BG65655B1 - Inhalation capsules - Google Patents

Abstract

The invention relates to inhaled capsules (inhalants) of specific materials for capsules with reduced moisture content. They contain the active substance tiotropium in the form of powder formulations and have increased stability.

Description

Technical field

The invention relates to inhaler capsules (inhalers) made from specific materials for capsules with reduced moisture content, which are used in the treatment of respiratory diseases.

BACKGROUND OF THE INVENTION

Tiotropium bromide is known from EP 418 716 A1 and has the following chemical structure:

H ₃ C +, CH ₃

Tiotropium bromide is a highly active, long-acting anticholinergic agent that can be used in the treatment of respiratory diseases and in particular in COPD (chronic obstructive pulmonary disease) and asthma. Tiotropium means free ammonium cation.

For the treatment of the aforementioned diseases, inhalation administration of the active substance is suggested. Of particular importance is not only the inhalation use of bronchodilator compounds in the form of dosing aerosols and solutions, but also the inhalation use of the powder forms of these drugs.

For active substances having a particularly high activity, only a small amount of the active substance is needed in a single dose to achieve the desired therapeutic effect. In such cases, the preparation of the inhalable powder requires dilution of the active substance with suitable excipients. When using high-activity active substances to ensure the repeatability of an always uniform portion of administration, it is particularly important that the drug is in a form having a high degree of stability. If this high degree of stability is not achieved, a uniform dosage of the active substance cannot be guaranteed.

It is an object of the invention to provide an inhalable capsule with inhalable powder containing tiotropium, in order to provide a sufficient degree of stability of the active substance.

It is a further object of the invention to provide an inhalable capsule with stability ensuring the release of the active substance with high dosage accuracy (both with respect to the amount of active substance introduced by the manufacturer and the powder mixture into one inhaler capsule, and with respect to the amount of active substance, spent for injection into the lungs by inhalation). Furthermore, it is an object of the present invention to further provide a capsule in which the capability of emptying the capsule is well achieved with the administration of the active substance.

It is a further object of the present invention to provide inhalable capsules with high stability and minimal brittleness, but with an easy puncture capability to ensure the smooth use of the capsules when inserted into a suitable applicator.

SUMMARY OF THE INVENTION

It was found that the tasks mentioned in the introduction were solved by the inhalation capsules (inhalers) described below.

Inhalation capsules (inhalers) according to the invention pertain to capsules containing tiotropium as a powder for inhalation in admixture with a physiologically harmless excipient and characterized in that the material from which the capsule is made has a reduced moisture content.

The concept of reduced moisture content is defined within the scope of the present invention as equivalent to the TEWS designation of less than 15%.

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The term TEWS moisture within the scope of the present invention refers to moisture that can be determined by a moisture meter MW 2200. The measurement method is an indirect method for determining water. The activities related to the water content (microwave absorption from the water contained in the product) are measured and the value is referred to as the microwave value. Calibration of the instrument for which calibration samples are used is required to determine the water content by weight. The resulting calibration curve is used to recalculate the measurements made with the same instrument. The moisture value is given in% and recorded.

For example, a halogen dehydrator may be used to calibrate the IEWS device, as was done in the context of the present invention. Due to the calibration of a TEWS device with a halogen dehydrator within the present invention, the term TEWS moisture is equivalent to the term halogen dehydrator. For example, within the scope of the present invention, 15% TEWS moisture corresponds to 15% halide dehydrator. While the TEWS device is a functionally conditioned relative method for determining water, the halogen dehydrator gives absolute values for the moisture content of the capsule. In the halogen dehydrator, the water content is determined by weight loss. The capsules are heated, resulting in loss of water. The drying of the capsules is continued to constant weight, after which the weight is read. The difference in mass of the initial and final weights (in grams) represents the water content and can be recalculated as a percentage by weight. When measuring water content, the IEWS compares the capsule measurement curves with the calibration curves. These calibration curves are prepared by capsules of known water content, the absolute value of the water content being previously determined by the halogen dehydrator method. Thus, the halogen dehydrator method establishes the relationship between the relative TEWS method and the absolute water content.

Preferred inhalation capsules according to the invention have TEWS moisture or halide dehydration moisture of less than 12%, particularly preferred? 10%.

Capsule material within the scope of the present invention is understood to mean the material from which the inhaler capsule shell is made. The capsule material is selected according to the invention from a group consisting of gelatin, cellulose derivatives, starch, starch derivatives, chitosan and synthetic plastics.

