 70 μg component 2, 21.7 μg component 2, 21.7 μg component 2, 21.7 μg component 2, 21.7 μg component 2, 21.7 μg component 2, 21.7 μg component 1, and 100 μg component 2, 21.7 μg component 1 and 110 μg component 2, 43.3 μm component 1 and 25 μg component 2, 43.3 μg component 2, and 43 μg component 2, 43.3 μg component 1 and 35 μg component 2, 43.3 μg component 1 and 40 μg component 2, 43.3 μg component 1 and 50 μg component 2, 43.3 μg component 1 and 60 μg component 2, 43.3 μg component 1 and 70 μg component 2, 43.3 μg component 1 and 80 μg component 2, 43.3 μg component 1 and 90 μg of component 2, 43.3 μg of component 1 and 100 μg of component 2, 43.3 μg of component 1, and 110 μg of component 2.

If, as a preferred combination of active ingredients 1 and 2 according to the invention, a combination is used in which salt 1 is tiotropium bromide crystalline monohydrate, then the amounts of tiotropium bromide 1 monohydrate 1 and active ingredient given above, as an example, correspond to the following amounts of active ingredients 1 and 2 substances 2 per dose: 5.6 μg component 1 and 25 μg component 2, 5.6 μg component 1 and 30 μg component 2, 5.6 μg component 1 and 35 μg component 2, 5.6 μg comp enta, 1 and 40 μg of component 2, 5.6 μg of component 1 and 50 μg of component 2, 5.6 μg of component 1 and 60 μg of component 2, 5.6 μg of component 1 and 70 μg of component 2, 5.6 μg of component 1 and 80 μg component 2, 5.6 μg component 1 and 90 μg component 2, 5.6 μg component 1 and 100 μg component 2, 5.6 μg component 1 and 110 μg component 2, 12.5 μg component 1 and 25 μg component 2, 12.5 μg component 1 and 30 μg component 2, 12.5 μg component 1 and 35 μg component 2, 12.5 μg component 1 and 40 μg component 2, 12.5 μg component 1 and 50 μg component 2, 12.5 μg component 1 and 60 μg component 2, 12.5 μg com onenta 1 and 70 μg component 2, 12.5 μg component 1 and 80 μg component 2, 12.5 μg component 1, and 90 μg component 2, 12.5 μg component 1 and 100 μg component 2, 12.5 μg component 1 and 110 μg component 2, 22.5 μg component 1 and 25 μg component 2, 22.5 μg component 1 and 30 μg component 2, 22.5 μg component 1 and 35 μg component 2, 22.5 μg component 1 and 40 μg component 2, 22.5 μg component 1 and 50 μg component 2, 22.5 μg component 1 and 60 μg component 2, 22.5 μg component 1 and 70 μg component 2, 22.5 μg component 1, and 80 μg of component 2, 22.5 μg of component 1 and 90 μg of component 2, 22.5 kg of component 1 and 100 μg of component 2, 22.5 μg of component 1 and 110 μg of component 2, 45 μg of component 1 and 25 μg of component 2, 45 μg of component 1 and 30 μg of component 2, 45 μg of component 1 and 35 μg of component 2 , 45 μg component 1 and 40 μg component 2, 45 μg component 1 and 50 μg component 2, 45 μg component 1 and 60 μg component 2, 45 μg component 1 and 70 μg component 2, 45 μg component 1 and 80 μg component 2 45 μg of component 1 and 90 μg of component 2, 45 μg of component 1 and 100 μg of component 2, 45 μg of component 1 and 110 μg of component 2.

As an example of physiologically harmless excipients that can be used to obtain inhalation powders used as the drugs of the invention, monosaccharides (e.g., glucose or arabinose), disaccharides (e.g., lactose, sucrose, maltose, trehalose), oligo - and polysaccharides (e.g. dextrans), polyalcohols (e.g. sorbitol, mannitol, xylitol) or salts (e.g. sodium chloride, calcium carbonate). Mono- or disaccharides are preferably used, with the use of lactose or glucose, especially, but not exclusively, in the form of their hydrates. Particularly preferred according to the invention is the use of lactose as an auxiliary substance, most preferably in the form of its monohydrate.

It is most preferable to use excipients with an average particle size of from 10 to 50 microns. In this context, the average size (or average particle size) of particles is understood as the size of 50% of all particles whose volume distribution by particle size was determined using a laser diffractometer using the dry dispersion method. In the most preferred inhalation powders, an excipient with an average particle size of 12 to

- 5,010,088 microns, particularly preferably from 13 to 30 microns.

It is most preferable to further use those auxiliary substances in which 10% falls on the fraction of a fine fraction of particles with a size of from 0.5 to 6 microns. A fine fraction, which accounts for 10%, is understood to mean a fraction of 10% of the total number of particles, the volumetric distribution of which by size was determined using a laser diffractometer. In other words, under the fine fraction, which accounts for 10%, in the context of the present invention refers to the fraction of particles with a size that no more than 10% of the particles of their total number (in terms of their volume distribution by size). Most preferred are especially those inhalation powders in which the particle size of the excipient in a fine fraction, which accounts for 10% of the total number of particles of the excipient, is from about 1 to 4 microns, preferably from about 1.5 to 3 microns. Inhalable powders in which an excipient with a specific surface of 0.2 to 1.5 m ² / g, preferably 0.3 to 1.0 m ² / g are further preferred according to the invention.

In the powder formulations according to the invention, it is preferable to use excipients with a high degree of crystallinity. The degree of crystallinity can be estimated based on the heat released during dissolution of the excipient (dissolution enthalpy). In the case of lactose monohydrate, which is most preferred for use in the inventive inhalation powders with an excipient, it is preferable to use lactose with a dissolution enthalpy of at least 45 J / g, preferably at least 50 J / g, most preferably at least 52 J / g.

One of the distinguishing features of the inhalation powders proposed in the invention consists in accordance with the objective laid down in the invention in the possibility of their administration into the body with consistently high accuracy of a single dosage. Moreover, the fluctuations of the amounts of inhalation powder administered at one time are less than 8%, preferably less than 6%, most preferably less than 4%, of the nominal amount.

