SK16202003A3 - Inhalation capsules - Google Patents

Abstract

The invention relates to inhalation capsules (Inhalettes) made from specific capsule material with reduced moisture content, containing the active agent tiotropium in the form of a powder preparation and characterised by an improved stability.

Description

The invention relates to inhaler capsules (inhalers) made of a specific material for reduced moisture capsules, which contain tiotropium as an active ingredient in the form of a powder formulation and are characterized by improved stability.

BACKGROUND OF THE INVENTION

Tiotropium is known from European patent application EP 418 716 A1 and has the following chemical structure:

Tiotropium bromide is a long-acting, highly effective anticholinergic that can be used to treat respiratory diseases, particularly COPD (chronic obstructive pulmonary disease) and asthma. Tiotropium is a free ammonium cation.

In the treatment of the above-mentioned diseases, the inhalation use of the active substances is possible. In addition to the inhalation use of broncholytically active compounds in the form of metered aerosols and solutions, the inhalational administration of these drugs in the form of powders containing the active ingredient is of particular importance.

In the case of active substances which are characterized by high efficacy, only very small amounts of active substance are required for a single dose to achieve the therapeutically desired effects. In such cases it is in production

Inhalable powders need to be diluted with the appropriate excipients.

For active substances which are characterized by high efficacy, it is of particular importance that reproducible particles are maintained when administered alone so that the medicament is manufactured in a form which is characterized by a high degree of stability. If such a high degree of stability is not achieved, the same dosage of active ingredient cannot be guaranteed.

It is an object of the invention to produce an inhalation capsule containing an inhalable powder containing tiotropium which provides a sufficient degree of stability of the active ingredient.

It is a further object of the present invention to provide an inhalation capsule which, by virtue of its stability, allows the release of the active ingredient with a high dose accuracy (relates to the amount of active ingredient filled into the inhalation capsule and powder mixture, .

It is a further object of the present invention to provide an inhalation capsule which permits administration of the active ingredient with good emptying of the capsule.

It is a further object of the present invention to produce inhalation capsules which exhibit good puncture at high stability and low breakage, and thus the inhalation tools for inhalers can be used without difficulty.

It has surprisingly been found that the above-mentioned tasks can be accomplished by means of the inhalation capsules according to the invention described below.

SUMMARY OF THE INVENTION

The present invention provides inhalation capsules which contain tiotropium as an inhalation powder in admixture with a physiologically acceptable excipient, wherein the capsules exhibit a reduced moisture content (TEWS moisture or halogen dryer less than 15%).

For the purposes of the present invention, TEWS-moisture means moisture which can be determined using a MW 2200 moisture meter from TEWS. The measurement method is an indirect method for the determination of water. The effects derived from the proportion of water (microwave absorption through the water contained in the product) are measured and expressed as microwave value. Calibration of the instrument using is required to determine the water content by weight

-3calibration samples. The resulting calibration curve for subsequent measurements by the instrument is attached to the calculations. The moisture content is expressed in% and stored.

For the purpose of calibrating the TEWS apparatus, e.g. use a halogen dryer. By calibrating the TEWS apparatus with a halogen dryer, within the meaning of the present invention, the term TEWS moisture is considered equivalent to moisture with a halogen dryer. For example, within the meaning of the present invention, a 15% TEWS moisture also corresponds to a 15% moisture by a halogen dryer. Since the TEWS instrument is a relative method for determining water, the halogen dryer delivers absolute moisture values to the capsules. The water content of a halogen dryer is determined by weight loss. The capsules are heated while water is lost. The capsules are dried to constant weight and then counted. The weight difference between the starting and final weights (in grams) represents the water content of the capsules and can be converted to weight percent. The TEWS device compares only the measurement curves of the actual capsules with the internal calibration curves for moisture content measurements. These calibration curves relate to the defined water content of the capsules in which the absolute water content was previously achieved by a drying method using a halogen dryer.

In this way, for a relative TEWS method, a comparison with absolute water fractions is determined by the halogen dryer method.

The inhalation capsules of the invention exhibit a TEWS moisture or moisture achieved using a halogen dryer of less than 12%, particularly preferably □ 10%.

For the purposes of the present invention, the term "capsule material" refers to the material from which the inhalation capsule shell is made. The capsule material according to the invention is selected from the group consisting of gelatin, cellulose derivatives, starches, starch derivatives and synthetic substances.

