ZA200502859B

ZA200502859B - Pulverulent formulation for inhalation containing tiotropium.

Info

Publication number: ZA200502859B
Application number: ZA200502859A
Authority: ZA
Inventors: Mareke Hartig; Michael Trunk; Michael Walz
Original assignee: Boehringer Ingelham Pharma Gmb
Priority date: 2002-11-28
Filing date: 2005-04-08
Publication date: 2006-02-22
Also published as: ES2310681T3; PT1567135E; BR0316343A; MEP51608A; TW200500066A; NO20053090D0; RS20050400A; SI1567135T1; DE50310208D1; IL168810A; MXPA05005485A; DK1567135T3; WO2004047796A2; AU2003294714B2; KR101066805B1; NO20053090L; CA2507579C; UY28096A1; CY1108420T1; UA81930C2

Description

"ee . v ' ’ 82486pct.212

Pulverulent formulation for inhalati on containing tiotropium

The invention relates to powdered preparations containing tiotropium for inhalation, processes for preparing them as well as their usse for preparing a pharmaceutical composition for treating respiratory complaints, goarticularly for treating COPD (chronic obstructive pulmonary disease) and asthma.

Background to the @nvention

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

H,C. N .CH, 0) Br~ 0)

HO 0) ~— —

N\_S SZ

Tiotropium bromide is a highly effective anticholi nergic with a long-lasting activity which can be used to treat respiratory complaint s, particularly COPD (chronic obstructive pulmonary disease) and asthma. The term tiotropium refers to the free ammonium cation.

For treating the abovementioned complaints, it is useful to administer the active substance by inhalation. In addition to the admirmistration of broncholytically active compounds in the form of metered aerosols and inhalable solutions, the use of inhalable powders containing active substance is of particular importance.

With active substances which have a particularly= high efficacy, only small amounts of the active substance are needed per single doses to achieve the desired therapeutic effect. In such cases, the active substance has teo be diluted with suitable excipients in order to prepare the inhalable powder. Because of the large amount of excipient, the properties of the inhalable powder are critica lly influenced by the choice of excipient. When choosing the excipient its partic.le size is particularly important. As a rule, the finer the excipient, the poorer its flow pr operties. However, good flow properties are a prerequisite for highly accurate mmetering when packing and dividing oe 2 up the individual doses of preparation, e.g. when producing capsules (inhalesttes) for powder inhalation or when the patient is metering the individual dose before= using a multi-dose inhaler. Moreover, the particle size of the excipient is very import ant for the emptying characteristics of capsules when used in an inhaler. It has als=o been found that the particle size of the excipient has a considerable influence on the proportion of active swbstance in the inhalable powder which is delivered for inhalation. The term imhalable proportion of active substance refers to the particles of the inhalable powder which are conveyed deep into the branches of the lunegs when inhaled with a breath. The particle size required for this is between 1 and 10 pm, preferably less than & ym.

The aim of the invention is to prepare an inhalable powder containing tiotropium which, while being accurately metered (in terms of the amount of active sub stance and powder mixture packed into each capsule by the manufacturer as well =s the quantity of active sub stance released and delivered to the lungs from each «capsule by the inhalation process) with only slight variations between batches, enab=les the active substance to b e administered in a large inhalable proportion. A further aim of the present invention is to prepare an inhalable powder containing tiotropiurm which ensures good emptying characteristics of the capsules, whether it is adminisstered to the patient using an inhaler, for example, as described in WO 94/28958, or _in vitro using an impactor or impinger.

The fact that tiotropiu m, particularly tiotropium bromide, has a therapeutic efficacy even at very low doses imposes further conditions on an inhalable powder wvhich is to be used with highly, accurate metering. Because only a low concentratiorm of the active substance is needed in the inhalable powder to achieve the therapeutic effect, a high degree of homogeneity of the powder mixture and only slight fluctuattions in the dispersion characteristics from one batch of capsules to the next are es-sential.

The homogeneity of t he powder mixture and minor fluctuations in the dispersion properties are crucial in ensuring that the inhalable proportion of active subsstance is released reproducibly in constant amounts and with the lowest possible var iability.