Under certain conditions, it may be appropriate to use, instead of the above excipients, their mixtures consisting of the active substance, presented in the form of particles of a larger size with an average size of from 17 to 50 microns, preferably from 20 to 40 microns, most preferably from 25 to 35 microns, and an auxiliary substance, presented in the form of particles of a smaller size with an average size of from 1 to 8 microns, preferably from 2 to 7 microns, most preferably from 3 to 6 microns. Under the average size, respectively, the average particle size, in this case, we mean the size of 50% of all particles, the volumetric distribution of which by size was determined using laser diffraction by the method of dry dispersion. When using the above mixtures of excipients, the particle size in a fine fraction of the excipient, presented in the form of particles of a larger size, which accounts for 10% of the total number of particles of this excipient, is from about 2 to 5 microns, preferably from about 3 to 4 microns and the particle size in the fine fraction of the auxiliary substance, presented in the form of particles of a smaller size, which accounts for 10% of the total number of particles of this auxiliary substance, is n about 0.5 to 1.5 microns. Inhaled powders are preferred in which the excipient, presented in the form of particles of a smaller size, in the composition of the whole composition accounts for from 2 to 10%, preferably from 3 to 7%, most preferably from 4 to 6%.

By the mixture of excipients referred to in the description of the present invention in all cases is meant a mixture obtained by mixing together predetermined precisely defined components. Accordingly, a mixture, for example, of auxiliary substances, one of which is presented in the form of particles of a larger size, and the other in the form of particles of a smaller size, means only such mixtures that are obtained by mixing an auxiliary substance, which is a component with particles of a larger size, with excipient, which is a component with particles of smaller particle size. Excipients presented in the form of particles of a larger and smaller size can be chemically identical or chemically different substances from those already mentioned above as excipients, inhalation powders in which an excipient presented in the form of particles of a larger size are preferred and excipient, presented in the form of particles of a smaller size, are one and the same chemical compound. So, for example, when using lactose monohydrate as an auxiliary substance, it is also preferable to apply it in the case of specially provided addition of an auxiliary substance in the form of a fraction with the aforementioned smaller average particle size.

To obtain the medicines proposed in the invention, it is first necessary to obtain salmeterol xinafoate 2 in a form that complies with the specifications specified above for this component 2. For this, according to the invention, it is preferable to work as follows. Salmeterol in the form of a free base known in the art, together with 1-hydroxy-2-naphthoic acid, is dissolved in a solvent, which is a mixture of alcohol and ether. Per mole use

At least 1 mol, preferably from 1 to 1.1 mol, most preferably 1 mol, of 1-hydroxy-2-naphthoic acid is used. As the alcohol of the invention, short chain alcohols, preferably ethanol, n-propanol or isopropanol, most preferably ethanol, can be used. As the ether according to the invention, it is most preferable to use diethyl ether, methyl ethyl ether, tetrahydrofuran, dioxane or tert-butyl methyl ether, the most preferred of which according to the invention is tert-butyl methyl ether. The alcohol and ether are preferably used according to the invention in a (volumetric) ratio between them of about 1: 2 to 2: 1, most preferably from about 1: 1.5 to 1.5: 1. In a particularly preferred embodiment, said ratio between alcohol and ether should be 1: 1. The total amount of solvent used is determined, as is obvious, by the volume of the reaction mixture. For a mole of salmeterol used as the free base, the solvent is preferably used in an amount of about 5 to 20 liters, most preferably about 7 to 15 liters. In a particularly preferred embodiment, about 9 to 12 L of solvent is used per mole of salmeterol used, in which the volume ratio between the two components, which are alcohol and ether, can correspond to the above values. After adding all of the above components, the resulting suspension is heated with stirring to a temperature equal to or greater than 40 ° C, preferably to a temperature equal to or greater than 50 ° C, most preferably to a temperature of the order of 55-56 ° C. Heating is continued until a clear solution is formed. This solution is then filtered and the filter, if necessary, washed with a small amount of the above solvent (which is used in an amount of about 1 to 1.5 liters per mole of salmeterol used). After this, the obtained filtrate is cooled to a temperature of about 30-40 ° C, preferably about 35-38 ° C, and stirred at this temperature until crystallization of salmeterol xinafoate begins. At this stage, under certain conditions, it may be appropriate to add salmeterol xinafoate to the suspension of seed crystals. With the start of crystallization, the suspension is cooled with stirring to an even lower temperature, preferably to a temperature of from about -10 to about 10 ° C, most preferably to a temperature of from about 0 to about 5 ° C. Crystallization is completed after about 20-60 minutes, after which the resulting product is separated by filtration through an appropriate filter and, if necessary, washed with alcohol and / or ether. The salmeterol xinafoate obtained in this way complies with the above specifications, which distinguish the inhalation powders according to the invention.

Accordingly, another object of the present invention is inhalation powders, which along with tiotropium 1 'also contain salmeterol xinafoate 2 obtained by the method described above.

After measuring by weighing the necessary portions of the starting materials from the excipient and the active substance, inhalation powder is prepared using methods known from the prior art. In this case, you can refer, for example, to the publication \ ¥ О 02/30390. Accordingly, the inhalation powders according to the invention can be obtained, for example, by the method described below. In the methods for the preparation of inhalation powders discussed below, these components are used in mass amounts that correspond to the quantities indicated above in the description of the compositions of the inhalation powders.

First, an auxiliary substance and a tiotropium salt 1 are loaded into a suitable mixer. The average particle size of the active ingredient 1 used is from 0.5 to 10 μm, preferably from 1 to 6 μm, most preferably from 2 to 5 μm. The active ingredient 1 and the excipient are preferably fed to the mixer through a sieve or sieve granulator with sieve openings of 0.1 to 2 mm, more preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm. In this case, it is preferable to first load the auxiliary substance into the mixer, and then feed the active substance into it. With this mixing technology, both components of the mixture are preferably fed into the mixer in separate batches. It is most preferable to feed both components into the mixer by alternately sieving them in layers. The excipient and the active substance 1 can be mixed together during the supply of both of these components to the mixer. It is more preferable, however, to begin mixing the two components only after they are sieved in layers.

When used as an auxiliary substance, a mixture of auxiliary substances, one of which is presented in the form of particles of a larger size with an average size of from 17 to 50 μm, most preferably from 20 to 35 μm, and the other in the form of particles of a smaller size with an average size of from 1 to 8 microns, preferably from 2 to 7 microns, most preferably from 3 to 6 microns, first prepare a similar mixture of both auxiliary substances, feeding them into the mixer by alternating, layer by layer sifting followed by their mixing.