If gelatin is used as a capsule material, it may be mixed with other additives selected from the group consisting of polyethylene glycol (PEG), preferably PEG 3350, glycerol, sorbitol, propylene glycol, PEO-PPRO block copolymers (polyethylene oxide-polypropylene oxide- block polymers) and other polyalcohols and polyethers. Particularly preferred within the present invention is gelatin in admixture with PEG, preferably PEG 3350. The shell of a gelatin capsule according to the invention particularly preferably contains PEG in an amount of 1 -10% (weight%), preferably 3-8%. Particularly preferred gelatin capsules contain PEG in an amount of 46%, with a PEG content of about 5% according to the invention being most preferred.

When gelatin-containing materials are used, is it preferable that the capsules according to the invention have a TEWS or halogen dehydration moisture of less than 12%, particularly preferred? 10%.

Where cellulose derivatives are used as capsule material, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose and hydroxyethylcellulose are preferred. Hydroxypropyl methylcellulose (HPMC) is particularly preferred in this case, HPMC 2910 is particularly preferred. When using cellulose derivatives as a capsule material, it is preferable that the degree of TEWS moisture or halide dehydration is less than 8% , particularly preferably less than 5%. Most preferably, the inhaler capsules of cellulose derivatives are dried to less than 4% TEWS or halide dehydrator moisture, especially preferably less than 2%, prior to filling with inhalable powders containing tiotropium.

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When synthetic plastics are used as the capsule material, they are selected according to the invention from the group consisting of polyethylene, polycarbonate, polyester, polypropylene and polyethylene terephthalate. Particularly preferred synthetic plastic materials for inhaler capsules according to the invention are polyethylene, polycarbonate or polyethylene terephthalate. When using polyethylene as one of the particularly preferred capsule materials according to the invention, polyethylene having a density between 900 and 1000 kg / m ³ , preferably 940 - 980 kg / m ³ , especially preferably 960 kg / m ³ (high density polyethylene, is preferred) - higtdensity Polyethylen). In the case of synthetic capsule materials, the degree of TEWS or halide dehydration is preferably less than 3%, possibly less than 1%.

After the empty capsules are made in one of the above embodiments, the inhaler capsules according to the invention are filled with inhalation powder containing tiotropium. This filling can be made by methods known in the art. Empty capsules intended for filling may also be manufactured by methods known in the art. For example, methods of production such as the immersion method, the pressurized blowing method, the injection molding method, the extrusion method and the immersion and drawing method may be mentioned as possible production methods.

Since the capsules, prior to filling with the inhalable powder containing the active substance, are not sufficiently reduced in moisture as a result of their storage or production, it is important that they be dried according to the invention. Drying is continued until a humidity level corresponding to the specification according to the invention of TEWS or halogen dehydration moisture of up to 15% is reached.

In the context of the present invention, the name of the inhaler capsule is unique to the name of the inhaler.

Another aspect of the present invention relates to the use of capsules characterized by TEWS or halogen dehydration moisture of less than 15% and made from the aforementioned inhaler preparation materials (inhaler capsules) containing inhalation powder containing tiotropium. In the context of the present invention, the capsule name refers to an empty, inhalable, powder-free inhalation capsule.

According to the invention, inhaler capsules containing an inhalable powder having a tiotropium content of 0.001 to 2% are preferred. Particularly preferred are inhaler capsules containing an inhalable powder of 0.04 to 0.8%, preferably 0.08 to 0.64%, especially preferably 0.16 to 0.4% tiotropium. The percentages given in the context of the present invention regarding the content of tiotropium correspond to weight percentages relative to the total amount of inhalable powder.

Tiotropium means free ammonium cation. As counterion (anion) are meant chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methyl sulfate. Of these anions, the bromide is preferred. Accordingly, the present invention preferably relates to inhalers containing inhalable powders having a niothopropium bromide content of 0.0012-2.41%.

Of particular interest according to the invention are inhalation powders containing tiotropium bromide from 0.048 to 0.96%, preferably from 0.096 to 0.77%, especially preferably from 0.19 to 0.48%.

The inhalable powder contained in the invention can contain the tiotropium bromide in the form of its hydrates according to the invention. The crystalline monohydrate of tiotropium bromide is particularly preferred. The present invention relates accordingly to inhalers containing inhalable powders having a crystalline monohydrate content of tiotropium bromide between 0.0012 and 2.5%. Inhalants containing inhalable powders of 0.05 and 1% crystalline monohydrate of tiotropium bromide, preferably 0.1 to 0.8%, particularly preferably 0.2 to 0.5%, are of particular interest in the invention.

