SK287379B6 - Capsules for inhalation, use thereof and method of manufacture - Google Patents

Abstract

Inhalation capsules made from a special capsule material with reduced moisture content, comprising powder tiotropium as an active agent, characterised by improved stability. The invention further relates to using said inhalation capsules for the manufacture of a medicament for treating asthma and COPD, and method for preparation thereof.

Description

The invention relates to inhaler capsules 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. It further includes their use in the preparation of a medicament for the treatment of asthma and COPD as well as a method for their manufacture.

BACKGROUND OF THE INVENTION

Tiotropium is known from European patent application EP418716A1 and has the following chemical structure:

h, c. +. ch ₃ N

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 aforementioned 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 a particularly high activity, only very small amounts of active substance are required for a single dose to achieve the therapeutically desired effects. In such cases, it is necessary to dilute the active ingredient with suitable excipients in the manufacture of inhalable powders. For active substances which are characterized by high efficacy, it is of particular importance that the administration itself retains reproducible particles in order to manufacture the medicament 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 manufacture inhalation capsules which have good puncture at high stability and low breakage, and thus a problem-free use of inhalers for inhalers can be achieved.

Surprisingly, it has been found that the above-mentioned tasks can be accomplished by the described inhaler capsules according to the invention.

SUMMARY OF THE INVENTION

The present invention provides capsules for inhalation which contain tiotropium as an inhalation powder in admixture with a physiologically acceptable excipient, wherein the capsule material is gelatin in admixture with other additives selected from the group consisting of polyethylene glycol-PEG, glycerol, sorbitol, propylene glycol, PEO- PPO-block copolymers and other polyalcohols and polyethers, wherein the capsule material has a reduced TEWS moisture or halogen dryer moisture content to < 10 wt.

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 calibration samples is required to determine the water content in weight per cent. The resulting calibration curve for subsequent measurements by the instrument is attached to the calculations. The moisture content is expressed in% by weight, 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 15 wt. The TEWS humidity also corresponds to 15% by weight, the humidity of the 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, a comparison with the absolute proportions of water is determined for a relative TEWS process by means of a halogen dryer.

The inhalation capsules of the invention have a TEWS moisture or halogen dryer moisture of less than 12 wt%, particularly preferably < 10 wt%.

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 gelatin which 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 copolymer and other polyalcohols and polyethers. Gelatin in admixture with PEG, preferably PEG 3350, is particularly suitable for the purposes of the present invention. Particularly preferably, the gelatin capsule of the invention comprises PEG in an amount of 1 to 10% by weight. %, preferably 3 to 8 wt. Particularly suitable gelatin capsules contain PEG in an amount of 4 to 6% by weight, with about 5% by weight being most preferred within the meaning of the invention.

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

The inhalation capsules of the present 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. The production of inhaler capsules for filling can also be carried out 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 of at most 15% by weight according to the specifications of the invention is reached. TEWS humidity or halogen dryer.

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

Another aspect of the present invention is the use of capsules that are characterized by less than 15% TEWS moisture or halogen dryer moisture 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% by weight 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% by weight, most preferably 0.16 to 0.4% by weight, 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% by weight.

According to the invention, inhalable powders which contain tiotropium bromide between 0.048 and 0.96% by weight, preferably between 0.096 and 0.77%, most preferably between 0.19 and 0.48% by weight, are of particular interest according to the invention.

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. Preferably, inhalants according to the invention are used for inhalation powders, the proportion of the finer excipient with respect to the total amount of excipient being 3 to 15% by weight, particularly preferably 5 to 10% by weight. For the purposes of the present invention, the percentages are by weight.

When, in the context of the present invention, reference is made to a mixture, this term is understood to mean a mixture which has been formed by mixing predefined components. Accordingly, e.g. only mixtures which are formed by mixing the coarse-weight component of the excipient with the more finely-divided component of the excipients are considered to be a mixture of coarse and fine particles.

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

When a mixture of coarser and finer excipient fractions is used as an excipient, these may also consist of chemically the same or chemically different substances, with inhalation powders in which a proportion of the coarser and finer particles come 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 capsules for inhalation according to the invention can be administered by means of 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 capsules for inhalation 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 to 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, inhalation 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. In a preferred filling of 4-6 mg of inhalation powder in an inhalation capsule, the content of tiotropium bromide monohydrate in the inhalation capsule is between 2 and 60 gg, preferably between 4 and 48 µg, particularly preferably between 8 and 30 µg.