When gelatin is used as a capsule material, it can be used in admixture with other additives selected from the group consisting of polyethylene glycol (PEG), preferably PEG 3350, glycerol, sorbitol, propylene glycol, PEO-PPO block polymer and other polyalcohols and polyethers. In the sense of the present

Particularly suitable gelatin in admixture with PEG, preferably PEG 3350. Particularly preferably, the gelatin capsule of the invention comprises PEG in an amount of 1 to 10 wt. %, preferably 3 to 8%. Particularly suitable gelatin capsules contain PEG in an amount of 4 to 6%, with a content of about 5% being most preferred within the meaning of the invention.

In the case of a gelatin-containing capsule material, the capsules of the invention have TEWS moisture or moisture obtained with a halogen dryer of less than 12%, particularly preferably zvlášť 10%.

When cellulose derivatives are used as the capsule material, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose and hydroxyethylcellulose are preferred for use. Particularly preferred in this case is the use of hydroxypropyl methylcellulose (HPMC), very preferably HPMC 2910. In the case of using cellulose derivatives as capsule material, the degree of TEWS moisture or moisture obtained by halogen dryer is less than 8%, particularly preferably less than 5%. Most preferably, the inhalation capsules of cellulose derivatives are dried to TEWS moisture or moisture obtained with a halogen dryer less than 4%, particularly preferably less than 2%, before being filled with a tiotropium-containing inhalable powder.

When synthetic materials are used as the capsule material, they are preferably selected from the group consisting of polyethylene, polycarbonate, polyester, polypropylene and polyethylene phthalate. Among the synthetic materials, polyethylene, polycarbonate or polyethylene phthalate are particularly preferred for the purposes of the present invention. If polyethylene is used as one of the most preferred capsule materials of the invention, e.g. polyethylene having a density between 900 to 1000 kg / m ³ , preferably 940 to 980 kg / m ³ , particularly preferably 960 kg / m ³ (high density polyethylene). In the case of using synthetic materials as capsule materials, the degree of TEWS of moisture or moisture obtained with a halogen dryer may be less than 3% or less than 1%.

The inhalation capsules of the invention are filled with tiotropium-containing inhalable powder after the manufacture of the empty capsules according to the above procedures. This filling can be carried out according to methods known in the art. Production

Inhalation capsules for filling may also be performed according to methods known in the art.

Examples of methods of manufacture include dip coating, blow molding, injection molding, extrusion and tensile coating, which are known in the art.

It is essential in the manufacture of the inhalation capsules according to the invention that if the capsule material is not adequately stored prior to filling with the active substance-containing inhalation powder or if the production is not carried out with a sufficiently reduced moisture content, the empty capsules are dried. This drying is carried out until a moisture level is reached which, according to the specifications of the invention, corresponds to a maximum of 15% TEWS or moisture by halogen drying.

For the purposes of the present invention, the inhalation capsule is equivalent to the inhaler.

Another aspect of the present invention is the use of capsules that are characterized by less than 15% TEWS moisture or moisture drying and which may form the capsule material described above for the manufacture of inhalers (inhalation capsules) containing a tiotropium-containing inhalable powder. For the purposes of the present invention, the term capsule refers to empty capsules, i. j. capsules not yet containing any inhalable powder.

Inhalation capsules containing inhalable powder having a tiotropium content of from 0.001 to 2% are preferred according to the invention. Particularly preferred are inhalation capsules which contain an inhalable powder with 0.04 to 0.8%, more preferably 0.08 to 0.64%, most preferably 0.16 to 0.4% tiotropium. The percentages of tiotropium for the purposes of the present invention correspond to weight percent relative to the total amount of inhalable powder.

Tiotropium is a free ammonium cation. Suitable counterion (s) are chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methylsulfate. The preferred anion is bromide. Accordingly, the present invention considers those inhalers which contain an inhalable powder which is characterized in that the proportion of tiortopium bromide is from 0.0012 to 2.41%.

In particular, inhalable powders which contain tiotropium bromide between 0.048 and 0.96%, preferably between 0.096 and 0.77%, most preferably between 0.19 and 0.48%, are of particular interest.

The inhalable powder contained in the inhalers of the invention may contain the tiotropium bromide of the invention preferably in the form of its hydrate. Crystalline tiotropium monohydrate is particularly preferred. Accordingly, the present invention relates to inhalers in which the inhalable powder comprises crystalline tiotropium bromide monohydrate in amounts of 0.0012 and 2.5%. Of particular interest according to the invention are inhalers in which the inhalable powders contain 0.05 to 1%, preferably 0.1 to 0.8%, most preferably 0.2 to 0.5% of crystalline tiotropium bromide.