In the context of the present invention, yes

65655 B1 is intended to mean that the term monohydrate tiotropium bromide refers predominantly to that crystalline tiotropium bromide monohydrate which is prepared in a synthetic manner, explained in detail in the experimental part.

The inhalation powders used in the inhaler capsules (inhalers) according to the invention contain, together with the active substance, at least one additional excipient. It may consist of a fraction of the excipient (eg, 15-80 µm) homogeneous to the average particle size, or optionally a mixture of coarser excipients with an average particle size of 15-80 µm and a finer excipient with an average particle size of 1 to 9 micrometer. If mixtures of dirt and finer excipients are used, the proportion of the finer excipient relative to the total excipient amount is preferably from 1 to 20%.

When the inhaler capsules according to the invention contain a mixture of coarser and thinner fractions of the excipient, it is preferable that the coarse excipient has an average particle size of 17 to 50 µm, particularly preferably 20 to 30 µm, and the nefarious excipient is with a particle size of from 2 to 8 microns, especially preferably from 3 to 7 microns. Medium particle size means the 50% value of the distributed volume measured by a laser diffractometer by the dry dispersion method. Inhalation powders are preferred for the preparation of inhalants according to the invention, in which the fraction of the finer excipient over the total amount of excipient is 3 to 15%, especially preferably 5 to 10%. Percentage data within the present invention always refer to weight percentages.

When a mixture is mentioned within the scope of the present invention, it is always understood to mean a mixture resulting from the mixing of clearly defined previously components. Accordingly, for example, a mixture of excipients with submersibles and finer ingredients means those mixtures that are obtained by mixing one ingredient of a coarser excipient with one finer excipient ingredient.

The constituents of the excipient may be of the same chemical or chemically different substance, preferably inhalation powders in which the constituents of the excipient are of the same chemical compound.

If a mixture is used as an excipient consisting of a coarser and finer fraction of the excipient, then these fractions may also be chemically identical or chemically different substances, inhalation powders in which the coarser and the finer constituent of the excipient is the same compound.

As physiologically harmless excipients that may be used in the inhalation powders in the presentation of the inhalants according to the present invention, for example, monosaccharides (e.g., glucose or arabinose), disaccharides (e.g., lactose, sucrose, maltose), oligosaccharides may be mentioned. eg dextrans), polyalcohols (eg sorbitol, mannitol, xylitol), salts (eg sodium chloride, calcium carbonate) or mixtures of these excipients. Preferably, monosaccharides and disaccharides are used, and lactose or glucose is preferably, but not exclusively, used in the form of their hydrates. Particularly preferred according to the invention is lactose, most preferably the use of lactose monohydrate as an excipient.

The inhalation capsules according to the invention can be used, for example, by inhalers as described in WO1994 / 028958. Figure 1 shows the inhaler circuit which is particularly preferred for the use of the inhalers according to the invention. This HandiHaler for inhalation of powder medicines from inhaler capsules is characterized by a housing with two windows 2, a lid 3 with openings for air inlet, the lid being connected to the chamber 6 for the capsule. The camera has a button 9 provided with two grinded needles 7. The button moves against a spring 8. Through a shaft axis 10, the mouthpiece 12 is movably connected to the housing 1, the cover 3 and the cap (cap) 11. The chamber for the capsule is closed with a filter 5 The filter holder is firmly connected to the mouthpiece 12.

Inhalation capsules according to the invention

65655 Bl solutions are for filling quantities of 2 to 50 mg, preferably 4 to 25 mg, of inhalation powder per capsule. Thus it contains between 1.2 and 80 µm of tiotropium. In a particularly preferred amount of 4 to 6 mg capsule inhalation powder, this content is between 1.6 and 48 micrometer, preferably between 3.2 and 38.4 micrometer, especially preferably between 6.4 and 24 micrometer tiotropium for inhalation capsule. A content of about 18 [mu] m tiotropium corresponds to a tiotropium bromide content of about 21.7 [mu] m.

Therefore, inhalation capsules with a fill amount of 3 to 10 mg of inhalable powder preferably contain between 1.4 and 96.3 [mu] m of tiotropium bromide. In a preferred amount of 4 to 6 mg inhalation powder per inhaler capsule contains between 1.9 and 57.8 micrometer, preferably between 3.9 and 46.2 micrometer, especially preferably between 7.7 and 28.9 micrometer inhaler capsule tiotropium bromide. Thus, for example, the content of 21.7 micrometer of tiotropium bromide corresponds to about 22.5 micrometer of tiotropium bromide monohydrate.