After obtaining the powder mixture containing the active ingredient 1 described above, salmeterol xinafoate 2 is added in a similar way to it. The average particle size of the active substance 2 is also from 0.5 to 10 μm, preferably from 1 to 6 μm, most preferred

- 7 010588 specifically from 2 to 5 microns. The active substance 2 and the powder mixture containing component 1 are preferably fed into the mixer through a sieve or sieve granulator with sieve openings of 0.1 to 2 mm, more preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm In this case, it is preferable to first load the powder mixture containing component 1 into the mixer, and then feed the active substance 2 into it. With this mixing technology, it is preferable to feed both components of the mixture into the mixer in separate portions. It is most preferable to feed both components into the mixer by alternately sieving them in layers. The powder mixture containing component 1 and the active substance 2 can be mixed together during the supply of both of these components to the mixer. It is more preferable, however, to begin mixing the two components only after they are sieved in layers.

In another embodiment of the invention, the inhalation powder according to the invention can also be prepared by first preparing a powder mixture from an excipient and an active substance 2 in the same way as described above, and then adding component 1 to it in accordance with the method described above.

According to another embodiment of the invention, the inhalation powder according to the invention can also be obtained by first loading a first portion of the excipient into the mixer, then feeding the first portion of the active substance 1 or the first portion of the active substance 2 to the mixer, and then again sifting the next portion of the excipient into the mixer and finally adding the first portion of the active substance 2, respectively, the first portion of the active substance 1. Adding components to the mixer prepared Vai mixtures which are auxiliary substance, the active substance 1 and the active compound 2, in such sequence is then repeated until all boot components in the mixer in the required quantities. And in this case, all three components are most preferably fed to the mixer by alternating them in layers. All these three components can be mixed with each other already in the process of their supply to the mixer. It is more preferable, however, to begin mixing the three indicated components only after they are sieved in layers.

In the case when the active substances 1 and 2 used in the preparation of the inhalation powder by the method described above are not presented immediately after their chemical preparation in crystalline form with particles whose size corresponds to the above values, they can be milled (so-called micronization) to bring the average size of their particles to a value that satisfies the above parameters. When using crystalline tiotropium bromide monohydrate as described in νΟ 02/30928 as the active substance 1, it is most expedient to use the method discussed below to micronize such a crystalline modification of the active substance 1. For this process, you can use traditional mills. Micronization is preferably carried out under conditions that exclude moisture, most preferably using the appropriate inert gas, for example nitrogen. For application for the above purposes, pneumatic jet mills have proven to be particularly preferred, in which the grinding of the milled material occurs as a result of collisions of its particles with each other, as well as as a result of their impact on the wall of the grinding chamber. It is preferable to use nitrogen as the working gas in this type of mills according to the invention. The milled material is moved / transported by the working gas at special pressure values (working pressure). In accordance with the present invention, such a working pressure is usually set to a value in the range of from about 2 to about 8 bar, preferably from about 3 to about 7 bar, most preferably from about 3.5 to about 6.5 bar. The milled material is fed into a pneumatic jet mill using a conveying gas at special pressure values (feed pressure). According to the present invention, the optimum supply pressure is from about 2 to about 8 bar, preferably from about 3 to about 7 bar, most preferably from about 3.5 to about 6 bar. It is also preferable to use an inert gas as the transporting gas, in which nitrogen is also most preferably used. The milled material (crystalline tiotropium bromide monohydrate 1) can be fed into the mill at a speed or flow rate of from about 5 to 35 g / min, preferably from about 10 to 30 g / min. As a non-limiting example of a pneumatic jet mill that can be used for the purposes provided by the invention, mention may be made of a 2-inch micron colloid mill equipped with a working ring with an opening of 0.8 mm, manufactured by 8i.1g1euap1 1ps., Located at 348 Snsiy 81gee1, Napoueg, MA 02239, I8A. When using this mill, the grinding process is preferably carried out with the following parameters:

working pressure: about 4.5-6.5 bar, feed pressure: about 4.5-6.5 bar, feed rate of the milled material: about 17-21 g / min.

- 8 010588

The milled product obtained in this way is then further processed under the following specific conditions. To this end, the resulting micronized product is kept in an atmosphere of water vapor with a temperature of from 15 to 40 ° C, preferably from 20 to 35 ° C, most preferably from 25 to 30 ° C, with a relative humidity of at least 40%. It is more preferable to maintain the micronized product at a relative humidity of 50 to 95%, more preferably 60 to 90%, most preferably 70 to 80%. Relative humidity (RH) in this case means the ratio of the elasticity of water vapor (partial pressure of water vapor) to the elasticity of saturated water vapor at the same temperature. The micronized product obtained from the grinding process described above is preferably kept under the above conditions for at least 6 hours. More preferably, however, the micronized product is kept under the conditions described above for a period of from about 12 to about 48 hours, more preferably from about 18 to about 36 hours, most preferably from about 20 to about 28 hours

The particles obtained by the above-described method of the micronized tiotropium bromide 1 according to the invention have an average size in the range from 1.0 to 3.5 μm, preferably from 1.1 to 3.3 μm, most preferably from 1.2 to 3.0 μm, when the value of P ( ₅ , ₈ ) is more than 60%, preferably more than 70%, most preferably more than 80%. The indicator P ( ₅ , ₈ ) corresponds to the number of particles, the size of which, in terms of the volume distribution of particle size, is less than 5.8 μm. The particle size according to the present invention was determined by laser diffraction (Fraunhofer diffraction). More detailed information regarding the method of determining particle sizes is given in the following description in the section on the experimental part.

Another characteristic indicator obtained by the micronized tiotropium method described above, the use of which is preferably according to the present invention, is the value of its specific surface lying in the range from 2 to 5 m ² / g, preferably from 2.5 to 4.5 m ² / g, the most preferably from 3.0 to 4.0 m ² / g.

One of the most preferred objects of the present invention are its inhalation powders, characterized in that they contain as component 1 the micronized tiotropium bromide monohydrate described above.

For micronization of salmeterol 2 xinafoate used according to the invention, it is most expedient to use the method discussed below. For this process, you can use traditional mills. Micronization is preferably carried out under conditions that exclude moisture, most preferably using the appropriate inert gas, for example nitrogen. For application for the above purposes, pneumatic jet mills have proven to be particularly preferred, in which the grinding of the milled material occurs as a result of collisions of its particles with each other, as well as as a result of their impact on the wall of the grinding chamber. It is preferable to use nitrogen as the working gas in this type of mills according to the invention. The milled material is moved / transported by the working gas at special pressure values (working pressure). In accordance with the present invention, such a working pressure is usually set to a value in the range of from about 2 to about 12 bar, preferably from about 5 to about 10 bar, most preferably from about 5 to about 8.5 bar. The milled material is fed into a pneumatic jet mill using a conveying gas at special pressure values (feed pressure). According to the present invention, the optimum supply pressure is from about 2 to about 12 bar, preferably from about 5.5 to about 10.5 bar, most preferably from about 5.5 to about 9 bar. It is also preferable to use an inert gas as the transporting gas, in which nitrogen is also most preferably used. The milled material (crystalline salmeterol xinafoate) can be fed into the mill at a rate or flow rate of from about 5 to 100 g / min, preferably from about 10 to 60 g / min.