Accordingly, a further aim of the present invention is to prepare an inhalable powder containing tiotropium which is characterised by a high degree of homogene ity and uniformity of dispersion. The present invention also sets out to provide an imhalable powder which allows the inhalable proportion of active substance to be administered with the lowest possible variability.

EE 3

Inhalable powders containirag tiotropium which conform to the requirements listed above are known for example from WO 02/30389. These inhalable powders are essentially characterised in that they contain in addition to the active sub stance tiotropium in the form of one of the pharmacologically acceptable salts fo rmed from tiotropium an excipient whic h is obtained by mixing coarser excipient fractions with finer excipienty fractions. However, technically complex manufacturing aand mixing methods are required in ord er to prepare these inhalable powders knowr from WO 02/30389. A further aim of the present invention is therefore to provide irahalable powders which not only solwe the problems mentioned above but can also be obtained by an easier techn ical method of preparation.

The characteristics of emptying from the powder reservoir (the container from which the inhalable powder containing the active substance is released for inhalation) play an important part, not exclusively, but especially in the administration of ¥ nhalable powders using capsules containing powder. If only a small amount of thes powder formulation is released from the powder reservoir as a result of minimal or poor emptying characteristics, significant amounts of the inhalable powder cortaining the active substance are left in the powder reservoir (e.g. the capsule) and a re unavailable to the patient fo r therapeutic use. The result of this is that th e dosage of active substance in the pow der mixture has to be increased so that the qguantity of active substance delivered i s sufficient to produce the desired therapeuti c effect.

Against this background thes present invention further sets out to provide an inhalable powder which is also characterised by very good emptying characteristics.

Detailed description of the invention

It was found that, surprising ly, the objectives outlined above can be achieved by means of the powdered preparations for inhalation (inhalable powders) according to the invention described hereinafter.

Accordingly, the present invention relates to inhalable powders containirag 0.001 to 3% of tiotropium mixed with a physiologicaily acceptable excipient, characterised in that the excipient has an average particle size of 10 - 50 ym, a 10 % fine2 content of 0.5 to 6 um and a specific s urface area of 0.1 to 2 m%/g .

By the average particle size is meant here the 50% value of the volume «distribution measured using a laser diffractometer by the dry dispersion method. Analogously, the 10% fine content in this instance refers to the 10% value of the volurmne a NO 2004/047796 PCT/EP2003/012911

EE 4 clistribution measured using a laser diffractometer. In other words, for the purposes oof the present invention, the 10% fine content deznotes the particle size below which "10% of the quantity of particles is found (based on the volume distribution).

By specific surface area is meant, for the purposses of the invention, the mass- specific powder surface area, calculated from thee N, absorption isotherm which is observed at the boiling point of liquid nitrogen (method of Brunauer, Emmett and

Teller).

Enhalable powders which contain 0.01 to 2% of t iotropium are preferred according to tthe 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%.

Of particular importance according to the inventi on are, finally, inhalable powders which contain about 0.08 to 0.22 % tiotropium.

By tiotropium is meant the free ammonium catiom. Where the term active substance us used within the scope of the present inventiorm, this should be interpreted as being a reference to tiotropium combined with a corresponding counter-ion. The counter-

Jon (anion) may preferably be chloride, bromide, iodide, methanesulphonate or para- “toluenesulphonate. Of these anions, the bromides is preferred.

Accordingly, the present invention preferably relates to inhalable powders which «contain between 0.0012 and 3.6 %, preferably 3.012 to 2.4 % tiotropium bromide. Of yoarticular interest according to the invention are inhalable powders which contain about 0.036 to 1.2 %, preferably 0.06 to 0.72 %,. more preferably 0.072 to 0.36 % tiotropium bromide. Of particular interest accord ing to the invention are inhalable powders which contain about 0.096 to 0.264 % ®&iotropium bromide. “The tiotropium bromide which is preferably contained in the inhalable powders according to the invention may include solvent rnolecules during crystallisation.