Therefore, inhalation capsules with a fill amount of 3 to 10 mg of inhalable powder preferably contain between 1.5 and 100 µm of tiotropium bromide monohydrate. In a preferred amount of 4 to 6 mg inhalation powder per capsule inhaler, the tiotropium bromide monohydrate is between 2 and 60 µm, preferably between 4 and 48 µm, especially between 8 and 30 µm per inhaler capsule.

In accordance with the object of the present invention, the inhaler capsules according to the invention are characterized by a high degree of homogeneity in terms of single dose dosing accuracy. This accuracy is in the range of <8%, preferably <6%, especially preferred <4%.

Preferred inhalation powders for filling the inhaler capsules according to the invention are prepared as described below.

After weighing the starting materials in cases where the excipient is a mixture of coarser and finer ingredients, the excipient is first prepared. If an auxiliary substance is used with respect to the average particle size fraction (eg 15-80 µm), this first step is eliminated.

The inhalation powder is then obtained from the excipient, possibly a mixture of excipients and the active substance. The inhaler capsules according to the invention are dried before filling with the tiotropium-containing inhalable powder until the maximum allowable degree of TEWS or halogen dehydrator moisture according to the invention is reached. Powder-containing inhaler capsules are then prepared using art-known techniques.

In the preparation methods described below, said components are given in parts by weight as reflected in the inhalable powder compositions described above.

When mixtures of coarser and finer particles are used as excipients, the coarser and finer excipients are placed in a suitable mixing vessel. The pouring of the two ingredients is preferably through a sieve with apertures of 0.1 to 2 mm, especially preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm. The coarse excipient is poured primarily first and then the finer excipient is added. In this method of mixing, it is preferable to feed the two ingredients in portions, first feeding a portion of the coarser ingredient and then alternating the finer and coarser portion. It is particularly preferred to obtain the admixture for joint formation by alternately sieving the two constituents. Preferably, the alternate sieving of the two ingredients is 15 to 45 layers, especially preferably 20 to 40 layers. Mixing of the two excipients can occur at the time of delivery of the two ingredients. However, it is preferable to mix after the final sieving of the two ingredients.

The above step is naturally dispensed with if particle size auxiliaries are used with respect to particle size (e.g.

average particle size of 15-80 [mu] m).

The excipient, optionally the mixture of excipients, and the active substance

65655 B1 substance is placed in a suitable mixer. The active substance used has an average particle size of 0.5 to 10 micrometer, preferably 1 to 6 micrometer, especially preferably 2 to 5 micrometer. The addition of the two ingredients is preferably through a sieve with apertures of 0.1 to 2 mm, especially preferably 0.3 to 1 ppm, most preferably 0.3 to 0.6 mm. It is preferred that the active substance is introduced into the mixer first. In this preparation method, it is preferable to feed the two ingredients in portions. When using a mixture of excipients, it is especially preferred that alternating sieving give the ingredients. Preferably, the sifting in the container of the two ingredients is 25 to 65 each, especially preferably 30 to 60 layers. Mixing the excipient mixture with the active substance can take place during the administration of both ingredients. However, it is preferable that the mixing is done after the final delivery of the two ingredients. The powder mixture thus obtained may eventually be sieved once and repeatedly passed through a sieve granulator and then stirred thereafter.

In a preferred embodiment of the invention, the inhaler capsules are filled with the inhalation powder obtained by the method described above and containing tiotropium bromide, and then subjected to the drying process described below.

In the first phase (drying phase), the filled capsules are left for 0.510 h, preferably 1.5-7 h, preferably 2-5.5 h, especially preferably about 2.5-4.5 h at a temperature of about 10 -50 ° C, preferably 2040 ° C, especially preferably about 25-35 ° C and at a relative humidity (rF) of at most 30% (g. E), preferably at most 20% (g. E), especially preferably about 5-15% (g. E). In the context of the present invention, relative humidity (g. E) is understood to mean the ratio of the partial pressure of water vapor to the vapor pressure of water at the appropriate temperature. In the next second phase (equilibrium phase), the capsules are left for 0.5-10 h, preferably 1.5-7 h, preferably 2-5.5 h, especially preferably about 2.5-4.5 h at temperature from about 10-50 ° C, preferably 20-40 ° C, especially preferably about 25-35 ° C at a relative humidity of at most 35% YE, preferably at most 25% YE, especially preferably about 10-20% g. E. The cooling phase is possible, as long as the temperature at the previous technological step is higher than room temperature (ie 23 ° C). In this cooling phase, the capsules are held for 0.1-6 h, preferably about 0.5-4 h, preferably 0.75-2.5 h, especially preferably about 1-2 h, at a temperature of about 23 ° C and relative humidity not more than 35% YE, preferably at most 25% YE, especially preferably 10-20% YE In one particularly preferred embodiment, the values for the relative humidity in the equilibrium phase and the cooling is identical.