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 and finer excipient particles is used as the excipient, first the preparation of the excipient mixture. If the excipient consists of a fraction with a medium particle size (e.g. 15 to 80 gm), 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 prior to filling the tiotropium-containing inhalable powder until the maximum TEWS or halogen dryer moisture content of the present invention is reached. 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-grain excipient is first introduced and finally a finer particle fraction is added to the mixer. Preferably, in this mixing process, the addition of both components is carried out in portions, with a portion of the more coarser excipient being introduced first and finally a finer and coarse excipient alternately added. In the preparation of the mixture of excipients, it is particularly advantageous to alternately sieve 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 μιη) is used.

Finally, the adjuvant or mixture of adjuvants and active ingredient is placed in a suitable mixer. The excipient used should have a mean particle size of from 0.5 to 10 μπ, preferably from 1 to 6 µm, particularly preferably from 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 can optionally be reintroduced or repeatedly into the 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 by the method described and subjected to the drying process described below.

The filled capsules are exposed for a period of from 0.5 to 10 hours, preferably from 1.5 to 7 hours, more preferably from 2 to 5.5 hours, particularly preferably from 2.5 to 4.5 hours, at a temperature of about 10 to 50 hours in the first phase (drying phase). ° 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 that follows (equilibrium phase), the capsules are exposed to a temperature of 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 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 to a temperature of about 23 ° C at a relative humidity of at most 35% for a period of 0.1 to 6 hours, preferably 0.5 to 4 hours, more preferably 0.75 to 2.5 hours, particularly preferably 1 to 2 hours. 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. For the purposes of the present invention, tiotropium bromide is to be understood as meaning 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. Crystalline tiotropium monohydrate produced according to the method described in detail can be used particularly preferably 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 Intemational, 5460 Veghel / NL under the designation Pharmatose 200M.

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

Production of crystalline tiotropium bromide monohydrate

In a suitable reaction vessel, 15.0 kg of tiotropium bromide was added to 25.7 kg of water. 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 formed is kept for at least 15 min. The mixture was stirred at 80-90 ° C and finally filtered through a heated filter into a preheated apparatus set to a jacket temperature of 70 ° C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled to 3 to 5 ° C in 20 min. cooled to 20-25 ° 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 described method 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 were read at a heat rate of 10 / min.

Crystalline tiotropium bromide monohydrate was characterized by IR spectroscopy. Data were read using a Nicolet FTIR spectrometer and evaluated by the Nicolet software package OMNIC 3.1. The measurement was performed with 2.5 gmol of 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 1035 Esther C-O Shifted freq 720 thiophene Circular oscillation

Crystalline tiotropium bromide monohydrate according to the method it has a simple monoclinic cell with the following dimensions: a = 18.0774 Å, b = 11.9711 Å, c = 9.9321 Å, β = 102.691 °, V = 2096.96 Å ^third These data were evaluated using an AFC7R-4-ring difftactometer (Rigaku) using mono-chromatized 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

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

Dispersing unit:

Quantity of sample:

Product Feed:

Vibration groove frequency:

Sample feed time:

Focal length:

Measuring time:

Cycle length:

Start / stop at:

Dispersing gas:

pressure:

vacuum:

Evaluation method:

HELOS Laser Spectrometer (SympaTec)

RODOS dry dispersant with suction funnel (SympaTec) from 100 mg Vibri groove, Fa Sympatec up to 100% ascending up to 15 s (in case of 100 mg)

100 mm (measuring range: 0.9 to 175 / im) approx. 15 s (in the case of 100 mg) ms% on channel 28 compressed air 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: Instrument and settings

The devices are operated in accordance with the manufacturer's operating instructions. Meter: Dispersing unit: Sample quantity: Product feed: Oscillating channel frequency: Sample feed duration: Focal length:

Measurement time: Cycle length:

Start / stop at: Dispersing gas: Pressure:

Vacuum: Evaluation method:

HELOS Laser Spectrometer (SympaTec)

RODOS dry dispersant with suction funnel (SympaTec) 50 mg to 400 mg Vibri groove, Sympatec Fa up to 100% ascending up to 25 s (in case of 200 mg)

100 mm (measuring range: 0.9 to 175 µm) approx. 15 s (for 200 mg) ms% on channel 28 compressed air bars (0.3 MPa) maximum

HRLD

Sample 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

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

Dispersing unit:

Quantity of sample:

HELOS Laser Spectrometer (SympaTec)

RODOS dry dispersant with suction funnel (SympaTec) 500 mg

Product Feed:

Vibration groove frequency:

Focal Length (1):

Focal Length (2): Sample Feed Duration:

Cycle length:

Start / stop at:

pressure:

vacuum:

Evaluation method:

vibrating trough Vibri, Fa Sympatec up to 100% ascending

200 mm (measuring range: 1.8 to 350 gm)

500 mm (measuring range: 4.5 to 875 gm) 10 ms ms per channel 19 bar (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 moved into the funnel of the vibrating trough. 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 BergischGladbach.