In accordance with this, another most preferred object of the present invention are its inhalation powders, characterized in that they contain micronized xinafo salmeterol 2 obtained by micronization as described above.

The present invention also relates to the use of its inhalation powders for the manufacture of a medicament for the treatment of respiratory diseases, especially for the treatment of COPD and / or asthma.

The inhalation powders according to the invention can be introduced into the body, for example, using inhalers in which a single dose is dispensed from a delivery container using a metering chamber (for example, according to I8 4570630) or other devices (for example, according to ΌΕ 3625685 A). It is obvious that the inhalation powders according to the invention are preferably packaged in capsules (to produce so-called inhalers), which are used in inhalers described, for example, in UO 94/28958.

For the administration of the inhalation powders according to the invention from the capsules containing them, it is most preferable to use the inhaler shown in FIG. 2. Featured on this

- 9 010588 drawing, the inhaler is characterized by the presence of a housing 1 with two windows 2, a plate partition 3, in which air inlets are provided and which is equipped with a mesh 5 held in assembled condition by a corresponding fastening element 4 connected to the plate partition 3 of the chamber 6 for capsule with inhalation powder, on the side of which (the chamber) a push button 9 is provided, equipped with two polished needles 7 and made movable against the force of the spring 8, the mouthpiece 12, which is hinged a spindle 10, connected to the housing 1, the deck 3 and a cover 11, and through holes 13 for the passage of air, serving for adjusting the flow resistance.

The present invention further relates to the use of the inhalation powders according to the invention for the manufacture of a medicament for the treatment of diseases of the respiratory tract, in particular for the treatment of COPD and / or asthma, characterized in that it is used as described above and shown in FIG. 2 inhaler.

When packaging the inventive inhalation powders into capsules, it is most preferable to use capsules whose material is selected from the group of synthetic polymers, particularly preferably from the group comprising polyethylene, polycarbonate, polyesters, polypropylene and polyethylene terephthalate. The most preferred synthetic polymer as the material for the manufacture of capsules is polyethylene, polycarbonate or polyethylene terephthalate. In the manufacture of capsules from polyethylene, which is one of the preferred materials according to the invention, it is preferable to use polyethylene with a density of from 900 to 1000 kg / m ³ , more preferably from 940 to 980 kg / m ³ , most preferably from about 960 to 970 kg / m ³ (high density polyethylene). Such polymeric materials according to the invention can be processed into capsules by a variety of methods known in the art. The preferred polymer processing method according to the invention is injection molding. In the manufacture of capsules by injection molding according to the most preferred embodiment, release agents are not used to remove the capsules from the mold. A similar method for the manufacture of capsules is characterized by well-developed technology and particularly high reproducibility.

Another object of the present invention are the above-described capsules containing the inventive inhalation powder described above. The content of the inhalation powder in such capsules may be from about 1 to 20 mg, preferably from about 3 to 15 mg, most preferably from about 4 to 12 mg. Preferred capsules according to the invention contain from 4 to 6 mg of inhalation powder. Equally preferred according to the invention are inhalation capsules containing the powder formulations according to the invention in an amount of from 8 to 12 mg, most preferably from 9 to 11 mg.

The present invention also relates to an inhalation kit consisting of one or more of the capsules described above containing the inhalation powders of the invention and the inhaler shown in FIG. 2.

The present invention further relates to the use of the above-described capsules containing the inhalation powders of the invention for the manufacture of a medicament for the treatment of respiratory diseases, especially for the treatment of COPD and / or asthma.

Capsules filled with the inhalation powders of the invention are made by methods known in the art by packaging the inhalation powders of the invention in empty capsules.

The invention is described in more detail below with examples, however, the scope of the invention is not limited to the specific embodiments considered in these examples.

Source materials

I) Excipient

1a

In Examples 1-24 below, lactose monohydrate is used as an adjuvant. As such, you can use, for example, a product manufactured by the company Vogs1o Eoto 1pdgeb1ep18, located at Vogs1o, Ib, under the trade name Laclioet Exlga Eshe Rotebeg. Lactose of this variety satisfies the specifications of the invention regarding its particle size and specific surface area. In addition, such lactose has the aforementioned, preferred according to the invention for lactose, enthalpy of dissolution. In the examples below, for example, powdered lactose with the following parameters was used:

a) average particle size: 17.9 microns, particle size in a fine fraction, which accounts for 10%: 2.3 microns, specific surface: 0.61 m ² / g;

b) average particle size: 18.5 microns, particle size in a fine fraction, which accounts for 10%: 2.2 microns, specific surface: 0.83 m ² / g;

c) average particle size: 21.6 microns, particle size in a fine fraction, which accounts for 10%: 2.5 microns, specific surface: 0.59 m ² / g;

d) average particle size: 16.0 microns, particle size in a fine fraction, which accounts for 10%: 2.0 microns, specific surface area: 0.79 m ² / g.

- 10 010588

1b

In examples 25-36 below, lactose monohydrate (200M) is used as an auxiliary substance presented as larger particles. As such, you can use, for example, a product manufactured by the company ΌΜν 1p1sgpa1yupa1. located at: 5460 Us§11s1. ΝΣ, under the trade name Ryagta Yuse 200Μ. The average particle size of this lactose is about 30 to 35 microns. The 200M lactose used in the examples has, for example, an average particle size of 31 microns with a fine particle size of 10%, 3.2 microns or has an average particle size of 34 microns with a particle size of fine fraction, which accounts for 10%, 3.5 microns.

In examples 25-36 below, lactose monohydrate with an average particle size of 3-4 microns is used as an auxiliary substance, presented in the form of particles of a smaller size. It can be obtained by conventional methods (micronization) from commercially available lactose monohydrate, for example, from the above lactose 200M. The micronized lactose used in the examples has, for example, an average particle size of 3.7 μm, with a fine particle size of 10%, 1.1 μm, or an average particle size of 3.2 μm , when the particle size in the fine fraction, which accounts for 10%, 1.0 microns.

