HK1085918B - Pulverulent formulation for inhalation containing tiotropium - Google Patents

Description

Tiotropium-containing powder formulations for inhalation

Technical Field

The present invention relates to tiotropium containing powder formulations for inhalation, a process for their preparation and their use in the manufacture of pharmaceutical compositions for the treatment of respiratory diseases, in particular for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.

Background

Tiotropium bromide is known from european patent application EP 418716 a1, having the following chemical structure:

tiotropium bromide is a highly potent anticholinergic with a long-lasting activity, which can be used for the treatment of respiratory diseases, especially COPD (chronic obstructive pulmonary disease) and asthma. The term tiotropium refers to the free ammonium cation.

For the treatment of the above-mentioned diseases, it is advantageous to administer the active substance by inhalation. In addition to the administration of bronchoactive compounds in the form of metered aerosols and inhalable solutions, the use of inhalable powders containing active substance is of particular importance.

For active substances with particularly high efficacy, only small amounts of the active substance are required per single dose to achieve the desired therapeutic effect. In this case, the active substance must be diluted with a suitable excipient to prepare an inhalable powder. Because of the large amount of excipient, the choice of excipient seriously affects the properties of the inhalable powder. The particle size is particularly important when selecting the excipient. Generally, the finer the excipient, the poorer the flow characteristics. However, good flow characteristics are a prerequisite for highly accurate metering when individual doses of the formulation are packed or divided, for example when capsules for powder inhalation (inhalation tubes) are manufactured or when individual doses are metered by a patient before using a multi-dose inhaler. Furthermore, the particle size of the excipients is extremely important for the emptying characteristics of the capsule when used in an inhaler. It has also been found that the particle size of the excipient has a greater effect on the fraction of active substance in the inhalable powder that is delivered for inhalation. The term "inhalable fraction of active substance" refers to the particles of the inhalable powder that, when inhaled by breathing, are transported to the depth of the pulmonary branches. The desired particle size is between 1 and 10 μm, preferably less than 6 μm.

Disclosure of Invention

The aim of the present invention is to produce an inhalable powder containing tiotropium which, when accurately metered (in terms of the amount of active substance and powder mixture filled into each capsule, and the amount of active substance released from each capsule and delivered to the lungs by the inhalation process) allows the active substance to be administered in a large inhalable fraction with only slight deviations between batches. Another object of the present invention is to prepare an inhalable powder containing tiotropium which guarantees good emptying characteristics of the capsule, whether or not it is administered to a patient ex vivo by means of an inhaler (for example, as described in WO 94/28958) or by means of a compressor or a striker.

The fact that tiotropium, and in particular tiotropium bromide, has therapeutic efficacy even at very low doses imposes further limitations on the inhalable powders used with high precision metering. Since only low concentrations of active substance are required in the inhalable powder to achieve the therapeutic effect, a high homogeneity of the powder mixture and its only slight fluctuations in the dispersion characteristics from one batch of capsules to the next are necessary. The homogeneity of the powder mixture and the small fluctuations in the dispersion characteristics are extremely critical to ensure a repeated (reproducible) release of the inhalable fraction of active substance in constant amounts and with the lowest possible variation.

It is therefore a further object of the present invention to prepare inhalable powders containing tiotropium which are characterized by a high uniformity and consistency of dispersion. The invention also provides an inhalable powder which allows the inhalable fraction of the active substance to be administered with the lowest possible variation.

Inhalable powders containing tiotropium which meet the requirements listed above are known, for example, from WO 02/30389. The essential feature of these inhalable powders is that they contain, in addition to the active substance tiotropium in the form of one of the pharmaceutically acceptable salts formed from tiotropium, an excipient obtained by mixing a coarser excipient fraction (fraction) with a finer excipient fraction. However, to prepare these inhalable powders known from WO02/30389, technically complex manufacturing and mixing processes are required. It is therefore a further object of the present invention to provide inhalable powders which not only solve the above-mentioned problems but are also obtainable by easier manufacturing technical processes.

The feature of emptying from the powder reservoir (the container from which the inhalable powder containing the active substance is released for inhalation) plays an important role, particularly (but not exclusively) in the use of powder-containing capsules for administering inhalable powders. If only a small amount of the powdered formulation is released from the powder reservoir due to a minimum or poor emptying characteristic, a large amount of inhalable powder containing the active substance is left in the powder reservoir (e.g. capsule) and cannot be used for treatment by the patient. This results in the necessity of increasing the dosage of the active substance in the powder mixture so that the amount of active substance delivered is sufficient to produce the desired therapeutic effect.

In view of this background, the present invention also provides an inhalable powder which is also characterized by excellent emptying characteristics.