Preferably, the hydrates of tiotropium bromide a re used to prepare the tiotropium- containing inhalable powder according to the invention. Most preferably, the crystalline tiotropium bromide monohydrate known from WO 02/30928 is used. This crystalline tiotropium bromide monohydrate is characterised by an endothermic maximum at 230 + 5°C at a heating rate of 10K/min, when thermally analysed by

DSC. Itis also characterised in that in the IR spectrum it has bands inter alia at wavelengths 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm™. Finally, this crystalline tiotropium bromide monohydrate has a simple monoclinic cell with the following dimensions: a= 18.0774 A b= 11.9711 A, c= 9.9321 A, B=102.691° V = 2096.96 A® as determined by monocrystalline X -ray structural analysis.

Co 5

Accordingly the present invention relates to powders for inhalation which contain between 0.0013 and 3.75 %, preferably 0.0125 to 2.5 % of tiotropium bromide monohydrate. Of particular interest according to the invention are inhalable powders which contain about 0.0375 to 1.25 %, preferably 0.0625 to 0.75 %, more preferably 0.075 to 0.375 % of tiotropium brormide monohydrate. Finally, of particular importance according to the invention are inhalable powders which contain about 0.1 to 0.275 % tiotropium bromide monohydrate.

The percentages given within the scope of the present invention are always percent by weight, unless specifically statexd to the contrary.

In particularly preferred inhalable powders the excipient is characterised by an average particle size of 12 to 35 pum, more preferably 13 to 30 um. Also particularly preferred are those inhalable powders wherein the 10% fine content is about 1 to 4 pm, preferably about 1.5 to 3 pm.

Also preferred according to the invention are those inhalable powders wherein th e excipient has a specific surface area of between 0.2 and 1.5 m%/g, preferably between 0.3 and 1.0 mg.

The excipients which are used for the purposes of the present invention are prepared by suitable milling and/or screening using conventional methods know in the art. In particular, the excipients used according to the invention are not mixtures of excipients obtained by mixing together excipient fractions with different average particle sizes.

Examples of physiologically acce ptable excipients which may be used to prepares the inhalable powders used for the inhalettes according to the invention include, for example, monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose, trehalose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), or salts (e.g. sodium chloride, calciium carbonate). Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrate s.

For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.

Preferably, excipients of high crystallinity are used for the powder formulations according to the invention. This crystallinity can be assessed by means of the

CL 6 enthalpy released as the excipient is dissolved (solution enthalpy). In the case of the excipient lactose mono-hydrate, which is most preferably used acording to the invention, it is preferabBe to use lactose which is characterised by a solutiosn enthalpy of > 45 J/g, preferably = 50 J/g, particularly preferably > 52 J/g.

The inhalable powders according to the invention are characterised, in accordance with the problem on whaich the invention is based, by a high degree of homogeneity in the sense of the accuracy of single doses. This is in the region of < 8 % , preferably < 6 % , most preferably < 4 %.

After the starting materaials have been weighed in the inhalable powders are prepared from the excipient and the active substance using methods known in the art. Reference may be smade to the disclosure of WO 02/30390, for exampele. The inhalable powders according to the invention may accordingly be obtained by the method described below, for example. In the preparation methods descritoed hereinafter the compon ents are used in the proportions by weight described in the above-mentioned compositions of the inhalable powders.

First, the excipient and the active substance are placed in a suitable mixing container. The active substance used has an average particle size of 0.5 te 10 um, preferably 1 to 6 pm, meost preferably 2 to 5 um. The excipient and the acti-ve substance are preferably added using a sieve or a granulating sieve with za mesh size of 0.1 to 2 mm, pre=ferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm .

Preferably, the excipien tis put in first and then the active substance is add ed to the mixing container. During this mixing process the two components are preferably added in batches. It is particularly preferred to sieve in the two componentss in alternate layers. The mi xing of the excipient with the active substance may- take place while the two comaponents are still being added. Preferably, however , mixing is only done once the two components have been sieved in layer by layer.

If after being chemically~ prepared the active substance used in the process described above is not already obtainable in a crystalline form with the particle sizes mentioned earlier, it cam be ground up into the particle sizes which conforrm to the above-mentioned parameters (so-called micronising).