II) Preparation of the salmeterol xinafoate of the invention g of salmeterol in the form of the free base and 9.1 g of 1-hydroxy-2-naphthoic acid are suspended in 260 ml of absolute ethanol and 260 ml of tert-butyl methyl ether. The resulting suspension is heated to 55-56 ° C and stirred until a clear solution is formed. This solution is then filtered and the filter washed with 30 ml of absolute ethanol and 30 ml of tert-butyl methyl ether. The filtrate is cooled to 38 ° C. and several crystals of salmeterol xinafoate are introduced as a seed. The solution is stirred for 1 h at 34-37 ° C, which is accompanied by the onset of crystallization. Then the suspension is cooled to 1-3 ° C and stirred at this temperature for about 30 minutes. The precipitate was suction filtered and washed with 20 ml of ethanol and 120 ml of tert-butyl methyl ether. The resulting solid was dried at 45 ° C. under nitrogen. Yield: 26 g (89.5%).

The crystalline salmeterol xinafoate obtained in this way has a volume after compaction of 0.27 g / cm ³ .

III) Micronization of Salmeterol Xinafoate

The salmeterol xinafoate obtained by the method described above is micronized in a pneumatic jet mill of type MS HETMESH 50 from kfyatt, located at νία δοΙΙο Βίδίο 42 a / s, 6828-Ba1egpa, 8ο1ι \\ Όίζ. When using nitrogen as a working gas, grinding is carried out, for example, with the following parameters:

operating pressure: 7.5 bar, feed pressure: 8.0 bar, feed (crystalline salmeterol xinafoate), respectively, flow rate: 40 g / min.

Thus obtained micronized xinafo salmeterol has a volume after compaction equal to 0.19 g / cm ³ .

IV) Micronization of crystalline tiotropium bromide monohydrate

Obtained according to XVO 02/30928, crystalline tiotropium bromide monohydrate is micronized in a pneumatic jet mill, which is used as a 2-inch micron colloid mill equipped with a working ring with a 0.8 mm hole, 81iPeuap1 Le., Located at 348 CPSU! 81teee1, Will sing, ΜΑ 02239, I8A. When using nitrogen as a working gas, grinding is carried out, for example, with the following parameters:

working pressure: 5.5 bar, feed pressure: 5.5 bar, feed (crystalline monohydrate), respectively, flow rate: 19 g / min.

The resulting milled material is then distributed on baking sheets with a layer of a thickness of about 1 cm and kept for 24-24.5 hours in an atmosphere with a temperature of 25-30 ° C and a relative humidity of 70-80%.

Measurement methods

I) X-ray analysis of salmeterol xinafoate

Measuring equipment and tuning parameters

To obtain an X-ray powder diffractogram according to the invention, a Vgikeg Ό8 Abuapsebe diffractometer was used, equipped with a position-sensitive detector (optical radiation detector) and a copper anode as an X-ray source (Κ _α copper radiation, λ = 1.5418 A, 40 kV, 40 mA) .

- 11 010588

The X-ray powder diffraction pattern obtained by X-ray diffraction analysis of salmeterol xinafoate used in the powder formulations of the invention is shown in FIG. 1. The data obtained as a result of this spectroscopic analysis are summarized in the table below. one.

Table 1. The intensity values (normalized) of x-ray diffraction maxima (reflexes)

20 [°] b [A] 1/1 ₀ [%] 4.10 21.5 one hundred 8.27 10.7 4 10.51 8.41 12 10.86 8.14 6 11.71 7.55 3 12.68 6.98 5 12.98 6.82 5 13.54 6.54 4 13.81 6.41 5 14.19 6.23 3 14.69 6.03 2 15,59 5.68 3 17.23 5.14 eighteen 17.73 5.00 3 18.69 4.74 nine 19.47 4,56 4 20.40 4.35 eleven 21.24 4.18 4 22.14 4.01 sixteen 23.24 3.82 3 23.77 3.74 4 24.50 3.63 22 25.93 3.43 4 26.23 3.40 3 27.34 3.26 3 28.26 3.16 3 28.70 s and 3 29.80 3.00 3 31.21 2.86 4 33.08 2.71 3 35.76 2,51 3

In the above table, 2θ [°] indicates the diffraction angle in degrees, and b [A] indicates the interplanar spacing in the crystal lattice in angstroms.

II) Determination of particle size distribution of micronized tiotropium bromide monohydrate

Measuring equipment and tuning parameters

They work with the equipment in accordance with the operating instructions developed by the manufacturer.

- 12 010588

Measuring device: ZutraTes laser diffraction spectrometer type NEOZ (determination of particle size distribution by Fraunhofer diffraction) Dispersant: ΚΟΌΟ8 type dispersant for dry dispersion with suction filter, ZutraTes company

Sample weight: 200 ± 150 mg

Product feed: νίΒη type vibratory chute, ZutraTes company

Vibration channel vibration frequency: increasing to 100%

Duration of sample supply: 15-25 s (with a sample weight of 200 mg)

Focal length: 100 mm (measuring range from 0.9 to 175 microns)

Duration of measurements / exposure time; about 15 s (with a sample weight of 200 mg)

Cycle Duration: 20 ms

Start / stop at: 1% on channel 28

Dispersing gas: compressed air

Pressure: 3 bar

Vacuum: maximum

Processing mode: ΗΚΕϋ (high-resolution laser diffraction) Sample preparation / product supply

Approximately 200 mg of analyte is poured onto a playing card. The edge of another playing card is crushed by all relatively large agglomerates. Then the powder is distributed in an even thin layer along the front half of the vibratory groove (starting from a distance of about 1 cm from the front edge). After the start of measurements, the vibration frequency of the vibratory gutter is changed in such a way as to ensure a continuous supply of the sample. However, to achieve the required degree of dispersion, the amount of product should not be too large.

III) Determination of the particle size distribution of lactose

Measuring equipment and tuning parameters

They work with the equipment in accordance with the operating instructions developed by the manufacturer.

Measuring device:

Dispersant:

Sample Weight:

ут.Ο5 type laser diffraction spectrometer, ZutraTes company (determination of particle size distribution by Fraunhofer diffraction) type K.СУО5 dispersant for dry dispersion with a suction filter, ZutraTes company

2001100 mg

Product Feeding:

Vibration frequency of the vibratory gutter:

Focal length:

Duration of measurements / exposure time:

Cycle time:

Start / stop at:

Dispersing gas:

Pressure:

Underpressure:

Processing Mode:

vibratory chute type U1BP, ZutraTes company with an increase of up to 100%

200 mm (measuring range 1.8 to 350 μm) approx. 10 s (with a sample weight of 200 mg) ms

1% per channel 28 bar maximum compressed air

NKJO

- 13 010588

Sample Preparation / Product Delivery

Approximately 200 mg of analyte is poured onto a playing card. The edge of another playing card is crushed by all relatively large agglomerates. Then the powder is placed on a vibratory gutter.