Detailed Description

It has surprisingly been found that the objects outlined above can be achieved by a powdered formulation for inhalation (inhalable powder) according to the invention as described below.

The invention therefore relates to an inhalable powder containing 0.001 to 3% tiotropium mixed with a physiologically acceptable excipient, characterized in that the excipient has a mean particle size of 10-50 μm, has a fine particle fraction (fine content) of 10% 0.5-6 μm and has a particle size of 0.1 to 2m²Specific surface area in g.

By average particle diameter is meant 50% of the volume distribution value measured by the dry dispersion method using a laser diffractometer. Similarly, the 10% fine particle fraction in this case refers to a 10% value of the volume distribution measured using a laser diffractometer. In other words, for the purposes of the present invention, the 10% fine particle fraction represents a particle size below this value, and a particle amount of 10% (based on the volume distribution) can be found.

By specific surface area is meant, for the purposes of the present invention, from N₂The powder surface area of the specific mass calculated by the sorption isotherm (which can be observed at the boiling point of liquid nitrogen) (method of Brunauer, Emmett and Teller).

Inhalable powders containing 0.01 to 2% tiotropium are preferred according to the invention. Particularly preferred inhalable powders contain tiotropium in an amount of about 0.03 to 1%, preferably 0.05 to 0.6%, more preferably 0.06 to 0.3%. Finally, inhalable powders according to the invention containing about 0.08 to 0.22% tiotropium are of particular importance.

By tiotropium is meant the free ammonium cation. Where the term active substance is used within the scope of the present invention, it is to be understood as referring to tiotropium in combination with the corresponding counter ion. The counter ion (anion) may preferably be chloride, bromide, iodide, mesylate or p-toluenesulfonate. Among these anions, bromide is preferred.

The invention therefore preferably relates to inhalable powders containing 0.0012 to 3.6%, preferably 0.012 to 2.4% tiotropium bromide. Inhalable powders containing about 0.036 to 1.2%, preferably 0.06 to 0.72%, more preferably 0.072 to 0.36% tiotropium bromide are of particular importance according to the invention. Inhalable powders containing between about 0.096 and 0.264% tiotropium bromide are of particular importance according to the invention.

Tiotropium bromide preferably contained in the inhalable powder according to the invention may comprise solvent molecules during the crystallization. Preferably, a hydrate of tiotropium bromide can be used for the preparation of tiotropium containing inhalable powders according to the invention. Most preferably, crystalline tiotropium bromide monohydrate known from WO 02/30928 is used. This crystalline tiotropium bromide monohydrate is characterized in that: when analyzed thermally by DSC, it has an endothermic maximum at 230. + -. 5 ℃ at a heating rate of 10K/min. It is also characterized in that: in the IR spectrum, they have wavelengths lying in particular at 3570, 3410, 3105, 1730, 1260, 1035 and 720cm^-1Band at wavelength. Finally, this crystalline tiotropium bromide monohydrate has simple monoclinic units, the dimensions of which, determined by single crystal X-ray structural analysis, are as follows:β＝102.691°，V＝2096.96A³。

the invention therefore relates to a powder for inhalation comprising 0.0013 to 3.75%, preferably 0.0125 to 2.5%, of tiotropium bromide monohydrate. Inhalable powders containing about 0.0375 to 1.25%, preferably 0.0625 to 0.75%, more preferably 0.075 to 0.375% tiotropium bromide monohydrate are of particular importance according to the present invention. Finally, inhalable powders containing between about 0.1 and 0.275% tiotropium bromide monohydrate are of particular importance according to the invention.

The percentages given within the scope of the invention are always percentages by weight, unless otherwise indicated.

In a particularly preferred inhalable powder, the excipient is characterized in that: the average particle diameter thereof is 12 to 35 μm, more preferably 13 to 30 μm. Also particularly preferred are inhalable powders in which the 10% fine-particle fraction is about 1 to 4 μm, preferably about 1.5 to 3 μm.

It is also preferred according to the invention wherein the excipient has a size of 0.2 to 1.5m²A/g, preferably from 0.3 to 1.0m²Inhalable powders of specific surface area/g.

Excipients for the purposes of the present invention are prepared by conventional methods known in the art with suitable milling and/or sieving. In particular, the excipient used according to the present invention is not an excipient mixture obtained by mixing excipient portions having different average particle diameters.

Examples of physiologically acceptable excipients that can be used to prepare the inhalable powders for use in the inhalation tubes of the invention include, for example, monosaccharides (such as glucose or arabinose), disaccharides (such as lactose, sucrose, maltose, trehalose), oligo-and polysaccharides (such as dextran), polyols (such as sorbitol, mannitol, xylitol), or salts (such as sodium chloride, calcium carbonate). Preferably, a monosaccharide or a disaccharide is used, and preferably, lactose or glucose is used, particularly but not limited to the form of hydrates thereof. For the purposes of the present invention, lactose is a particularly preferred excipient, and lactose monohydrate is most particularly preferred.