For the purposes of the present invention, tiotropium bromide monohydrate is any crystalline tiotropium bromide monohydrate obtainable according to the synthetic procedures detailed in the experimental section.

The inhalable powders used in the inhalation capsules of the invention (inhalers) contain at least one excipient in addition to the active ingredient. This may consist of an excipient fraction consisting of medium-sized excipient particles (e.g., 15 to 80 µm) or optionally a mixture of a coarser-sized excipient with a mean particle size of 15 to 80 µm and a finer excipient with a mean particle size of 1 to 9 pm. When mixtures of excipients of coarser and finer excipient particles are used, the proportion of finer excipient with respect to the total amount of excipient is preferably 1 to 20%.

If a mixture of coarser and finer excipient fractions is present in the inhalation capsules according to the invention, the mean coarse particle size is 17 to 50 µm, particularly preferably 20 to 30 µm and the mean particle size of the finer excipient is 2 to 8 µm, particularly preferably 3 to 7 µm. pm. As used herein, mean particle size refers to a 50% volume distribution value measured by a laser diffractometer according to the dry dispersion method. Preference is given to using inhalants according to the invention for inhalation powders in which the proportion of finer excipient with respect to the total amount of excipient is 3 to 15%, particularly preferably 5 to 10%. For the purposes of the present invention, the percentages are by weight.

When referring to the term blend for the purposes of the present invention, the term is understood to mean a blend resulting from mixing of clearly defined ingredients. Accordingly, e.g. only mixtures which are formed by mixing the coarse-grained excipient component with the finer-grained excipient component are considered to be a mixture of coarse and fine particles.

The ingredients which form the excipients may consist of chemically identical or chemically different substances, with those excipients which are derived from the same chemical compound being preferred.

If a mixture of coarser and finer excipient fractions is used as an excipient, these may also consist of chemically identical or chemically different substances, with inhalation powders in which the proportion of coarser and finer particles comes from the same chemical compound.

Physiologically acceptable excipients which can be used in the inhalers of the invention for the production of inhalable powders include monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. Mono- or disaccharides are preferred, the use of lactose or glucose being preferred, particularly but not exclusively in the form of their hydrates. The use of lactose is particularly preferred within the meaning of the invention, and the use of lactose monohydrate as an excipient is most preferred.

The inhalation capsules of the invention may be administered using inhalers as described in WO 94/28958. One particularly preferred inhaler for use of inhalers according to the invention is shown in the drawing.

This inhaler (HandiHaler) for inhaling powdered medicaments from inhalation capsules is characterized by a housing comprising 2 windows, one closure with air inlet openings, which is connected to the capsule chamber 6 and is equipped with two ground needles 7, movable a pen button 9 as well as an axis 10 connected to the housing 1, the closure 3 and the cap 11 connected to the mouthpiece 12. The capsule chamber is closed by a filter. The filter is inserted into a filter holder that is firmly attached to the mouthpiece.

In the inhalation capsules according to the invention, amounts of filling of from 2 to 50 mg, preferably 4 to 25 mg of inhalation powder in an inhalation capsule are offered. These contain between 1.2 and 80 µg tiotropium. With a particularly preferred amount of filling of from 4 to 6 mg inhalation powder in the inhalation capsule, the tiotropium content of the inhalation capsule is 1.6 to 48 pg, preferably 3.2 to 38.4 pg, particularly preferably between 6.4 and 24 pg. Content e.g. 18 pg of tiotropium corresponds to a tiotropium bromide content of approximately 21.7 pg.

Thus, inhalation capsules filled with 3-10 mg of inhalable powder according to the invention preferably contain between 1.4 and 96.3 µg of tiotropium bromide. With a preferred filling of 4 to 6 mg inhalation powder in the inhalation capsule, the content of tiotropium bromide in the inhalation capsule is between 1.9 and 57.8 pg, preferably between 3.9 and 46.2 pg, particularly preferably between 7.7 and 28.9 pg . Content e.g. 21.7 pg of tiotropium bromide corresponds to a content of approximately 22.5 pg of tiotropium bromide monohydrate.

Thus, inhaler capsules filled with 3 to 10 mg of inhalable powder according to the invention preferably contain between 1.5 and 100 µg of tiotropium bromide monohydrate. With a preferred filling of 4 to 6 mg inhalation powder in the inhalation capsule, the content of tiotropium bromide monohydrate in the inhalation capsule is between 2 and 60 pg, preferably between 4 and 48 pg, particularly preferably between 8 and 30 pg.

The inhalation capsules according to the invention, in accordance with the basic requirement of the present invention, are characterized by a high degree of homogeneity in terms of single dose accuracy. This is in the region of <8%, preferably <6%, particularly preferably <4%.