In the context of the present invention, the term active substance refers to tiotropium, which is a free ammonium cation. According to the invention, this also relates to tiotropium in the form of a salt (tiotropium salt) which contains an anion as a counterion. Useful tiotropium salts within the scope of the present invention include compounds which, in addition to tiotropium, contain as counterion (anion) chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methyl sulfate. Within the scope of the present invention, tiotropium bromide is preferred over all tiotropium salts. The reference to tiotropium bromide within the scope of the present invention always refers to all possible amorphous and crystalline modifications of tiotropium bromide. They may, for example, include solvent molecules in the crystal structure. Of all the crystalline modifications of tiotropium bromide according to the invention, those which include water (hydrates) are preferred. In the context of the present invention, it is particularly preferred to use the crystalline monohydrate of tiotropium bromide prepared in the manner detailed below. For the preparation of inhaler capsules according to the invention containing tiotropium, it is first necessary to provide tiotropium in a form suitable for pharmaceutical use. It is preferred for this purpose that the tiotropium bromide, which can be produced as described in EP 418 716 A1, is subjected to another crystallization step. According to the choice of conditions, at

65655 B1 which undergoes reaction, and various crystal modifications are obtained on the solvent. The crystalline monohydrate of tiotropium bromide has proved particularly suitable for the preparation of the inhaler capsules according to the invention.

The following examples are a broader explanation of the present invention, without limiting the scope of the invention in exemplary embodiments.

Examples of carrying out the invention

Starting materials

In the following examples, lactose monohydrate (200M) is used as an excipient. It can be supplied, for example, by DMV International, 5460 Veghel / NL under the name Pharmatose 200M.

In the following examples, lactose monohydrate (200M) is also used as a submerged excipient when the excipient is a mixture. It can, for example, be supplied by DMV International, 5460 Veghel / NL under the name Pharmatose 200M.

In the following examples, when the excipient is a mixture, lactose monohydrate (5 micro) is used as a finer excipient. It can be obtained from lactose 200M monohydrate by conventional methods (micronization). For example, lactose monohydrate 200M may be supplied by DMV International, 5460 Veghel / NL under the name Pharmatose 200M.

Preparation of crystalline tiotropium bromide monohydrate kg Tiotropium bromide was added to 25.7 kg of water in a suitable container. The mixture was heated to 80-90 ° C and stirred at constant temperature until a clear solution was obtained. Suspend the water-moistened charcoal (0.8 kg) in 4.4 kg of water, add to the solution containing tiotropium bromide and rinse with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 minutes at 80-90 ° C and then filtered through a heated filter into a preheated apparatus with a jacket temperature of 70 ° C. The filter was washed with another 8.6 kg of water. The contents of the apparatus are cooled by 3-5 ° C per minute to a temperature of 20-25 ° C. The water was further cooled to 10-15 ° C by water cooling, and crystallization was completed completely by at least one hour of stirring. The crystallizate was isolated through a suction filter, the crystalline slurry was washed with 91 cold water (10-15 ° C) and cold acetone (10-15 ° C). The crystals obtained were dried under a stream of nitrogen for more than 2 hours at 25 ° C.

Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory)

The crystalline tiotropium bromide crystalline monohydrate obtained as described above was tested by differential scanning calorimetry (DSC). The DSC diagram shows two characteristic signals. The first, relatively broad endothermic signal between 5-120 ° C is explained by the dehydration of the tiotropium bromide monohydrate to a water-free form. The second, relatively clear, endothermic maximum at 230 ± 5 ° C is related to the melting of the substance. These data were obtained with Mettler DSC 821 and interpreted with Mettler Software-Paket STAR. Data were taken at a heating rate of 10 K / min.

The crystalline monohydrate of tiotropium bromide was characterized by IR spectroscopy. Data were taken with a Nicolet FTIR spectrometer and interpreted with Nicolet Softwarepaket OMNIC, Version 3.1. The measurement was carried out with 2.5 micromol monohydrate of tiotropium bromide in 300 mg KBr.

The following table summarizes some of the important spectral bands of the IR spectrum.