The distance between the vibratory chute and the suction filter is set to 1.2-1.4 mm. After the start of measurements, the vibration frequency of the vibratory gutter is changed as continuously as possible up to 100% at the end of the measurement process.

IV) Determination of the specific surface of micronized thiotropium bromide monohydrate (1-point BET method)

The principle of the measurement method

To determine the specific surface, a powder sample is kept in the atmosphere from a mixture of nitrogen with helium at various pressure values. As a result of sample cooling, nitrogen molecules condense on the surface of the particles. The amount of condensed nitrogen is determined by the change in the thermal conductivity of the mixture of nitrogen with helium, and the surface area of the sample is calculated based on the surface area required for nitrogen condensation. Based on this value and the weighted amount of the sample, its specific surface area is calculated.

Measuring equipment and tuning parameters

Measuring instrument: Mopozog, firm

Heater: Mopoek (og, company Oyagyashote

Analytical and dry gas: nitrogen (5.0) / helium (4.6) at a ratio of 70:30, company

Mevzeg

Adsorbate:

Refrigerant:

Measuring cell:

Calibration Syringe:

Analytical balance:

nitrogen, 30% helium liquid nitrogen with a capillary tube, company XV. RaZssy

OTN & Co. KO

1000 μl, firm Ргес18юп 8ашр1ш§ Comp.

K. 160 R, company 8a1opiz

Specific Surface Calculation

The measured values are displayed on the indicator of the measuring device in [m ² ] and are usually converted to [cm ² / g] in terms of a sample (dry matter mass) according to the following formula:

_And _ IZh10000 ^t St. where

And _beats denotes the specific surface in [cm ² / g],

FROM means the measured value in [m ² ], t _St. denotes the mass of dry matter in [g],

10000 is the conversion factor in [cm ² / m ² ].

V) Determination of the heat of dissolution (enthalpy of dissolution) E _with lactose

The enthalpy of dissolution is determined using a dissolution calorimeter of the type 2225 Rhasezop 8o1yop Ca1opte1eg of the company T11egtote1ps. The heat of dissolution is calculated on the basis of the temperature change that occurs as a result of the dissolution process and on the basis of the temperature change calculated on the basis of the baseline due to the characteristics of the system. Before and after opening the ampoules, an electrical calibration is performed using the built-in resistance heating element of exactly known power. At the same time, a certain amount of heat is given into the system over a strictly specified period of time, and a temperature jump is measured.

- 14 010588

Measuring equipment and tuning parameters

Dissolution Calorimeter: 2225 Rgsshop δοϊιιίίοη Ca1opte1eg, firm TIegtote (ps Reaction cell: 100 ml Thermistor Resistance: 30.0 kOhm (at 25 ° C) Mixer rotation speed: 500 rpm Thermostat: thermostat from device 2277 Tiegta1 Asyunu ΜοηϊίΟΓ TAM, Tiegottates firm Temperature: 25 + 0.0001 ° C (within 24 hours) Analytical ampoules: breakable volume ampoules 1 ml, company Tiegtote1ps Seal: silicone corks and beeswax, Tiegottates company Hitch: 40 to 50 mg Solvent: chemically pure water Solvent Volume: 100 ml Bath temperature: 25 ° C Temperature Resolution: high Initial temperature: temperature correction -40 mK (± 10 mK) Interface: 2280-002 TAM assensogu payegase, 50 Hz, firm Tekpposheyls

Software: 8о1Са1, version 1.1, for the operating system

Processing: automatic processing according to the choice in the menu item ’ΌΑΕΟυΣΑΤΙΟΝ / ΑΝΑΕΥδΕ ΕΧΡΕΚ.ΙΜΕΝΤ (dynamics of the baseline, calibration after opening the ampoule)

Electrical calibration

Electrical calibration is performed during the measurement process once before and once after opening the ampoule. To process the measurement results, calibration is used after opening the ampoule.

Heat Amount: 2.5 J

Power Consumption: 500 mW

Duration of heating: Yus

Duration of baseline: 5 min (before and after heating)

Obtaining proposed in the invention powder preparations

To obtain inhalation powders, you can use, for example, the following machines and apparatus.

Mixer, or powder mixer, for example: 2 L turbo mixer, type 2C, manufacturer: \ νί11ν A. VasNoGsp AS, located at SN-4500, Vaeg1.

Manual sieve: mesh size 0.135 mm.

It is possible to pack inhaled powders containing tiotropium into empty capsules for inhalation manually or in an automated mode. You can use the following equipment.

Capsule filling machine: MS2, type C100, manufacturer: MS2 8.G.1. Company, located at: 1-40065 P1ap άί Masta άί P1apogo (VO), Pa1u.

- 15 010588

Example 1. Powder mixture

To obtain a powder mixture, 295.43 g of excipient, 0.61 g of micronized tiotropium bromide monohydrate and 3.96 micronized salmeterol xinafoate are used. In an inhalation powder of 300 g obtained from these quantities of excipients and active substances, 0.2% of the active substance is 1%, and 2-1.32% of the active substance.

About 40-45 g of excipient are poured into a suitable mixer through a manual sieve with a mesh size of 0.315 mm. Then, tiotropium bromide monohydrate 1 is sieved in succession in layers of approximately 90-110 mg each and the excipient in portions of approximately 4045 g. The excipient and active ingredient 1 are loaded into the mixer with 7th or 6th layers respectively. The components of the inhalation powder thus sieved are then mixed in a mixer (stirring at 900 rpm). The final mixture obtained in this way is sieved twice more through a hand sieve and after each sieving is mixed (stirring at 900 rpm).

Then, about 40-45 g of the powder mixture obtained by the above-described method is added to a suitable mixer through a manual sieve with a mesh size of 0.315 mm. the active substance 1 powder mixture in portions of approximately 40-45 g. The powder mixture containing the active substance 1 and the active substance 2 are loaded into the mixer with 7, respectively, 6 layers. The components of the inhalation powder thus sieved are then mixed in a mixer (stirring at 900 rpm). The final mixture obtained in this way is sieved twice more through a hand sieve and after each sieving is mixed (stirring at 900 rpm).