If the active substance wsed is the crystalline tiotropium bromide monohydrate disclosed by WO 02/30928 which is particularly preferred according to the invention the following procedure has proved particularly suitable for micronising this- crystalline active substa nce modification. The process may be carried out using

Co 7 conventional mills. Preferably, the micronisation is carried out with the exclusion of moisture, more preferably, using a corre=sponding inert gas such as nitrogen, for example. It has proved particularly preferable to use air jet mills in which the material is comminuted by the impact of the parti cles on one another and on the walls of the grinding container. According to the invention, nitrogen is preferably used as the grinding gas. The material for grinding i s conveyed by the grinding gas under specific pressures (grinding pressure). Within the scope of the present invention, the grinding pressure is usually set to a vallae between about 2 and 8 bar, preferably between about 3 and 7 bar, most preferably between about 3.5 and 6.5 bar. The material for grinding is fed into the air jet mill by means of the feed gas under specific pressures (feed pressure). Within the scope of the present invention a feed pressure of between about 2 and 8 bar, preferably between about 3 and 7 bar and most preferably between about 3.5 and € bar has proved satisfactory. The feed gas used is also preferably an inert gas, mosst preferably nitrogen again. The material to be ground (crystalline tiotropium bromide monohydrate) may be fed in at a rate of about 5 - 35 g/min, preferably at about 1 0-30 g/min.

For example, without restricting the subj ect of the invention thereto, the following apparatus has proved suitable as a possible embodiment of an air jet mill: a 2-inch

Microniser with grinding ring, 0.8 mm bo re, made by Messrs Sturtevant Inc., 348

Circuit Street, Hanover, MA 022339, USA. Using the apparatus, the grinding process is preferably carried out with the followirag grinding parameters: grinding pressure: about 4.5 - 6.5 bar; feed pressure: about 4.5 - 6.5 bar; supply of grinding material: about 17 - 21 g/min.

The ground material thus obtained is then further processed under the following specific conditions. The micronisate is exposed to a water vapour at a relative humidity of at least 40% at a temperatur e of 15-40°C, preferably 20-35°C, most preferably 25-30°C . Preferably, the hurmidity is set to a value of 50-95% r. h., preferably 60 - 90% r.h., most preferably 70 - 80% r.h. By relative humidity (r.h.) is meant the quotient of the partial steam pressure and the steam pressure of the water at the temperature in question. Preferab ly, the micronisate obtained from the grinding process described above is subjected to the chamber conditions mentioned above for a period of at least 6 hours. Prreferably, however, the micronisate is subjected to the chamber conditions me ntioned above for about 12 to 48 hours, preferably about 18 to 36 hours, more preferably about 20 to 28 hours.

The micronisate of tiotropium bromide obtainable by the above method has a characteristic particle size of between 1. O um and 3.5 pm, preferably between 1.1um

Coe 8 and 3.3 um, most preferably between 1.2 prm and 3.0pm and Q, of more than 60%, preferably more than 70 %, most preferably more than 80%. The characteristic value

Qs indicates the quantity of particles belovv 5.8 um , based on the volume distribution of the particles. The particle sizes were determined within the scope of the present invention by laser diffraction (Fr-aunhofer diffraction). More detailed information on this subject can be found in the experimental descriptions of the invention.

Also characteristic of the tiotropium micronisate according to the invention which was prepared by the above process are Specific Surface Area values in the range between 2 m?/g and 5 m?/g, more particularly between 2.5 m?g and 4.5 m?/g and most outstandingly between 3.0 m?/g and 4_0 m¥g.

A particularly preferred aspect of the preset invention relates to the inhalable powders according to the invention which ame characterised by a content of the tiotropium bromide monohydrate micronisat e described hereinbefore.

The present invention further relates to the ‘use of the inhalable powders according to the invention for preparing a pharmaceut ical composition for the treatment of respiratory diseases, particularly for treating COPD and/or asthma.

The inhalable powders according to the inveention may for example be administered using inhalers which meter a single dose from a reservoir by means of a measuring chamber (e.g. according to US 4570630A) er by other means (e.g. according to DE 36 25 685 A). Preferably, however, the inhalable powders according to the invention are packed into capsules (to make so-called inhalettes), which are used in inhalers such as those described in WO 94/28958, f or example.

Most preferably, the capsules containing thee inhalable powder according to the invention are administered using an inhaler as shown in Figure 1. This inhaler is characterised by a housing 1 containing two windows 2, a deck 3 in which there are air inlet ports and which is provided with a screen § secured via a screen housing 4, an inhalation chamber 6 connected to the deck 3 on which there is a push button 9 provided with two sharpened pins 7 and movable counter to a spring 8, and a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut and airholes 13 for adjusting the flow resistance.