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Wave number ^ cm ' ¹ ) Relative Kind of jitter 3570,3410 3105 1730 1260 1035 720 O-aryl C-H C = O epoxide C-0 ester C-OC thiophene valence oscillations valence oscillations valence oscillations valence oscillations valence oscillations skeletal oscillations

The crystalline tiotropium bromide crystalline monohydrate obtained above shows, according to crystal X-ray diffraction analysis, a simple monoclinic cell of the following dimensions a = 18.0774 A, b = 11.9711A, c = 9.9321 A, beta = 102.691 °, V - 2096.96 A ³ . These data were taken with an AFC7R-4-KpbroB diffractometer (Rigaku) using a monochromatized Honey-ray copper. Structure detection and more accurate crystal structure reading were done using direct methods (SHELXS86 program) and FMLQ refinement (TeXsan program).

The tiotropium bromide monohydrate thus obtained is micronised in a known manner to prepare the active substance in a medium particle size formulation according to the specification according to the invention.

The following describes how the average particle size of the various constituents of the formulations according to the invention can be determined.

A) Determination of fine lactose particle size

Measurement and adjustment device:

Working with the appliances followed the manufacturer's operating instructions.

Measuring device: HELOS Laser Spectrometer (Sympa Tec) Disperser: Dry material dispersant with RODOS suction funnel (Sympa Tec) Number of samples: 100 mg or more Product Submission: Oscillating Chute Vibri, Fa. Sympatec Frequency of vibration chute: 40 to 100% increasing Sample submission time: 1 to 15 s (at 100 mg) Focal length: 100 mm (measuring range: 0.9-175 microm) Measurement time: About 15 s (at 100 mg) Cycle duration: 20 ms Start / stop: 1% per channel 28 Dispersing gas: Pressurized air Pressure: 3 bar Pressurized: maximum Rating: HRLD

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Sample Preparation / Product Submission;

At least 100 mg of test substance is weighed on a sheet material. Using another sheet, all the larger 5 agglomerates are saturated. The powder is well distributed over the front half of the oscillating chute (about 1 cm inward from the leading edge). After starting the measurement, the frequency of the oscillating chute varies from about 40% to 100% (towards the end of the measurement). The time for submission of the whole sample is 10 to 15 s.

B) Determination of particle size of tiotropium monohydrate

Measurement and adjustment device:

Working with the appliances followed the manufacturer's operating instructions.

Measuring device: Laser Spectrometer (HELOS), Sympatec Disperser: Disperser of RODOS dry material with suction funnel, Sympatec Number of samples: 50-400 mg Product Submission: Oscillating Chute Vibri, Fa. Sympatec Frequency of vibration chute: 40 to 100% increasing Sample submission time: 15 to 25 s (at 200 mg) Focal length: 100 mm (measuring range: 0.9-175 microm) Measurement time: About 15 s (at 200 mg) Cycle duration: 20 ms Start / stop: 1% per channel 28 Dispersing gas: Pressurized air Pressure: 3 bar Pressurized: maximum Rating: HRLD

Sample Preparation / Product Submission:

About 200 mg of test substance are weighed on a sheet material. Using another sheet, all larger agglomerates are saturated on another sheet. The powder is well distributed over the front half of the oscillating chute (about 1 cm inward from the leading edge). After starting the measurement, the frequency of the oscillating chute varies from about 40 to 100% (towards the end of the measurement). Submission of the sample should be continuous as far as possible. However, the quantity of product should not be too large to achieve sufficient dispersion. The time taken for the whole sample to be given at 200 mg, e.g. is about 15 to 25 s.

B) Determination of 200M lactose particle size

Measurement and adjustment device

Working with the appliances followed the manufacturer's operating instructions.

Measuring device: Laser Spectrometer (HELOS), Sympatec Disperser: Disperser of RODOS dry material with suction funnel, Sympatec Number of samples: 500 mg

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Product Submission:

Frequency of vibration chute:

Focal length (1): Focal length (2):

Measurement time / Waiting time Cycle duration: Start / stop: Pressure:

Pressure: Rating:

Sample Preparation / Product Submission:

About 500 mg of test substance are weighed on a sheet material. Using another sheet, all larger agglomerates are saturated. Dust is poured into the funnel of the vibration chute. A distance of 1.2 to 1.4 mm is left between the vibration chute and the funnel. After starting the measurement, the amplitude of the oscillating chute increases from 0 to 40% until a continuous supply of the product is achieved. Then the amplitude decreases to about 18%. At the end of the measurement, the amplitude is increased to 100%.

Appliances

For example, the following machines and apparatus may be used to prepare inhalation powder:

Mixer or mixer respectively. powder mixer: Rhonradmischer 200 L; Tour: DFW80N-4; Manufacturer: Engelsmann, D-67059 Ludwigshafen.