Inhalable powders for filling into inhalation capsules according to the invention can be obtained according to the following procedures.

The weighing of the starting materials is followed in cases where a mixture of coarser-grained and finer excipient particles is used as the excipient, first the preparation of the excipient mixture. If the excipient is a fraction of medium particle size (e.g., 15 to 80 µm), this first step is omitted.

Finally, the inhalation powder is prepared from an excipient or a mixture of excipients and the active ingredient. The inhalation capsules of the invention are dried before filling the tiotropium-containing inhalable powder until the maximum degree of moisture according to the invention is achieved using TEWS or

-9 halogen dryer. Thereafter, the manufacture of powder-containing inhalation capsules is terminated in a manner known in the art.

In the following production descriptions, the ingredients are used in amounts by weight as already described in the inhalable powder compositions. When mixtures of coarser and finer excipient particles are used as the excipient, the coarser and finer excipient particles are placed in a suitable mixer. The addition of both components is preferably carried out through a sieve granulator with a mesh size of 0.1 to 2 mm, particularly preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm. Preferably, a coarser-sized excipient is first introduced and finally a finer particle fraction is added to the mixer. Advantageously, in this mixing process, the addition of both components is carried out in portions, with a portion of the coarser excipient being introduced first and finally an alternately finer and coarse excipient is added. In the preparation of the excipient mixture, it is particularly advantageous to alternate screening the two components in portions. E.g. The sieving of each of the two components takes place in 15 to 45, particularly preferably 20 to 40 batches. The mixing of both components can already take place during the addition of these components. Preferably, however, the two portions are mixed only after sieving them in batches.

Of course, the previous step is omitted if a fraction of excipients with a uniform particle size (e.g., a mean particle size of from 15 to 80 µm) is used.

Finally, the excipient or mixture of excipients and active ingredient is placed in a suitable mixer. The excipient used should have a mean particle size of from 0.5 to 10 µm, preferably from 1 to 6 µm, particularly preferably 2 to 5 µm. The addition of both components preferably follows through a sieve granulator with a mesh size of 0.1 to 2 mm, particularly preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.

Advantageously an excipient and finally an active ingredient are introduced into the mixer. Preferably, this mixing is followed by the addition of both components after the batches. If an adjuvant mixture is used, it is particularly advantageous to alternately sieve both components in batches. E.g. the sieving of each of the two components takes place in 25 to 65, particularly preferably 30 to 60, batches. The mixing of both components can already take place during the addition of these components. Preferably, however, the two portions are mixed only after sieving them in batches.

The powder mixture thus obtained may optionally be reintroduced or repeatedly into a sieve granulator and always subjected to further mixing.

In a further preferred embodiment of the invention, the inhalation capsules are filled with the tiotropium-containing inhalable powder obtained as described above and subjected to the drying process described below.

The filled capsules are exposed for a period of from 0.5 to 10 h, preferably from 1.5 to 7 h, more preferably from 2 to 5.5 h, particularly preferably from 2.5 to 4.5 h, at a temperature of about 10 to 10 h in the first phase (drying phase). 50 ° C, preferably about 20 to 40 ° C, particularly preferably about 25 to 35 ° C at a relative humidity (rh) of at most 30%, preferably at most 20%, particularly preferably about 5 to 15%. For the purposes of the present invention, relative humidity (r.v.) is understood to mean the quotient of the partial pressures of water vapor and the pressure of water vapor at said temperature. In the second phase following (equilibrium phase), the capsules are exposed for 0.5 to 10 h, preferably 1.5 to 7 h, more preferably 2 to 5.5 h, particularly preferably 2.5 to 4.5 h a temperature of about 10 to 50 ° C, preferably about 20 to 40, particularly preferably about 25 to 35 ° C at a relative humidity of at most 35% r. v., preferably at most 25% r. %, particularly preferably about 10 to 20% r. in. Then, if the temperature of the above process steps has been set to a temperature higher than room temperature (23 ° C), an optional cooling phase follows. In this cooling phase, the capsules are exposed for a period of 0.1 to 6 h, preferably 0.5 to 4 h, more preferably 0.75 to 2.5 h, particularly preferably 1 to 2 h, at a temperature of about 23 ° C at a relative humidity of at most 35 ° C. % r. v., preferably at most 25% r. %, particularly preferably about 10 to 20% r. in. In a particularly preferred embodiment, the set relative humidity values for the equilibrium phase and the cooling phase are identical.