By the method described in example 1 or analogously, inhalation powders can be obtained, after packaging of which into the corresponding polymer capsules, for example, the following capsules for inhalation are prepared.

Example 2

tiotropium bromide monohydrate 0.0113 mg salmeterol xinafoate 0.0726 mg lactose monohydrate 5.4161 mg plastic capsules _________ 100.0 mg

Total 105.5 mg

- 16 010588

Example 3

tiotropium bromide monohydrate 0.0113 mg salmeterol xinafoate 0.1450 mg lactose monohydrate 5.3437 mg plastic capsules 100.0 mg Total 105.5 mg Example 4 tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.1450 mg lactose monohydrate 5.3325 mg plastic capsules 100.0 mg Total 105.5 mg Example 5 tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.2180 mg lactose monohydrate 10.7595 mg plastic capsules 100.0 mg Total 111.0 mg Example 6 tiotropium bromide monohydrate 0.0056 mg salmeterol xinafoate 0.0726 mg lactose monohydrate 5.4218 mg plastic capsules 100.0 mg Total 105.5 mg Example 7 tiotropium bromide monohydrate 0.0056 mg salmeterol xinafoate 0.1090 mg lactose monohydrate 5.3854 mg plastic capsules 100.0 mg Total 105.5 mg

- 17 010588

Prnmer 8 tiotropium bromide monohydrate salmeterol xinafoate 0.0125 mg 0.0363 mg lactose monohydrate 9.9512 mg plastic capsules 100.0 mg Total 110.0 mg

Example 9 tiotropium bromide monohydrate salmeterol xinafoate 0.0125 mg 0.0435 mg lactose monohydrate 9.9440 mg plastic capsules 100.0 mg Total 110.0 mg

Example 10 tiotropium bromide monohydrate 0.0125 mg salmeterol xinafoate 0.0508 mg lactose monohydrate 9.9367 mg polyethylene capsules _________ 100.0 mg

Total 110.0 mg

Example 11 tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.0435 mg lactose monohydrate 9.9340 mg polyethylene capsules _________ 100.0 mg

Total 110.0 mg

Example 12 tiotropium bromide monohydrate 0.0063 mg salmeterol xinafoate 0.0435 mg lactose monohydrate 9.9502 mg plastic capsules _________ 100.0 mg

Total 110.0 mg

Example 13. Powder mixture

To obtain a powder mixture, 295.43 g of excipient, 0.61 g of micronized tiotropium bromide monohydrate and 3.96 micronized salmeterol xinafoate are used. In an inhalation powder of 300 g obtained from these quantities of excipients and active substances, 0.2% of the active substance is 1%, and 2-1.32% of the active substance.

About 20-23 g of excipient are poured into a suitable mixer through a manual sieve with a mesh size of 0.315 mm. Then, tiotropium bromide monohydrate 1 is sieved alternately in layers of approximately 90-110 mg in portions of the mixer, approximately 20-23 g portions of the excipient and salmeterol xinafoate in approximately 650-670 mg portions. This process is repeated 6 times. Finally, the last portion of the auxiliary substance is loaded into the mixer in an amount of about 20-23 g. The components of the inhalation powder sifted in this way (6 layers of active substances 1

- 18 010588 and 2, as well as 13 layers of excipient) are then mixed in a mixer (mixing at 900 rpm). The final mixture obtained in this way is sieved twice more through a hand sieve and after each sieving is mixed (stirring at 900 rpm).

By the method described in example 13 or analogously, inhalation powders can be obtained, after packaging of which into the corresponding polymer capsules, for example, the capsules for inhalation described below are obtained.

Example 14 tiotropium bromide monohydrate 0.0113 mg salmeterol xinafoate 0.0726 mg lactose monohydrate 5.4161 mg plastic capsules 100.0 mg Total 105.5 mg Example 15 tiotropium bromide monohydrate 0.0113 mg salmeterol xinafoate 0.1450 mg lactose monohydrate 5.3437 mg plastic capsules 100.0 mg

Total 105.5 mg

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Example 16

tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.1450 mg lactose monohydrate 5.3325 mg plastic capsules 100.0 mg Total 105.5 mg Example 17 tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.2180 mg lactose monohydrate 10.7595 mg plastic capsules 100.0 mg Total 111.0 mg Example 18 tiotropium bromide monohydrate 0.0056 mg salmeterol xinafoate 0.0726 mg lactose monohydrate 5.4218 mg plastic capsules 100.0 mg Total 105.5 mg Example 19 tiotropium bromide monohydrate 0.0056 mg salmeterol xinafoate 0.1090 mg lactose monohydrate 5.3854 mg plastic capsules 100.0 mg Total 105.5 mg Example 20 tiotropium bromide monohydrate 0.0125 mg salmeterol xinafoate 0.0363 mg lactose monohydrate 9.9512 mg plastic capsules 100.0 mg Total 110.0 mg

- 20 010588

Example 21 tiotropium bromide monohydrate 0.0125 mg salmeterol xinafoate 0.0435 mg lactose monohydrate 9.9440 mg polyethylene capsules _________ 100.0 mg

Total 110.0 mg

Example 22 tiotropium bromide monohydrate 0.0125 mg salmeterol xinafoate 0.0508 mg lactose monohydrate 9.9367 mg polyethylene capsules _________ 100.0 mg

110.0 mg total

Example 23 tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.0435 mg lactose monohydrate 9.9340 mg polyethylene capsules _________ 100.0 mg

Total 110.0 mg

Example 24 tiotropium bromide monohydrate 0.0063 mg salmeterol xinafoate 0.0435 mg lactose monohydrate 9.9502 mg plastic capsules _________ 100.0 mg

Total 110.0 mg

Example 25. Powder mixture

To obtain a powder mixture, 295.43 g of excipient, 0.61 g of micronized tiotropium bromide monohydrate and 3.96 micronized salmeterol xinafoate are used. In an inhalation powder of 300 g obtained from these quantities of excipients and active substances, 0.2% of the active substance is 1%, and 2-1.32% of the active substance.

As an auxiliary substance, a mixture of 280.43 g of the lactose monohydrate indicated in clause 16 above and 15 g of lactose monohydrate specified in clause 16 above with an average particle size of about 3-4 μm is used. In the drug obtained from these components, the fraction of the excipient with a smaller average particle size accounts for 5%.