Sieve Granulator: Quadro Comil; Tour: 197S; Manufacturer: Joisten & Kettenbaum, D-51429 Bergisch-Gladbach.

The following device is used to determine the TEWS moisture, following the manufacturer's instructions for use.

TEWS Moisture Detector:

Manufacturer: TEWS Elektronik, Hamburg

Type: MW 2200

Measuring range: 1 to 85% humidity Measurement accuracy: 1% of the final value of the selected range

E-mail mains: 220 V ± 10%, 50-60 Hz

For the determination of the halide dehydrator as well as for setting up the TEWS unit

Vibri Oscillation Chute, Sympatec up to 100% growing

200 mm (measuring range: 1.8-350 micrometer) 500 mm (measuring range: 4.5-875 micrometer) 10 s ms

1% per channel 19 bar maximum

The HRLD is used with the following device in accordance with the manufacturer's operating instructions.

Halogen dehydrator:

Mettler Halogentrockner HR 73; 2Q Manufacturer: Mettler-Toledo, D-35396 Gieben;

The following device is used to fill the empty inhaler capsules with inhalation powder containing tiotropium.

Capsule Filling Machine:

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

Example 1.

1.1. Mixture of excipients βθ 31.82 kg of lactose monohydrate for inhalation purposes (200M) is used as a coarser ingredient of the excipient. 1.68 kg of lactose monohydrate (5 µm) is used as a finer ingredient of the excipient. In the semi25 portion of this mixture, the fraction of the finer ingredient is 5%.

Pour about 0.8 to 1.2 kg of lactose monohydrate for inhalation purposes (200M) through a suitable sieve granulator with a bright opening of 0.5 ₄ θ mm into a suitable mixer. Lactose monohydrate (5 [mu] m) in portions of from about 0.05 to 0.07 kg and lactose monohydrate for inhalation purposes (200 M) in portions from 0.8 to 1.2 kg are then alternated in layers. Lactose monohydrate 45 for inhalation purposes (200M) and lactose monohydrate (5 µm) were layered in 31 resp. 30 layers (tolerance; ± 6 layers).

Finally, the sieved ingredients are mixed (mixing: 900 rpm).

¹ .2. The final mixture

65655 Bl (mixing: 900 rpm).

1.2. The final mixture

32.87 kg of the excipient mixture (1.1) and 0.13 kg of micronized tiotropium bromide monohydrate are used to prepare the final mixture. In the resulting 33.0 kg inhalation powder, the fraction of active substance is 0.4%.

This also applies when only 32.87 kg of lactose monohydrate (200M) is used, if a particle size fraction is included as an excipient. In this case, the implementation of step 1.1 naturally ceases.

Approximately 1.1 to 1.7 kg of the excipient or mixture of excipient (1.1) is sieved through a suitable sieve granulator with a bright opening of 0.5 pill in a suitable mixer. Then, in layers, tritotropium bromide monohydrate is sieved in portions of about 0.003 kg and the excipient or mixture of excipients (1.1) in portions from 0.6 to 0.8 kg. Submission of the excipient or mixture of excipients and the active substance takes place at 47 resp. 45 layers (tolerance: ± 9 layers).

The sieved ingredients are then mixed (mixing: 900 rpm). The final mixture was sieved twice more through a sieve granulator and stirred each time (stirring: 900 rpm).

Example 2.

The mixture obtained according to Example 1 produces inhaler capsules (inhalers) with the following composition in mg:

Tiotropium monohydrate bromide: 0,0225 Lactose monohydrate (200M): 5,2025 Lactose monohydrate (5 microm): 0,2750 Hard gelatin capsule (5% PEG 3350: 9% TEWS moisture): 49.0 Everything: 54.5 Example 3. Inhaler capsule, mg: Tiotropium bromide monohydrate: 0,0225 Lactose monohydrate (200M): 4,9275

Lactose monohydrate (5 microm): Hard gelatin capsule (5% PEG 3350: 9% -T 0,5500 EWS moisture): 49.0 Everything: 54.5 Needed to receive of inha- lateral capsule inhalation powder was more arched analogously to example 1. Example 4. Inhaler capsule, mg: Tiotropium bromide monohydrate: Monohydrate of 0,0225 lactose (200M): Monohydrate of 5,2025 lactose (5 microns): 0,2750 HPMC (<2% TEWS moisture): 49.0 Everything: 54.5 Needed to receive of inha- lateral capsule inhalation powder was more arched analogously to example 1. Example 5. Inhaler capsule, mg: Tiotropium bromide monohydrate: 0,0225 Lactose monohydrate (200M): 5,2025 lactose (5 microns): 0,2750 Polyethylene (<1% TEWS moisture) 100.0 Everything 105,5 Needed to receive of inha- lateral capsule inhalation powder was more arched analogously to example 1. Example 6 Inhaler capsule, mg: Tiotropium bromide monohydrate: 0,0225 Lactose monohydrate (200M): 5,4775 Polyethylene (<1% TEWS moisture) 100,0 Everything: 105,5 Needed to receive of inha-

the lateral capsule inhalation powder was prepared analogously to example 1.