Preferably, excipients with a high degree of crystallinity are used for the pulverulent formulation according to the invention. This crystallinity can be assessed by the enthalpy released when the excipient dissolves (enthalpy of dissolution). In the case of the lactose monohydrate excipient most preferably used according to the invention, it is preferred to use lactose having the following characteristics: the enthalpy of dissolution is 45J/g or more, preferably 50J/g or more, particularly preferably 52J/g or more.

The inhalable powders according to the invention are characterized (according to the problem on which the invention is based) in that: high uniformity in the sense of accuracy of a single dose. This range is < 8%, preferably < 6%, more preferably < 4%.

After the starting materials have been weighed, the inhalable powder is prepared from excipients and active substance by using methods known in the art. For example, reference is made to the disclosure of WO 02/30390. Thus, the inhalable powders according to the invention may be obtained by a method such as described below. In the preparation methods described below, these ingredients are used in the weight ratios described above for the compositions of inhalable powders.

First, the excipients and the active substance are placed in a suitable mixing vessel. The average particle size of the active substance used is from 0.5 to 10 μm, preferably from 1 to 6 μm, most preferably from 2 to 5 μm. The excipients and the active substance are preferably added using a sieve or a granulation sieve having a mesh size of 0.1 to 2mm, preferably 0.3 to 1mm, most preferably 0.3 to 0.6 mm. Preferably, the excipient is first placed and then the active substance is added to the mixing container. During this mixing, the two components are preferably added in a batch manner. Particular preference is given to sieving (sieve) the two components in alternating layers. The excipients may be mixed with the active substance while still adding the two ingredients. However, it is preferred that mixing is only performed when the two components have been screened layer by layer.

If, after chemical preparation, the active substance used in the above process has not yet reached its crystalline form with the aforementioned particle size, it can be milled to a particle size which meets the aforementioned parameters (so-called micronization).

If the active substance used is crystalline tiotropium bromide monohydrate as disclosed in WO 02/30928, which is particularly preferred according to the invention, the following procedure has proved to be particularly suitable for micronization of this crystalline active substance modification. The process can be carried out using a conventional mill. This micronization is preferably done under exclusion of moisture, more preferably under use of a corresponding inert gas (e.g. nitrogen). It has proven particularly preferred to use air jet mills in which the material is comminuted by mutual impact of the particles and impact against the wall of the grinding vessel. According to the invention, nitrogen is preferably used as the grinding gas. The material for grinding is conveyed by the grinding gas under a specific pressure (grinding pressure). Within the scope of the present invention, the grinding pressure is generally set to about 2 to 8 bar, preferably about 3 to 7 bar, most preferably about 3.5 to 6.5 bar. The material for grinding is conveyed into the air jet mill by a feed gas at a specific pressure (feed pressure). Within the scope of the present invention, a feed pressure of about 2 to 8 bar, preferably about 3 to 7 bar and most preferably about 3.5 to 6 bar has proven satisfactory. The feed gas used is also preferably an inert gas, and most preferably nitrogen. The material to be milled (crystalline tiotropium bromide monohydrate) may be fed at a rate of about 5-35 g/min, preferably about 10-30 g/min.

For example, without limiting the subject matter of the invention, the following device has proved suitable for a possible embodiment acting as an air jet mill: a 2 inch pulverizer with grinding rings, 0.8mm pore size, manufactured by Messrs Sturtevant inc, 348 circuitsimple street, Hanover, MA 02239, USA. Using this apparatus, the grinding process is preferably carried out by the following grinding parameters: grinding pressure: about 4.5-6.5 bar; feeding pressure: about 4.5-6.5 bar; supply of abrasive material: about 17-21 g/min.

Subsequently, the abrasive material thus obtained was further processed under the following specific conditions. Exposing the micropowder to water vapor at a relative humidity of at least 40% and a temperature of 15-40 deg.C, preferably 20-35 deg.C, most preferably 25-30 deg.C. The humidity is preferably set to 50-95% r.h., preferably 60-90% r.h., most preferably 70-80% r.h. By relative humidity (r.h.), it is meant the ratio of the partial vapor pressure to the vapor pressure of water at the temperature in question. The micropowder obtained from the aforementioned grinding process is preferably subjected to the aforementioned chamber conditions for a period of at least 6 hours. However, the micropowder is preferably subjected to the above-described chamber conditions for about 12 to 48 hours, preferably about 18 to 36 hours, more preferably about 20 to 28 hours.