As used herein, the term "active agent" refers to tiotropium. The term tiotropium, which represents a free ammonium cation, according to the invention corresponds to the designation tiotropium in the form of a salt (tiotropium salt) which contains an anion as counterion. Tiotropium salts within the meaning of the present invention which can be used are compounds which, in addition to tiotropium as counterion (anion), contain chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methylsulfate. Within the meaning of the present invention, of all tiotropium salts, particularly preferred is tiotropium bromide. Under the term tiotropium bromide is meant

The present invention is understood to mean all possible amorphous and crystalline modifications of tiotropium bromide. These can e.g. contain solvent molecules in the crystalline structure. Of all the crystalline modifications of tiotropium bromide, all containing water (hydrates) are preferred. Particularly preferably, crystalline tiotropium monohydrate produced according to the method described in detail below may be used for the purposes of the present invention. For the production of tiotropium-containing inhalation capsules according to the invention, it is first necessary to produce tiotropium in a form suitable for pharmaceutical use. It is preferred that tiotropium, the preparation of which is described in EP 418 716 A1, is subjected to one more crystallization step. Depending on the reaction conditions and solvents, various crystalline modifications are obtained.

Tiotropium bromide monohydrate has proven to be particularly suitable for the manufacture of the inhalation capsules of the invention.

The following examples serve to illustrate the present invention without, however, limiting the scope of the invention to the following production methods in the examples.

Starting materials

In the following examples, lactose monohydrate (200M) is used as excipient. This may come from e.g. from DMV International, 5460 Veghel / NL under the product designation Pharmatose 200M.

In the following examples, lactose monohydrate (200M) can also be used as a coarser-grained excipient, if it is convenient to use mixtures of excipients. This may come from e.g. from DMV International, 5460 Veghel / NL under the product designation Pharmatose 200M.

In the following examples, lactose monohydrate (5μ) is used as the finer excipient when using excipient mixtures. This can be obtained by conventional procedures (micronization) from lactose monohydrate (200M) e.g. from DMV International, 5460 Veghel / NL under the product designation Pharmatose 200M.

Production of crystalline tiotropium bromide monohydrate

15.0 kg of tiotropium bromide are placed in 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 ° C and stirred at this temperature until a clear solution is formed. Activated charcoal (0.8 kg) moistened with water is slurried in 4.4 kg of water, this mixture is added to a solution containing tiotropium and is poured into 4.3 kg of water. The mixture thus obtained is stirred at 80 to 90 ° C for at least 15 minutes and finally filtered through a heated filter into a preheated apparatus set at a jacket temperature of 70 ° C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled to 20 to 25 ° C over a period of 20 minutes while cooling at 3 to 5 ° C. By cooling with cold water to 10-15 ° C, the apparatus is further cooled and crystallization is complete after stirring for at least 1 hour. The crystallizate is isolated through a suction dryer, the isolated crystalline slurry is washed with 9 L of cold water (10-15 ° C) and cold acetone (10-15 ° C). The resulting crystals were dried for 2 h under a stream of nitrogen at 25 ° C.

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

The crystalline tiotropium bromide obtained according to the method described above was evaluated by DSC (differential scanning calorimetry). The DSC diagram shows 2 characteristics. The first, relatively broad, endothermic feature between 50 to 120 ° C involves the dewatering of tiotropium monohydrate to the anhydrous form. The second, relatively sharp endothermic maximum at 230 ± 5 ° C belongs to the substance melt. This data was evaluated using the Mettler DSC 821 and the Mettler STAR software package. Data was read at a heat rate of 10K / min.

Crystalline tiotropium bromide monohydrate was characterized by IR spectroscopy. Data were read using a Nicolet FTIR spectrometer and evaluated by Nicolet with the OMNIC 3.1 software package. The measurement was performed with 2.5 pmol tiotropium monohydrate in 300 mg KBr.

The following table lists some significant waves of IR spectra.

Number of wines assignment Type of oscillation 3570.3410 O-H Shifted freq 3105 Aryl C-H Shifted freq 1730 C-O Shifted freq 1260 C-O epoxide Shifted freq

Esther C-0 Shifted freq thiophene Circular oscillation

Crystalline tiotropium bromide monohydrate according to the method above shows a single monoclinic cell with the following dimensions: a = 18.0774, b = 11.9711, c = 9.9321, β = 102.691 °, V = 2096.96 ³ . These data were evaluated using an AFC7R-4-ring diffractometer (Rigaku) using monochromatized copper radiation. Structure determination and crystal structure refinement were obtained using direct methods (Program SHELXS86) and FMLQ refinements (Program TeXsan).