Co. 9

The present invention further relates to the use of the inhalable powders according to the invention for preparing a p harmaceutical composition for treating respiratory complaints, particularly for the treatment of COPD and/or asthma, characterised in that the inhaler described above and shown in Figure 1 is used.

For administering the inhalable psowders according to the invention using powder- filled capsules it is particularly preferred to use capsules the material of which is selected from among the synthetic plastics, most preferably selected from among polyethylene, polycarbonate, pol-yester, polypropylene and polyethylene terephthalate. Particularly preferred synthetic plastic materials are polyethylene, polycarbonate or polyethylene te=rephthalate. If polyethylene is used as one of the capsule materials which is particularly preferred according to the invention, it is preferable to use polyethylene w ith a density of between 900 and 1000 kg/m? preferably 940 - 980 kg/m*® , mores preferably about 960 - 970 kg/m? (high density polyethylene).

The synthetic plastics according to the invention may be processed in various ways using manufacturing methods krmown in the art. Injection moulding of the plastics is preferred according to the invent ion. injection moulding without the use of mould release agents is particularly preferred. This method of production is well defined and is characterised by being pa rticularly reproducible.

In another aspect the present inwention relates to the abovementioned capsules which contain the abovemention«ed inhalable powders according to the invention.

These capsules may contain about 1 to 20 mg, preferably about 3 to 15 mg, most preferably about 4 to 12 mg of irmhalable powder. Preferred formulations according to the invention contain 4 to 6 mg of inhalable powder. Of equivalent importance according to the invention are capsules for inhalation which contain the formulations according to the invention in an amount of from 8 to 12 mg.

The present invention also relates to an inhalation kit consisting of one or more of the above capsules characterise d by a content of inhalable powder according to the invention in conjunction with the inhaler according to Figure 1.

The present invention also relates to the use of the abovementioned capsules characterised by a content of intalable powder according to the invention, for preparing a pharmaceutical com position for treating respiratory complaints, especially for treating COPD and/or asthma.

CooL 10

Filled capsules which contain the inhalable powders according to the invention are produced by methods known in the art, by filling the empty capsules with the inhalable powders according to the invention.

The following Examples serve to illustrate the present invention in more detail without restricting the scope of the invention to the exemplifying embodirments that follow.

Starting materials

I) Excipient:

In the Examples t hat follow lactose-monohydrate is used as excipient. It may be obtained for example from Borculo Domo Ingredients, Borculo/NL under the product name Lactochem Extra Fine Powder. The specifications according to thes invention for the particle size and specific surface area are met by this grade of lacctose. In addition, this lactose has the above-mentioned preferred solution enthalgoy values for lactose according to the invention.

Il) Micronisation of crystalline tiotropium bromide monohydrate:

The tiotropium bromide monohydrate obtainable according to WO 02/30 928 is micronised with a n air jet mill of the 2-inch microniser type with grinding ring, 0.8 mm bore, made by Messrs Sturtevant Inc., 348 Circuit Street, Hanover, MA (O2239, USA.

Using nitrogen ass the grinding gas the following grinding parameters ares set, for example: grinding pressure-: 5.5 bar; feed pressure: 5.5 bar; supply (of crystalline monohydrate) or €low speed: 19 g/min.

The ground mate rial obtained is then spread out on sheet metal racks irm a layer thickness of abouat 1 cm and subjected to the following climatic conditiorms for 24 - 24.5 hours: temperature: 25 - 30 °C; relative humidity: 70-80%.

Co 11

Measuring methods:

Determining the particle size of mnicronised tiotropium monohydrate:

Measuring equipment and settings:

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

Measuring equipment: HELO» S Laser-diffraction spectrometer, (SympaTec)

Dispersing unit: RODQOS dry disperser with suction funnel, (SympaTec)

Sample quantity: 200 reg +150 mg

Product feed: Vibri \W/ibrating channel, Messrs. Sympatec

Frequency of vibrating channel: rising to 100 %

Duration of sample feed: 15 to 225 sec. (in the case of 200 mg)

Focal length: 100 mem (measuring range: 0.9 - 175 ym)

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

Cycle time: 20 ms

Start/stop at: 1 % om channel 28

Dispersing gas: compressed air

Pressure: 3 bar

Vacuum: maximum

Evaluation method: HRLD

Sample preparation /product feed:

About 200 mg of the test substances are weighed onto a piece of card.