The fine powder of tiotropium bromide obtained by the above method has a particle size of 1.0 to 3.5 μm, preferablyA characteristic particle size of 1.1 μm to 3.3 μm, most preferably 1.2 μm to 3.0 μm; and has a Q of greater than 60%, preferably greater than 70%, most preferably greater than 80%_{(5 8)}. Characteristic value Q_{(5 8)}Indicating an amount of particles below 5.8 μm based on the volume distribution of the particles. The particle size in the context of the present invention is determined by laser diffraction (Fraunhofer diffraction). More detailed information on this subject can be found in the experimental description of the invention.

The tiotropium micropowder prepared by the aforementioned process according to the present invention is characterized by a specific surface area value of 2m²G to 5m²In g, more particularly in the range of 2.5m²G to 4.5m²G, and most notably at 3.0m²G to 4.0m²In the range of/g.

A particularly preferred aspect of the invention relates to an inhalable powder according to the invention, characterized by the content of tiotropium bromide monohydrate micropowder described above.

The invention further relates to the use of the inhalable powder according to the invention for the preparation of a pharmaceutical composition for the treatment of respiratory diseases, in particular for the treatment of COPD and/or asthma.

The inhalable powders according to the invention may for example be administered using an inhaler which meters a single dose from a reservoir either through a measuring chamber (e.g. according to US 4570630a) or through other means (e.g. according to DE 3625685 a). However, the inhalable powders according to the invention are preferably encapsulated (to make so-called inhalants) which are used in inhalers, for example as described in WO 94/28958.

Capsules containing the inhalable powder according to the invention are most preferably administered by means of an inhaler as shown in figure 1. This inhaler is characterized in that: a housing 1 comprising two windows 2; a cover plate (deck)3 in which a plurality of air inlets are provided and which is equipped with a mesh screen 5 protected by a mesh screen jacket 4; a suction chamber 6 connected to the cover 3 and provided with a push-button 9, the push-button 9 being equipped with two pointed pegs 7 and moving in the opposite direction to the spring 8; and a mouthpiece (mouthpiece)12 connected to the housing 1, the cover plate 3 and the housing 11 by a shaft 10 so that the mouthpiece can be flipped open or closed; and an air hole 13 for adjusting flow resistance.

The invention further relates to the use of the inhalable powder according to the invention for the preparation of a pharmaceutical composition for the treatment of respiratory diseases, in particular for the treatment of COPD and/or asthma, characterized in that an inhaler as described above and shown in fig. 1 is used.

For administering the inhalable powders according to the invention with powder-filled capsules, it is especially preferred to use capsules of a material selected from the following synthetic plastics, most preferably from the group consisting of polyethylene, polycarbonate, polyester, polypropylene and polyethylene terephthalate. Particularly preferred synthetic plastics materials are polyethylene, polycarbonate or polyethylene terephthalate. If the particularly preferred polyethylene according to the invention is used as one of the capsule materials, preference is given to using a density of from 900 to 1000kg/m³Preferably 940-³More preferably about 960-³Polyethylene (high density polyethylene).

The synthetic plastics according to the invention can be treated in various ways using manufacturing methods known in the art. According to the invention, injection moulding of plastics is preferred. Injection molding without using a mold release agent is particularly preferred. The production process is specified and characterized in that it is particularly reproducible.

Another aspect of the invention relates to the above-described capsule containing the above-described inhalable powder according to the invention. These capsules may contain about 1 to 20mg, preferably about 3 to 15mg, most preferably about 4 to 12mg of inhalable powder. Preferred formulations according to the invention contain 4 to 6mg of inhalable powder. Equally important according to the invention are capsules for inhalation containing 8 to 12mg of the formulation according to the invention.

The invention also relates to an inhalation device (inhalation kit) comprising one or more of the above-described capsules characterized by the content of inhalable powder according to the invention and combined with an inhaler according to fig. 1.

The invention also relates to the use of the above-mentioned capsules, characterized by the content of inhalable powders according to the invention, for the preparation of a pharmaceutical composition for the treatment of respiratory diseases, in particular for the treatment of CODP and/or asthma.

Filled capsules containing the inhalable powder according to the invention are prepared by filling the inhalable powder according to the invention into empty capsules by methods known in the art.

The following examples are intended to illustrate the invention in detail without limiting the scope of the invention to the following exemplary examples.

Starting material

I) Excipient:

in the following examples, lactose monohydrate was used as excipient. It is obtained, for example, from BorculoDomo Ingredients, Borculo/NL, product name Lacochem Extra Fine Powder. This grade of lactose meets the specifications according to the invention regarding particle size and specific surface area. Furthermore, the lactose has the preferred enthalpy of dissolution of the lactose according to the invention described above.