To determine the TEWS-moisture, the apparatus is used using the method described 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.

Moisture Drying Device Mettler Halogen Dryer HR 73; manufacturer: Firma Mettler-Toledo, D-35396 Giessen.

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

Capsule filling machine:

MG2, type G100, manufacturer: MG2 S. r. 1., 1-40065 Plana di Macina di Pianoro (BO), Italy.

BRIEF DESCRIPTION OF THE DRAWINGS

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 the more vibrant components. 1.68 kg of lactose monohydrate (5 gm) was 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 (5 µm) at doses of about 0.05 to 0.07 kg and lactose monohydrate per inhalation (200M) at doses of 0.8 to 1.2 kg in batches are added alternately by sieving through a sieve. Lactose monohydrate for inhalation (200M) and lactose monohydrate (5μηι) are added in 31 or 30 batches (tolerance ± 6 batches). 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%.

Correspondingly, use 32.87 kg of lactose monohydrate (200M) alone when an excipient fraction of medium particle size is required as an excipient. Naturally, in this case, 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 about 0.003 to 0.07 kg and the excipient or mixture of excipients (1.1) in batches of 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: 0.0225mg

Lactose monohydrate (200M): 5.2025mg

Lactose monohydrate (5 gm): 0.2750mg

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

Overall: 54.5 mg Example 3 Inhalation capsule Tiotropium bromide monohydrate: 0.0225 mg Lactose monohydrate (200M): 4.9275 mg Lactose monohydrate (5 gm): 0.5500 mg Solid gelatin capsule (5 wt% PEG 3350; 9 wt% TEWS humidity): 49.0 mg Overall: 54.5 mg 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 μ m): 0.2750 mg HPMC (<2% TEWS Moisture): 49.0 mg Overall: 54.5 mg Inhalable 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 μιη): 0.2750 mg Polywash (<5% TEWS moisture): 100.0 mg Overall: 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: 0.0225 mg Lactose monohydrate (200M): 5.4775 mg Polywash (<1% TEWS moisture): 100,0 me Overall: 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 μιή): 0.2750 mg Solid gelatin capsule (5% PEG 3350): 49,0 me Overall: 54.5 mg

These capsules are adjusted to a water content of about 8.7% by weight under suitable environmental conditions in the climate chamber. (TEWS Microwave Moisture Meter) using the method described above.

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: Deň: 29 ° C 10% y. in. (relative humidity) 3,5 h equilibrium phase: 30 ° C in. 3,5 h cooling phase: 23 ° C 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 gm 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.

PATENT CLAIMS

Claims (9)

Capsules for inhalation which contain tiotropium as an inhalation powder in admixture with a physiologically acceptable excipient, wherein the capsule material is gelatin in admixture with other additives selected from the group consisting of polyethylene glycol-PEG, glycerol, sorbitol, propylene glycol, PEO-PPO block copolymers and other polyalcohols and polyethers, characterized in that the capsule material has a reduced TEWS moisture content to < 10 wt. Capsules for inhalation according to claim 1, characterized in that the capsule material contains, in addition to gelatin, PEG in an amount of 1 to 10% by weight. Capsules for inhalation according to claim 1 or 2, characterized in that the inhalation powder contains 0.001 to 2% by weight of an inhalation powder. tiotropium in admixture with a physiologically acceptable excipient. Capsules for inhalation according to claim 3, 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 µηι, the proportion of finer excipient % of the total amount of excipient is 1 to 20 wt. Capsules for inhalation according to claim 4, characterized in that tiotropium is present in the form of chloride, bromide, iodide, methanesulfonate, para-toluenesulfonate or methylsulfate. Use of the capsules for inhalation according to any one of claims 1 to 5 for the preparation of a medicament for the treatment of asthma or COPD. 5 A method for producing capsules for inhalation according to any one of claims 1 to 5, comprising exposing the filled capsules to a relative humidity of 10 to 20%, for 0.5 to 10 hours, at a temperature of 10 to 50 ° C. A method for producing capsules for inhalation according to any one of claims 1 to 5, characterized in that, in a first phase, it comprises subjecting the filled capsules, for a period of 0.5 to 10 hours, at a temperature of 10 - 50 ° C, 10 relative humidity of 5-15%, and in a subsequent second phase, exposing the filled capsules to a relative humidity of 10-20%, for 0.5-10 hours, at a temperature of 10-50 ° C. Method according to claim 7 or 8, characterized in that the cooling phase is followed if the temperature in the preceding steps has been set to a level exceeding ambient temperature of -1, j. 23 ° C, during which the capsules are exposed to a relative humidity of 10-20%, for 0.1 to 6 hours, at 23 ° C.