Using another piece of card all the [ arger lumps are broken up. The powder is then sprinkled finely over the front half of the vibrating channel (starting about 1 cm from the front edge). After the start of the measurement the frequency of the vibrating channel is varied so that the sample is fed in as continuously as possible. However, the quantity of product should not b e too great either, so as to ensure adequate dispersal.

Il) Determining the particle size o f the lactose:

Measuring equipment and settings:

The equipment is operated accordimg to the manufacturer's instructions.

CL 12

Measuring equipment: HELOS Laser-diffraction spectrometer, (SympaT ec)

Dispersing unit: IRODOS dry disperser with suction funnel, «SympaTec)

Sample quantity: 200 mg +100 mg

Product feed: “Vibri Vibrating channel, Messrs. Sympatec

Frequency of vibrating channel: 100 % rising

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

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

Cycle time: 10 ms

Start/stop at: 1 % on channel 28

Dispersing gas: compressed air

Pressure: 3 bar

Vacuum: maximum

Evaluation method: HRLD

Sample preparation /product feed:

About 200 mg of the test substance are weighed onto a piece of card.

Using another piece of card all the larger lumps are broken up. The powder iss transferred into the vibrating channel. A gap of 1.2 to 1.4 mm is set between t:he vibrating channel and funnel. After the start of the measurement the frequenc y of the vibrating channel is increased as continuously as possible to 100 % towards the end of the measurement. 11) Determining the specific surface area of tiotropium bromide monohydrate, micronised { 1-point BET method).

Method:

The specific surface is deterrmined by exposing the powder sample to a nitrogen/helium atmosphere at different pressures. Cooling the sample cause=s the nitrogen molecules to be con densed on the surface of the particles. The quartity of condensed nitrogen is determined by means of the change in the thermal heat conductivity of the nitrogen/h elium mixture and the surface of the sample is calculated by means of the s urface nitrogen requirement. Using this value a nd the weight of the sample, the specific surface is calculated.

Equipment and materials:

Measuring equipment: Monosorb, Messrs Quantachrome

Heater: Monotektor, Messrs Quantachrome

Coe 13

Measuring and drying gas: nitrogen (5.0) / helium (4.6) 7€/30, Messer

Griesheim

Adsorbate: 30% nitrogen in helium

Coolant: liquid nitrogen

Measuring cell: with capillary tube, Messrs. W. Pabiscth GmbH&Co.KG

Calibration peak; 1000 ul, Messrs. Precision Sampling C- orp.

Analytical scale: R 160 P, Messrs. Satorius

Calculating the specific surface:

The measured values are indicated by the equipment in [m?] ard are usually converted into [crm¥g] on weighing (dry mass):

Aspez = specific surface [cm?/cg]

MWY *10000 - 2

Aspez =————— | MW =Measured value [m<]

Me Mir = dry mass [g] 10000 = conversion factor [cm<=/m2]

IV) Determining the specific surface area of the lactose (multi-point BET method):

Method:

The specific surface is determined by exposing the powder sarmple to a nitrogen atmosphere at different pressures. Cooling the sample causes the nitrogen molecules to be condensed on the surface of the particles. The quantity of condensed nitrogeen is determined by means of the drop in pre=ssure in the system and the specific surface of the sample is calculated by means eof the surface nitrogen requirement and the weight of the sample.

The equipment iss operated according to the manufacturer's instructions.

Measuring equiprment and settings:

Measuring equiprment Tri Star Multi Point BET, Messrs Micrormeritics

Heater: VacPrep 061, Messrs. Micromeritics

Heating: about 12h / 40°C

Sample tube: Ye inch; use filler rod

Analysis Conditioen: 10 point BET surface 0,1 to 0,20 p/p0O

CL 14

Absolute P. tolerance: 5.0 mmHg rel. P. tolerance: 5.0%

Evacuation rate: 50.0 mmHg/sec.