II) micronization of crystalline tiotropium bromide monohydrate:

tiotropium bromide monohydrate obtained according to WO 02/30928 was micronized by means of an air jet mill of the 2 inch mill type with grinding rings, 0.8mm holes, manufactured by Messrs Sturtevant inc, 348 Circuit Street, Hanover, MA 02239, USA. With nitrogen as the polishing gas, the following polishing parameters were set, for example:

grinding pressure: 5.5 bar; feeding pressure: 5.5 bar; supply or flow rate (of crystalline monohydrate): 19 g/min.

The obtained abrasive material was then dispersed on a thin sheet metal holder in a layer thickness of about 1cm and subjected to the following climatic conditions for 24-24.5 hours: temperature: 25-30 ℃; relative humidity: 70-80 percent.

The measuring method comprises the following steps:

the particle size of the micronized tiotropium monohydrate was determined:

measuring device and setting

The apparatus is operated according to the manufacturer's instructions.

The measuring equipment comprises: HELOS laser-diffraction spectrometer (SympaTec)

Dispersing element: RODOS Dry disperser with suction filtration funnel, (SympaTec)

Sample amount: 200 mg. + -. 150mg

Product feeding: vibri vibrating trough, messrs. sympatec

Frequency of vibration groove: increasing the content to 100 percent

Sample feed duration: 15 to 25 seconds (in the case of 200 mg)

Focal length: 100mm (measuring range: 0.9-175 μm)

Measuring time: about 15 seconds (in the case of 200 mg)

Cycle time: 20ms

Start/end with: 1% on the groove 28

Dispersing gas: compressed air

Pressure: 3 bar

Vacuum: maximum of

The evaluation method comprises the following steps: HRLD

Sample preparation/product feed：

Approximately 200mg of the test substance was weighed onto a card. All larger pieces were broken up using another card. The powder was then sprinkled finely in the first half of the vibrating trough (starting at about 1cm from the leading edge). After the start of the measurement, the frequency of the vibrating trough is changed so that the sample is fed as continuously as possible. However, the amount of product should not be too great to ensure adequate dispersion.

II) determination of the particle size of lactose:

measurement equipment and setting:

the apparatus is operated according to the manufacturer's instructions.

The measuring equipment comprises: HELOS laser-diffraction spectrometer (SympaTec)

Dispersing element: RODOS Dry disperser with suction filtration funnel, (SympaTec)

Sample amount: 200 mg. + -. 100mg

Product feeding: vibri vibrating trough, messrs. sympatec

Frequency of vibration groove: increasing the content to 100 percent

Focal length: 200mm (measuring range: 1.8-350 μm)

Measuring time: about 10 seconds (in the case of 200 mg)

Cycle time: 10ms

Start/end with: 1% on the groove 28

Dispersing gas: compressed air

Pressure: 3 bar

Vacuum: maximum of

The evaluation method comprises the following steps: HRLD

Sample preparation/product feed:

approximately 200mg of the test substance was weighed onto a card. All larger pieces were broken up using another card. The powder was then transferred to a vibrating tank. A gap of 1.2 to 1.4mm was set between the vibrating trough and the funnel. After the start of the measurement, the frequency of the vibrating trough is increased as continuously as possible to reach 100% at the end of the measurement.

III) determination of the specific surface area of micronized tiotropium bromide monohydrate (1 point BET method):

the method comprises the following steps:

the specific surface was determined by exposing the powder samples to nitrogen/helium atmospheres at different pressures. The sample is cooled, causing nitrogen molecules to condense on the surface of the particles. The amount of condensed nitrogen is determined by the change in thermal conductivity of the nitrogen/helium mixture and the surface of the sample is calculated from the amount of nitrogen required at the surface. The specific surface was calculated using this value and the weight of the sample.

Equipment and materials:

the measuring equipment comprises: monosorb, Messrs Quantachrome

A heater: monotektor, Messrs Quantachrome

Measuring and drying gas: nitrogen (5.0)/helium (4.6)70/30, Messer Griesheim

Adsorbate: 30% nitrogen in helium

Cooling agent: liquid nitrogen

Measurement cell (measurement cell): through capillary, Messrs.W.Pabisch GmbH & Co.KG

Correcting the peak value: 1000. mu.l, Messrs. precision Sampling Corp.

Analytical scale (analytical scale): R160P, messrs

Calculating the specific surface:

the measured value is passed through the apparatus in [ m ]²]Expressed, and usually converted to [ cm ] by weight²/g](dry mass):

IV) determination of the specific surface area of lactose (multipoint BET method):

the method comprises the following steps:

the specific surface was determined by exposing the powder samples to nitrogen atmosphere at different pressures. The sample is cooled, causing nitrogen molecules to condense on the surface of the particles. The amount of condensed nitrogen is determined by the reduction of pressure in the system and the specific surface of the sample is calculated from the amount of nitrogen required at the surface and the weight of the sample.