The crystalline tiotropium bromide monohydrate thus obtained is micronized according to known procedures to produce the active ingredient in the form of a medium particle size which complies with the specifications of the invention.

The following is a description of an embodiment of determining the particle size of the different components of the composition of the invention.

1) Determination of fine particle size of lactose

Device and settings

Measuring devices:

Dispersing unit:

Quantity of sample:

Product Feed:

Oscillating groove frequency: Sample feed duration: Focal length: Measurement time:

Cycle length:

Start / stop at:

Dispersing gas:

in accordance with the manufacturer's operating instructions

HELOS laser spectrometer (SympaTec) RODOS dry dispersant with suction funnel (SympaTec) from 100 mg oscillating trough Vibri, Fa Sympatec 40 to 100% ascending 1 to 15 s (in case of 100 mg)

100 mm (measuring range: 0.9 to 175 pm) approx. 15 s (for 100 mg) ms% on channel 28 compressed air

- 14Pressure:

vacuum:

Evaluation method:

bars (0.3 MPa) maximum

HRLD

Sample preparation / product feed

At least 100 mg of test sample per weigh. Another large agglomerate is broken up by the next card. The powder is then finely divided on the front half of the oscillating groove (approximately 1 cm from the front edge). After the start of the measurement, the frequency of the oscillating trough is from 40% to 100% (towards the end of the measurement). The time at which the entire sample is always supplied is 10 to 15 seconds.

B) Determination of particle size of tiotropium monohydrate, micronized:

Device and settings

The devices are operated in accordance with the manufacturer's operating instructions.

Measuring instrument: HELOS laser spectrometer (SympaTec)

Dispersion unit: RODOS dry dispersant with suction

Quantity of sample:

Product Feed:

Oscillating groove frequency: Sample feed duration: Focal length: Measurement time:

Cycle length:

Start / stop at:

Dispersing gas:

pressure:

vacuum:

Evaluation method:

funnel (SympaTec) mg to 400 mg vibrating trough Vibri, Fa Sympatec 40 to 100% ascending 15 to 25 s (for 200 mg)

100 mm (measuring range: 0.9 to 175 pm) approx. 15 s (in the case of 200 mg) ms% on channel 28 compressed air bars (0.3 MPa) maximum

HRLD

- 15Sample preparation / product feed

Approximately 200 mg of test sample per card. Another large agglomerate is broken up by the next card. The powder is then finely divided on the front half of the oscillating groove (approximately 1 cm from the front edge).

After the start of the measurement, the frequency of the oscillating trough is from 40% to 100% (towards the end of the measurement). The sample feed should preferably be continuous. However, the amount of product must not be too large to achieve sufficient dispersibility. The time at which the entire sample is always delivered is for 200 mg e.g. 15 to 25 seconds.

C) Determination of 200M lactose particle size

Device and settings

Measuring devices:

Dispersing unit:

Quantity of sample:

Product Feed:

Oscillating groove frequency: Focal length (1): Focal length (2): Duration of sample feed: Cycle length:

Start / stop at:

pressure:

vacuum:

Evaluation method:

in accordance with the manufacturer's operating instructions. HELOS laser spectrometer (SympaTec) RODOS dry dispersant with suction funnel (SympaTec)

500 mg Vibri groove, Fa Sympatec up to 100% ascending

200 mm (measuring range: 1.8 to 350 pm)

500 mm (measuring range: 4.5 to 875 pm)

10s ms% on channel 19 3 bars (0.3 MPa) maximum HRLD

Sample preparation / product feed

Approximately 500 mg of test sample per card. Another large agglomerate is broken up by the next card. The powder is transferred to a vibratory funnel

- 16 grooves. Placed at a distance of 1.2 to 1.4 mm between the vibrating trough and the funnel. After the start of the measurement, the oscillation channel amplitude adjustment is adjusted from 0% to 40% until the product flow is continuous. Then the amplitude is reduced by approximately 18%. At the end of the measurement, the amplitude is amplified to 100%.

instruments

For the production of inhalable powder, e.g. use the following devices and instruments:

The container of the mixture, such as e.g. powder mixer: Rhonrad mixer 200 L; Model: DFW80N-4; manufacturer: Firma Enfelsmann, D-67059 Ludwigshafen.

Screen granulator: Quadro Comil; Type: 197 / S; manufacturer: Joisten & Kettenbaum, D-51429 Bergisch-Gladbach.

The following apparatus is used to determine the TEWS-moisture using the method indicated by the manufacturer.