65655 Bl

Example 7.

The mixture prepared according to Example 1 produces inhaler capsules (inhalers) with the following composition in mg:

Tiotropium monohydrate bromide: 0,0225 Monohydrate lactose (200M): 5,2025 Monohydrate of lactose (5 microns): 0,2750 Hard capsule gelatin (5% PEG 3350): 49,0 Everything: 54.5 Under suitable climatic conditions these

The capsules were adjusted to the water content of about 8.7% (microwave TEWS measurement) as described below.

The first phase is the drying phase followed by the equilibrium phase. Finally, the capsules are cooled (cooling phase). The capsules thus dried are immediately packaged in storage containers.

Method parameters

Setting the climatic conditions to the following setpoints:

Drying phase: 30 ° C

10% relative humidity (E.E)

3,5 h

Equilibrium phase: 30 °

16% relative humidity (E.E)

3.5h

Cooling phase: 23 ° C

16% relative humidity (E.E)

1.5h

By relative humidity (g. E) within the scope of the present invention is meant the ratio of the partial pressure of water vapor to the vapor pressure at the corresponding temperature.

An average particle size in the meaning of the present invention is understood to be a value in microms relative to which the size of 50% of the particles in volume is the same or smaller than the given size. The laser diffraction / dry dispersion method is used to determine the total particle size distribution.

Claims (16)

Claims Inhaler capsules containing tiotropium inhalation powder in admixture with a physiologically safe excipient, characterized in that the capsule material has a reduced moisture content, such as TEWS moisture or halide dehydrator, of less than 15%. Inhaler capsules according to claim 1, characterized in that the capsule material is selected from the group consisting of gelatin, cellulose derivatives, starch, starch derivatives, chitosan and synthetic plastics. Inhaler capsules according to claim 2, characterized in that gelatin is used as a capsule material in admixture with other additives selected from the group consisting of polyethylene glycol (PEG), preferably PEG 3350, glycerol, sorbitol, propylene glycol, PEORRO - block copolymers and other polyalcohols and polyethers. Inhaler capsules according to claim 3, characterized in that the capsule material, in addition to gelatin, contains PEGs in the proportion of 1-10% (wt.%). Inhaler capsules according to claim 3 or 4, characterized in that the capsule material has a TEWS moisture or halogen dehydration moisture of less than 12%, particularly preferred? 10%. Inhaler capsules according to claim 2, characterized in that the capsule material is selected from the group of cellulose derivatives hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose and hydroxyethylcellulose. 7. Inhaler capsules according to claim 6, characterized in that the capsule material exhibits TEWS moisture or halogen dehydration moisture of less than 8%, particularly preferred? 5%. Inhaler capsules according to claim 2, characterized in that the capsule material is selected from the group of synthetic plastics polyethylene, polycarbonate, polyester, polypropylene or polyethylene terephthalate. 65655 Bl Inhaler capsules according to claim 8, characterized in that the capsule material is selected from polyethylene, polycarbonate and polyethylene terephthalate. Inhaler capsules according to claim 8 or 9, characterized in that the capsule material exhibits a TEWS moisture or halogen dehydration moisture of less than 3%, particularly preferred? 1%. Inhaler capsules according to claims 1 to 10, characterized in that the inhalable powder contains from 0.001 to 2% tiotropium in admixture with a physiologically harmless excipient. Inhaler capsules according to claim 11, characterized in that the excipient consists of a mixture of excipient with an average particle size of 15 to 80 µm and an excipient with an average particle size of 1 to 9 µm, wherein the proportion of the second excipient is 1 to 20% of the total excipient. Inhaler capsules according to claim 12, characterized in that the tiotropium is present in the form of chloride, bromide, iodide, methanesulfonate, paratoluenesulfonate or methyl sulfate. Use of inhaler capsules according to one of claims 1 to 13 for use in an inhaler suitable for use in inhalation powders. Use according to claim 14 for use in asthma or COPD. Use of empty capsules characterized by TEWS or halide dehydrator of less than 15% for the preparation of inhaler capsules containing tiotropium according to any one of claims 1 to 13.