The apparatus is operated according to the manufacturer's instructions.

Measurement equipment and setting:

the measuring equipment comprises: tri Star Multi Point BET, Messrs Micromeritics

A heater: VacPrep 061, messrs micromeritics

Heating: about 12 hours/40 deg.C

Sample tube: 1/2 inches; using a filling rod (filler rod)

Analysis conditions were as follows: 10 point BET surface area 0.1 to 0.20p/p0

Absolute p. tolerance: 5.0mmHg

Relative p. tolerance: 5.0 percent

Evacuation rate: 50.0mmHg/sec.

Undefined evacuation frequency: 10.0mmHg

Evacuation time: 0.1 hour

Free space: lower Dewa, time: 0.5 hour

Balancing interval: 20 seconds

Minimum equilibrium delay: 600 seconds

Adsorbate: nitrogen gas

V) determination of the heat of dissolution (enthalpy of dissolution) E_c：

The enthalpy of dissolution was determined by a Calorimeter 2225 precision solution Calorimeter manufactured by messrs.

The heat of dissolution is calculated by the occurrence of a temperature change (caused by the dissolution process) and the change in temperature associated with the system calculated from the baseline.

Before and after breaking the ampoule (ampoule), electrical correction is made by means of an integrated heating resistor with precise known power. A known heat output is delivered to the system over a fixed period and the temperature jump is measured.

Method and device parameters:

dissolution calorimeter: 2225 Precision solution calorimeter (2225 Precision solution calorimeter), meters Thermometer

A reaction tank: 100ml of

Thermistor resistance: 30.0 k.OMEGA. (at 25 ℃ C.)

Stirring speed: 500U/min

A thermostat: 2277 thermostat for Thermal Activity Monitor (Thermal Activity Monitor) TAM, Messrs Thermometer

Temperature: 25 ℃ plus or minus 0.0001 ℃ (24 hours)

Measuring an ampoule: crushed ampoules 1ml, Messrs Thermometric

Sealing: silicon plugs or beeswax, messrs

Weight: 40 to 50mg

Solvent: chemical pure water

Volume of solvent: 100ml of

Bath temperature: 25 deg.C

Temperature resolution: height of

Initial temperature: -40mK (+ -10 mK) temperature excursion

Interface: 2280 + 002TAM attachment interface 50Hz, Messrs Thermometric

Software: solcal V1.1 for WINDOWS

And (3) evaluation: the assessment was automated by means of Menu point Calculation/Analysse EXPERIMENT. (kinetics of baseline; correction after ampoule rupture).

And (3) electrical correction:

the electrical correction takes place during the measurement, once before and once after the ampoule has been broken. The correction after ampoule breakage was used for evaluation.

Heat quantity: 2.5J

Heating power: 500nW

Heating time: 10 seconds

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

Preparation of the pulverulent formulation according to the invention:

I) device for measuring the position of a moving object

For example, the following machines and apparatuses may be used for the preparation of inhalable powders:

mixing vessel or powder mixer: turbulamischer 2L, model 2C; manufactured by Willy A.Bachofen AG, CH-4500Basel

Hand-held mesh screen: mesh size of 0.135mm

The tiotropium containing inhalable powder can be filled into empty inhalation capsules either manually or mechanically. The following equipment may be used.

Capsule filling machine:

MG2, model G100, manufacturer: r.l, I-40065Pian di Macina dipianato (BO), Italy

Example 1:

powder mixture:

to prepare the powder mixture 299.39g of excipient and 0.61g of micronized tiotropium bromide monohydrate were used. The content of active substance in the 300g of inhalable powder obtained was 0.2% (based on tiotropium).

About 40-45g of excipient was placed in a suitable mixing container through a hand held mesh screen having a mesh size of 0.315 mm. Next, batches of about 90-110mg of tiotropium bromide monohydrate and batches of about 40-45g of excipient were sieved in alternating layers. 7 layers of excipient and 6 layers of active substance were added, respectively.

After sifting in, the components are then mixed (mixing speed 900 rpm). The final mixture was passed through the hand held screen two more times and then remixed at 900 rpm.