Unrestricted evacf.. 10.0 mmHg

Evac. time: 0.1 hours

Free Space: Lower Dewar, time: 0,5 h

Equilibration interv.: 20 sec

Min. equl. delay: 600 sec

Adsorptive: Nitrogen

V) Determining the heat of solution (enthalpy of solution) E:

The solution enthalpy is determined using a solution calorimeter 2225 Precision

Solution Calorimeter made by Messrs. Thermometric.

The heat of solution is calculated by means of the change in temperature occurring (as a result of the dissolving process) and the system—related change in temperature calculated from the base line.

Before and after the ampoule is broken, electrical calibration is carried out with an integrated heating resistor of a precisely known power. A known heat output is delivered to the system over a set period and the jump in temperature is determined.

Method and equipment parameters:

Solution calorimeter. 2225 Precision Solution Calorimeter,

Messrs Thermometric

Reaction cell: 100 ml

Thermistor resistance: 30.0 kQ (at 25 °C)

Speed of stirrer: 500 U/min

Thermostat: Thermostat of 2277 Thermal Activity Monitor TAM, Messrs

Thermometric

Temperature: 25 °C + 0.0001 °C (over 24h)

Measuring ampoules: Crushing ampoules 1 ml, Messwrs Thermometric

Seal: Silicon stopper and beeswax, Mlessrs. Thermometric

Weight: 40 to 50 mg

Solvent: Chemically pure water

Volume of solvent: 100 m!

Bath temperature: 25°C

Temperature resolution: High

Starting temperature: -40mK (+ 10mK) temperature-o-ffset

Interface: 2280-002 TAM accessory interface 50 Hz,

Messrs Thermometric

Co 15

Softwa re: SolCal V 1.1 for WINDOWS

Evalua tion: Automatic evaluation with Menu poimt CALCULATION!

ANALYSE EXPERIMENT. (Dynamics of base line ; calibration after breakage of ampoule).

Electrical calibration:

The electrical calibration takes place during the measurement, once before and once after th e breakage of the ampoule. The calibration after thee breakage of the ampou le is used for the evaluation.

Amount of heat: 25 J

Heating power: 500 mW

Heating time: 10s

Duration of base lines: 5 min (before and after heating)

Preparation of the powder formulations according to the invention:

I) Apparatus

The following machines and equipment, for example, may be used to prepare the inhalalb»le powders:

Mixing container or powder mixer: Turbulamischer 2 L, Typee 2C; made by Willy A.

Bachofen AG, CH-4500 Basel

Hand-heeld screen: 0.135 mm mesh size

The empty inhalation capsules may be filled with inhalable powders containing tiotropium by hand or mechanically. The following equipment may be used.

Capsule filling machine:

MG2, Type G100, manufacturer: MG2 S.r.1, I-40065 Pian d i Macina di Pianoro (BO),

Italy

Ce 16

Example 1:

Powder mixture :

To prepare the powdear mixture, 299.39 g of excipient and 0.61 g of micronised tiotropium bromide-monohydrate are used. In the resulting 300 g of inhallable powder the content of active ssubstance is 0.2 % (based on tiotropium).

About 40-45 g of excipient are placed in a suitable mixing container through a hand- held screen with a me=sh size of 0.315 mm. Then tiotropium bromide-morohydrate in batches of about 90-1 10 mg and excipient in batches of about 40-45 g a re screened in in alternate layers. “The excipient and active substance are added in 7 and 6 layers, respectively.

Having been screened in, the ingredients are then mixed (mixing speed *900 rpm).

The final mixture is paassed twice more through a hand-held screen and then mixed again at 900 rpm.

Using the method desscribed in Example 1 it is possible to obtain inhalab 3e powders which when packed irato suitable plastic capsules may be used to produce the following capsules for inhalation, for example:

Example 2: tiotropium bromicde monohydrate: 0.0113 mg lactose monohydrate®: 5.4887 mg polyethylene capsules: 100.0 mg

Total: 105.5 mg * the excipient is characterised by the following parameters: average particle size: 17.9 pm; % fine contemt: 2.3 um; specific surface: 0.61 mig;

Example 3: tiotropium bromiede monohydrate: 0.0113 mg lactose monohydrate®: 5.4887 mg polyethylene capsules: 100.0 mg