TEWS-moisture determination device:

Manufacturer: Firma TEWS Elektronik, Hamburg

Type: MW 2200

Measuring range 1 to 85% humidity

Measurement accuracy: 1% of the final value of the selected range

Mains setting: 220 V +/- 10%, 50 to 60 Hz

To determine the humidity of the halogen dryer as well as the capability of the TEWS apparatus, the following apparatus shall be used according to the method of use indicated by the manufacturer.

Apparatus for determining the humidity with a halogen dryer

Mettler halogen dryer HR 73; manufacturer: Mettler-Toledo, D-35396 Giessen;

The following apparatus is used to fill empty inhalation capsules with tiotropium-containing inhalation powder.

- 17Capsule filling machine:

MG2, type G100, manufacturer: MG2 S. r. I., I-40065 Plana di Macina di Pianoro (BO),

Italy:

Overview of the figures in the drawing

The figure shows a particularly preferred inhaler for use of inhalers according to the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

1.1. Mixture of excipients

31,82 kg of lactose monohydrate for inhalation (200M) are used as coarser ingredients. 1.68 kg of lactose monohydrate (5 µm) were used as finer excipient components. In the resulting mixture of excipients 33.5 kg, the proportion of finer components is 5%.

Approximately 0.8 to 1.2 kg of lactose monohydrate for inhalation (200M) is placed in a suitable mixing container through a suitable 0.5 mm mesh sieve granulator. Finally, lactose monohydrate (5pm) is added alternately by sieving through a sieve at doses from about 0.05 to 0.07 kg and lactose monohydrate per inhalation (200M) at doses from 0.8 to 1.2 kg in batches. Lactose monohydrate for inhalation (200M) and lactose monohydrate (5pm) are added in 31 and 30 batches (± 6 batches, respectively).

The sieved parts are finally mixed (mixing: 900 rpm).

1.2. Final mixture

32.87 kg of the mixture of excipients (1.1) and 0.13 kg of micronized tiotropium bromide monohydrate are used to make the final mixture. In the mixture of 33.0 kg of inhalable powder resulting therefrom, the active ingredient content is 0.4%.

- 18Use accordingly, use 32.87 kg of lactose monohydrate alone (200M), if the excipient fraction of medium particle size is required as an excipient. In this case, of course, step 1.1 is omitted.

Approximately 1.1 to 1.7 kg of excipient or excipient mixture (1.1) are placed in a suitable mixing container through a suitable sieve granulator with a mesh size of 0.5 mm. Finally, alternately, by sieving through the sieve, lactose monohydrate is added at doses of approximately 0.003 to 0.07 kg and the excipient or excipient mixture (1.1). in batches from 0,6 to 0,8 kg. The addition of the excipients or of the mixture of excipients and the active ingredient takes place in 47 or 45 batches (tolerance ± 9 batches).

The sieved parts are finally mixed (mixing: 900 rpm). The final mixture is placed twice more in a sieve granulator and finally mixed (stirring: 900 rpm).

Example 2

Inhalation capsules (inhalants) having the following composition are obtained from the composition of Example 1:

Tiotropium bromide monohydrate: 0.0225 mg

Lactose monohydrate (200M): 5.2025 mg

Lactose monohydrate (5 µm): 0.2750 mg

Solid gelatin capsule (5% PEG 3350; 9% TEWS humidity): 49.0 mg

Total: 54.5 mg

Example 3

Inhalation capsule

Tiotropium bromide monohydrate:

Lactose monohydrate (200M):

Lactose monohydrate (5 pm):

Solid gelatin capsule (5% PEG 3350; 9% TEWS humidity):

Overall:

0.0225 mg 4.9275 mg 0.5500 mg

49.0 mg

54.5 mg

An inhalable powder for the manufacture of inhalation capsules was obtained analogously to Example 1.

Example 4

Inhalation capsule

Tiotropium bromide monohydrate: 0.0225 mg

Lactose monohydrate (200M): 5.2025 mg

Lactose monohydrate (5 µm): 0.2750 mg

HPMC (<2% TEWS humidity): __ 49.0 mg

Total: 54.5 mg

An inhalation powder for the manufacture of inhalation capsules was obtained analogously to Example 1.

Example 5

Inhalation capsule

Tiotropium bromide monohydrate: 0.0225 mg

Lactose monohydrate (200M): 5.2025 mg

Lactose monohydrate (5 µm): 0.2750 mg

Polyethylene (<5% TEWS humidity): __ 100.0 mg

Total: 105.5 mg

An inhalation powder for the manufacture of inhalation capsules was obtained analogously to Example 1.