Using the method described in example 1, an inhalable powder can be obtained which, when encapsulated in a suitable plastic capsule, can be used to produce the following capsules for inhalation, for example:

example 2:

tiotropium bromide monohydrate: 0.0113mg

Lactose monohydrate^*)： 5.4887mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 17.9 μm;

10% fine particle fraction: 2.3 μm; :

specific surface area: 0.61m²/g；

Example 3:

tiotropium bromide monohydrate: 0.0113mg

Lactose monohydrate^*)： 5.4887mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 18.5 μm;

10% fine particle fraction: 2.2 μm;

specific surface area: 0.83m²/g；

Example 4:

tiotropium bromide monohydrate: 0.0113mg

Lactose monohydrate^*)： 5.4887mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 21.6 μm;

10% fine particle fraction: 2.5 μm;

specific surface area: 0.59m²/g；

Example 5:

tiotropium bromide monohydrate: 0.0113mg

Lactose monohydrate^*)： 5.4887mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 16.0 μm;

10% fine particle fraction: 2.0 μm;

specific surface area: 0.79m²/g；

Example 6:

tiotropium bromide monohydrate: 0.0225mg

Lactose monohydrate^*)： 5.4775mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 17.9 μm;

10% fine particle fraction: 2.3 μm;

specific surface area: 0.61m²/g；

Example 7:

tiotropium bromide monohydrate: 0.0225mg

Lactose monohydrate^*)： 5.4775mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 18.5 μm;

10% fine particle fraction: 2.2 μm;

specific surface area: 0.83m²/g；

Example 8:

tiotropium bromide monohydrate: 0.0225mg

Lactose monohydrate^*)： 5.4775mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 21.6 μm;

10% fine particle fraction: 2.5 μm;

specific surface area: 0.59m²/g；

Example 9:

tiotropium bromide monohydrate: 0.0225mg

Lactose monohydrate^*)： 5.4775mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 16.0 μm;

10% fine particle fraction: 2.0 μm;

specific surface area: 0.79m²/g；

Example 10:

tiotropium bromide monohydrate: 0.0056mg

Lactose monohydrate^*)： 5.4944mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 17.9 μm;

10% fine particle fraction: 2.3 μm;

specific surface area: 0.61m²/g；

Example 11:

tiotropium bromide monohydrate: 0.0056mg

Lactose monohydrate^*)： 5.4944mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 18.5 μm;

10% fine particle fraction: 2.2 μm;

specific surface area: 0.83m²/g；

Example 12:

tiotropium bromide monohydrate: 0.0056mg

Lactose monohydrate^*)： 5.4944mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 21.6 μm;

10% fine particle fraction: 2.5 μm;

specific surface area: 0.59m²/g；

Example 13:

tiotropium bromide monohydrate: 0.0056mg

Lactose monohydrate^*)： 5.4944mg

Polyethylene capsule: 100.0mg

In total: 105.5mg

^*)The excipient is characterized by the following parameters:

average particle size: 16.0 μm;

10% fine particle fraction: 2.0 μm;

specific surface area: 0.79m²/g；

Example 14:

tiotropium bromide monohydrate: 0.0056mg

Lactose monohydrate^*)： 9.9944mg

Polyethylene capsule: 100.0mg

In total: 110.0mg

^*)The excipient is characterized by the following parameters:

average particle size: 17.9 μm;

10% fine particle fraction: 2.3 μm;

specific surface area: 0.61m²/g；

Example 15:

tiotropium bromide monohydrate: 0.0113mg

Lactose monohydrate^*)： 9.9887mg

Polyethylene capsule: 100.0mg

In total: 110.0mg

^*)The excipient is characterized by the following parameters:

average particle size: 18.5 μm;

10% fine particle fraction: 2.2 μm;

specific surface area: 0.83m²/g；

Example 16:

tiotropium bromide monohydrate: 0.0225mg

Lactose monohydrate^*)： 9.9775mg

Polyethylene capsule: 100.0mg

In total: 110.0mg

^*)The excipient is characterized by the following parameters:

average particle size: 21.6 μm;

10% fine particle fraction: 2.5 μm;

specific surface area: 0.59m²/g；

Example 17:

tiotropium bromide monohydrate: 0.0125mg

Lactose monohydrate^*)： 9.9875mg

Polyethylene capsule: 100.0mg

In total: 110.0mg

^*)The excipient is characterized by the following parameters:

average particle size: 17.9 μm;

10% fine particle fraction: 2.3 μm;

specific surface area: 0.61m²/g；

Example 18:

tiotropium bromide monohydrate: 0.0125mg

Lactose monohydrate^*)： 9.9875mg

Polyethylene capsule: 100.0mg

In total: 110.0mg

^*)The excipient is characterized by the following parameters:

average particle size: 18.5 μm;

10% fine particle fraction: 2.2 μm;

specific surface area: 0.83m²/g；

Example 19:

tiotropium bromide monohydrate: 0.0125mg

Lactose monohydrate^*)： 9.9875mg

Polyethylene capsule: 100.0mg

In total: 110.0mg

^*)The excipient is characterized by the following parameters:

average particle size: 21.6 μm;