About 29-33 g of excipient, presented in the form of particles of a larger size, is poured into a suitable mixer through a manual sieve with a mesh size of 0.315 mm. Then about 1.5-2 g of excipient, presented in the form of particles of smaller size, are sieved in a mixer in layers. This process is repeated 8 times. Finally, the last portion of the excipient, presented in the form of larger particles, in an amount of about 2023, is loaded into the mixer. The components thus sifted (9 layers of the excipient, presented in the form of larger particles, and 8 layers of the micronized excipient) are then mixed into mixer (stirring at 900 rpm).

Thus obtained mixture of excipients is used in the preparation of the final mixture according to the procedure described in example 13. The components of the inhalation powder sifted in this way (6 layers of active ingredients 1 and 2, as well as 13 layers of a mixture of excipients) are then mixed in a mixer (stirring at 900 rpm). The final mixture obtained in this way is sieved twice more through a hand sieve and after each sieving is mixed (stirring at 900 rpm).

- 21 010588

By the method described in example 25 or similarly, inhalation powders can be obtained, after packaging of which into the corresponding polymer capsules, for example, the following capsules for inhalation are prepared. In the examples below, the designation lactose monohydrate (3-4 μm) corresponds to micronized lactose, and the designation lactose monohydrate corresponds to lactose, presented in the form of larger particles.

Example 26 tiotropium bromide monohydrate 0.0113 mg salmeterol xinafoate 0.0726 mg lactose monohydrate (3-4 microns) 0.2750 mg lactose monohydrate 5.1411 mg plastic capsules 100.0 mg

Total 105.5 mg Example 27 tiotropium bromide monohydrate 0.0113 mg salmeterol xinafoate 0.1450 mg lactose monohydrate (3-4 microns) 0.2750 mg lactose monohydrate 5.0687 mg plastic capsules 100.0 mg

Total 105.5 mg Example 28 tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.1450 mg lactose monohydrate (3-4 microns) 0.2750 mg lactose monohydrate 5.0575 mg plastic capsules 100.0 mg Total 105.5 mg Example 29 tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.2180 mg lactose monohydrate (3-4 microns) 0.5500 mg lactose monohydrate 10.2095 mg plastic capsules 100.0 mg Total 111.0 mg

- 22 010588

Example 30

tiotropium bromide monohydrate salmeterol xinafoate lactose monohydrate (3-4 microns) 0.0056 mg 0.0726 mg 0.2750 mg lactose monohydrate 5.1468 mg plastic capsules 100.0 mg Total Example 31 lactose monohydrate tiotropium bromide xinafoate salmeterol monohydrate (3-4 microns) 105.5 mg 0.0056 mg 0.1090 mg 0.2750 mg lactose monohydrate 5.1104 mg plastic capsules 100.0 mg Total 105.5 mg Example 32 tiotropium bromide monohydrate salmeterol xinafoate lactose monohydrate (3-4 μm) 0.0125 mg 0.0363 mg 0.5000 mg lactose monohydrate 9.4512 mg plastic capsules 100.0 mg Total Example 33 lactose monohydrate tiotropium bromide xinafoate salmeterol monohydrate (3-4 microns) 110.0 mg 0.0125 mg 0.0435 mg 0.5000 mg lactose monohydrate 9.4440 mg plastic capsules 100.0 mg Total 110.0 mg

- 23 010588

Example 34

tiotropium bromide monohydrate 0.0125 mg salmeterol xinafoate 0.0508 mg lactose monohydrate (3-4 microns) 0.5000 mg lactose monohydrate 9.4367 mg plastic capsules 100.0 mg Total 110.0 mg Example 35 tiotropium bromide monohydrate 0.0225 mg salmeterol xinafoate 0.0435 mg lactose monohydrate (3-4 microns) 0.5000 mg lactose monohydrate 9.4340 mg plastic capsules 100.0 mg Total 110.0 mg Example 36 tiotropium bromide monohydrate 0.0063 mg salmeterol xinafoate 0.0435 mg lactose monohydrate (3-4 microns) 0.5000 mg lactose monohydrate 9.4502 mg plastic capsules 100.0 mg Total 110.0 mg

CLAIM

Claims (12)

CLAIM 1. A capsule containing an inhalation powder containing tiotropium 1 'and salmeterol xinafoate 2, where 2 is characterized by a melting point of about 124 ° C, mixed with a physiologically harmless excipient, while the capsule contains from 8 to 12 mg of inhalation powder. 2. The capsule according to claim 1, characterized in that tiotropium 1 'is present in combination with a counterion selected from the group consisting of chloride, bromide, iodide, methanesulfonate and paratoluene sulfonate. 3. The capsule according to claim 1 or 2, despite the fact that the x-ray powder diffractogram of the used salmeterol xinafoate 2 contains, among others, the following characteristic values of b: 21.5A, 8.41 A, 5.14 A, 4.35 A, 4 , 01 A and 3.63 A. 4. The capsule according to claims 1, 2 or 3, while the volume of salmeterol 2 xinafoate used after compaction is at least 0.134 g / cm ³ , preferably at least 0.14 g / cm ³ . 5. The capsule according to one of claims 1 to 4, characterized in that the content of salmeterol 2 xinafoate is from 0.002 to 15%. 6. The capsule according to one of claims 1 to 5, characterized in that the content of tiotropium 1 'is from 0.001 to 5%. 7. The capsule according to one of claims 1 to 6, characterized in that tiotropium 1 'and salmeterol xinafoate 2 are jointly contained in dosages from 5 to 5000 μg. 8. The capsule according to one of claims 1 to 7, characterized in that the physiologically harmless excipient is selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides, polyhydric alcohols and salts. 9. The capsule according to one of claims 1 to 8, characterized in that the physiologically harmless excipient is selected from the group comprising glucose, arabinose, lactose, sucrose, maltose and trehalose, optionally in the form of their hydrates. 10. The capsule according to one of claims 1 to 9, characterized in that it contains 10 mg of inhalation powder. 11. Inhalation kit, consisting of a capsule according to one of claims 1 to 10 and an inhaler that can be used to administer inhaled powders from the capsules containing them. 12. The inhalation kit according to claim 11, characterized in that the inhaler has a housing (1) with two windows (2), a plate partition (3), in which air inlets are provided and - 24 010588 which is equipped with a mesh (3) held in assembled condition by a corresponding fastening element (4), a chamber (6) connected to the plate partition (3) for the capsule with an inhalation composition, a push button (9) is provided on the side of which (the chamber), equipped with two polished needles (7) and made movable against the force of the spring (8), the mouthpiece (12), which is hinged with the possibility of rotation around the axis connecting it to the body (1), plate partition (3) and cap (11), and through holes (13) for air passage, pre designed to regulate aerohydrodynamic drag.