Example 6

Inhalation capsule

Tiotropium bromide monohydrate: Lactose monohydrate (200M):

0.0225 mg 5.4775 mg

-20Polyethylene (<1% TEWS humidity):

Overall:

100.0 mg

105.5 mg

An inhalation powder for the manufacture of inhalation capsules was obtained analogously to Example 1.

Example 7

Inhalation capsules (inhalers) having the following composition are prepared from the mixture of Example 1:

Tiotropium bromide monohydrate: 0.0225 mg

Lactose monohydrate (200M): 5.2025 mg

Lactose monohydrate (5 µm): 0.2750 mg

Solid gelatin capsule (5% PEG 3350): 49.0 mg

Total: 54.5 mg

These capsules are adjusted to a water content of about 8.7% (TEWS microwave moisture meter) under suitable environmental conditions in the climate chamber using the method described below.

At the beginning, a drying phase is carried out, followed by a so-called drying step. equilibrium phase. Finally, the capsules are exposed to so-called &quot; cooling phase. The capsules thus dried are ultimately packaged directly into the corresponding stable storage containers.

Conditions for implementation

Setting the environment to the following desired values:

Drying phase: 30 ° C

10% y. in. (relative humidity)

3.5 h 30 ° C 16% r. in.

3,5 h equilibrium phase:

-21 cooling phase:

° C 16% r. in. 1.5 h

The term relative humidity (r.v.) in the present invention refers to the quotient of the water vapor particle pressure and the water pressure at an appropriate temperature.

For the purposes of the present invention, "mean particle size" refers to a value in µm where 50% of the particles of the volume distribution have less than or equal to the stated particle size. Laser diffraction / dry dispersion is used as a measurement method to determine the overall particle size distribution.

Claims (15)

PATENT CLAIMS Inhalable capsules which contain tiotropium as an inhalation powder in admixture with a physiologically acceptable excipient, characterized in that they have a reduced moisture content - TEWS-moisture or halogen-drier moisture content of less than 15%. Inhalable capsules according to claim 1, characterized in that the material from which the capsules are made is selected from the group consisting of gelatin, cellulose derivatives, starches, starch derivatives and synthetic substances. Inhalable capsules according to claim 2, characterized in that the capsule material is made of gelatin in admixture with other substances selected from the group consisting of polyethylene glycol (PEG), preferably PEG 3350, glycerol, sorbitol, propylene glycol, PEO-PPO- block polymers and other polyalcohols and polyethers. Inhalable capsules according to claim 3, characterized in that the capsule material contains, in addition to gelatin, 1 to 10% by weight of PEG, preferably 3 to 8% by weight. Inhalable capsules according to claim 3 or 4, characterized in that the capsule material has a TEWS moisture or halogen dryer less than 12%, preferably 10%. Inhalation capsules according to claim 2, characterized in that the capsule material is selected from the group comprising a cellulose derivative such as hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose and hydroxyethylcellulose. -237. Inhalation capsules according to claim 6, characterized in that the capsule material has a TEWS moisture or halogen dryer moisture of less than 8%, preferably 5%. Inhalable capsules according to claim 2, characterized in that the capsule material is selected from the group consisting of synthetic substances such as polyethylene, polycarbonate, polyester, polypropylene and polyethylene terephthalate. Inhalation capsules according to claim 8, characterized in that the capsule material is selected from the group consisting of polyethylene, polycarbonate and polyethylene terephthalate. Inhalation capsule according to claim 8 or 9, characterized in that the capsule material has a TEWS moisture or halogen dryer moisture of less than 3%, preferably 1%. Inhalable capsules according to claims 1 to 10, characterized in that the inhalable powder contains 0.001 to 2% tiotropium in admixture with a physiologically acceptable excipient. Inhalable capsules according to claim 11, characterized in that the excipient consists of a mixture of a coarser excipient with a mean particle size of 15 to 80 µm and a finer excipient with a mean particle size of 1 to 9 µm, the proportion of finer excipient based on the total amount of excipient, it is 1 to 20%. Inhalation capsules according to claim 12, characterized in that tiotropium is in the form of chloride, bromide, iodide, methanesulfonate, paratoluenesulfonate or methylsulfate. Use of inhaler capsules according to any one of claims 1 to 13 in any inhaler suitable for administration of inhalable powders. - 24 Use according to claim 14 for the treatment of asthma or COPD. Use of empty capsules having a TEWS moisture or halogen dryer moisture of less than 15% for the manufacture of tiotropium-containing inhalation capsules according to any one of claims 1 to 13. TP HZv -ίοβζ,