10% fine particle fraction: 2.5 μm;

specific surface area: 0.59m²/g；

Example 20:

tiotropium bromide monohydrate: 0.0125mg

Lactose monohydrate^*)： 9.9875mg

Polyethylene capsule: 100.0mg

In total: 110.0mg

^*)The excipient is characterized by the following parameters:

average particle size: 16.0 μm;

10% fine particle fraction: 2.0 μm;

specific surface area: 0.79m²/g；

Claims (38)

1. Capsule containing an inhalable powder, wherein the capsule material is selected from polyethylene, polyester and polypropylene, and wherein the inhalable powder comprises 0.001-3% tiotropium mixed with a physiologically acceptable excipient selected from glucose, arabinose, lactose, sucrose, maltose and trehalose, optionally in the form of its hydrates, the excipient having an average particle size of 10-50 μm, a 10% fine particle fraction of 0.5-6 μm and a specific surface area of 0.1-2 m²/g。

2. Capsule according to claim 1, characterized in that the polyester is polycarbonate or polyethylene terephthalate.

3. Capsule according to claim 1, characterized in that the tiotropium is present in the form of its chloride, bromide, iodide, mesylate or tosylate.

4. Capsule according to claim 1, characterized in that the capsule material is selected from polyethylene, polycarbonate or polyethylene terephthalate.

5. Capsule according to claim 3, characterized in that the capsule material is selected from polyethylene, polycarbonate or polyethylene terephthalate.

6. Capsule according to claim 1, characterized in that the capsule material is of 900-³A polyethylene of density.

7. Capsule according to claim 3, characterized in that the capsule material is of the order of 900-³A polyethylene of density.

8. Capsule according to claim 4, characterized in that the capsule material is of the order of 900-³A polyethylene of density.

9. Capsule according to claim 1, characterized in that it contains 1-20mg of powder for inhalation.

10. Capsule according to claim 3, characterized in that it contains 1-20mg of powder for inhalation.

11. Capsule according to claim 4, characterized in that it contains 1-20mg of powder for inhalation.

12. Capsule according to claim 5, characterized in that it contains 1-20mg of powder for inhalation.

13. Capsule according to claim 6, characterized in that it contains 1-20mg of powder for inhalation.

14. Capsule according to claim 7, characterized in that it contains 1-20mg of powder for inhalation.

15. Capsule according to claim 8, characterized in that it contains 1-20mg of powder for inhalation.

16. Capsule according to one of claims 1 to 15, characterized in that the tiotropium is present in the form of bromide.

17. Capsule according to claim 16, characterized in that the tiotropium is present in the form of a micronized tiotropium bromide, characterized by a particle size ranging from 1.0 μm to 3.5 μm and a particle quantity (Q) lower than 5.8 μm₍₅₈₎) More than 60 percent and the specific surface area value is 2m²G to 5m²/g。

18. Capsule according to one of claims 1 to 15, wherein the inhalable powder comprises tiotropium in an amount of 0.03-1%.

19. Capsule according to claim 16, wherein the inhalable powder comprises tiotropium in an amount of 0.03-1%.

20. Capsule according to claim 17, wherein the inhalable powder comprises tiotropium in an amount of 0.03-1%.

21. Capsule according to claim 18, wherein the inhalable powder comprises tiotropium in an amount of 0.05-0.6%.

22. Capsule according to claim 19, wherein the inhalable powder comprises tiotropium in an amount of 0.05-0.6%.

23. Capsule according to claim 20, wherein the inhalable powder comprises tiotropium in an amount of 0.05-0.6%.

24. Capsule according to claim 18, wherein the inhalable powder comprises tiotropium in an amount of 0.06-0.3%.

25. Capsule according to claim 19, wherein the inhalable powder comprises tiotropium in an amount of 0.06-0.3%.

26. Capsule according to claim 20, wherein the inhalable powder comprises tiotropium in an amount of 0.06-0.3%.

27. Use of a capsule according to one of claims 1 to 15 for the preparation of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

28. Use of a capsule according to claim 16 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

29. Use of a capsule according to claim 17 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

30. Use of a capsule according to claim 18 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

31. Use of a capsule according to claim 19 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

32. Use of a capsule according to claim 20 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

33. Use of a capsule according to claim 21 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

34. Use of a capsule according to claim 22 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

35. Use of a capsule according to claim 23 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

36. Use of a capsule according to claim 24 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

37. Use of a capsule according to claim 25 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.

38. Use of a capsule according to claim 26 in the manufacture of a pharmaceutical composition for the treatment of a respiratory disease selected from COPD and asthma.