Total: 105.5 mg * the excipient is characterised by the following parameters: average particle size: 18.5 pm;

Ce 17 % fine content : 2.2 um; specific surface: 0.83 mg;

Example 4: tiotropium bromid« monohydrate: 0.0113 mg lactose monohydr-ate®: 5.4887 mg polyethylene capsules: 100.0 mg

Total: 105.5 mg * the excipient is characterised by the following parameters: average particle size: 21.6 pm; 10 % fine content : 2.5 um; specific surface: 0.59 m¥g;

Example 5: tiotropium bromide monohydrate: 0.0113 mg lactose monohydrate®: 5.4887 mg polyethylene capsules: 100.0 mg

Total: 105.5 mg * the excipient is characterised by the following parameters: average particle size: 16.0 um; 10 % fine content : 2.0 pm; specific surface: 0.79 m?g;

Example 6: tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate: 5.4775 mg polyethylene capsules: 100.0 mg

Total: 105.5 mg *) the excipient is charaacterised by the following parameters: average particle s-ize: 17.9 pm; 10 % fine content: 2.3 pm; specific surface: 0.61 mg;

Cee 18

Example 7: tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate: 5.4775 mg polyethylene capsules: 100.0 mg

Total: 105.5 mg * the excipient is characterised by the following parameters: average particle size: 18.5 um; % fine content: 2.2 um; specific surface: 0.83 m¥g:

Example 8: tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate: 5.4775 mg polyethylene capsules: 100.0 mg

Total: 105.5 mg * the excipient is characterised by the following parameters: average particle size: 21.6 um; 10 % fine content: 2.5 pm; specific surface: 0.59 m¥g;

Example 9: tiotropium bromide monohyd rate: 0.0225 mg lactose monohydrate®: 5.4775 mg polyethylene capsules: 100.0 mg

Total: 105.5 mg * the excipient is characterised by~ the following parameters: average particle size: 16.0 um; 10 % fine content: 2.0 um; specific surface: 0.79 mg;

. sv 19

Example 10: tiotropium bromide monohydrate: 0.0056 mg lactose monohydrate: 5.4944 mg polyethylene caps ules: 100.0 mg

Total: 105.5 mg * the excipient is characterised by the following parameters: average particle size: 17.9 ym; % fine content: 2.3 um; specific surface: 0.61 mg;

Example 11: tiotropium bromide monohydrate: 0.0056 mg lactose monohydrate®: 5.4944 mg polyethylene caps ules: 100.0 mg

Total: 105.5 mg * the excipient is characterised by the following parameters: average particle size: 18.5 um; 10 % fine content: 2.2 um; specific surface: 0.83 m?/g;

Example 12: tiotropium bromide monohydrate: 0.0056 mg lactose monohydrate™: 5.4944 mg polyethylene caps ules: 100.0 mg

Total: 105.5 mg * the excipient is characterised by the following parameters: average particle size: 21.6 pm; 10 % fine content: 2.5 ym; specific surface: 0.59 mg;

r WO 2004/047796 PCT/EP2003/012911 coe. 20

Example 13: tiotropium bromide monohydrate: 0.0056 ng lactose monohydrate: 5.4944 ng polyethylene capsules: 100.0m g

Total: 1055mg * the excipient is characterised by the following parameters: average particle size: 16.0 ume, % fine content: 2.0 um; specific surface: 0.79 mq;

Example 14: tiotropium bromide monohydrate: 0.0056 ng lactose monohydrate® 9.9944 ng polyethylene capsules: 100.0 mag

Total: 110.0 mag * the excipient is characterised by the following pearameters: average particle size: 17.9 um ; 10 % fine content: 23 um ; specific surface: 0.61 m¥g;

Example 15: tiotropium bromide monohydrate: 0.0113 mag lactose monohydrate®: 9.9887 rg polyethylene capsules: 100.0 mg

Total: 110.0 mg * the excipient is characterised by the following p-arameters: average particle size: 18.5 pn; 10 % fine content: 2.2 pm; specific surface: 0.83 mg;

oo WO 2004/047796 PCT/EP2003/012911

SETI 21

Example 16: tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate™: 9.9775 mg polyethylene capsules: 100.O mg

Total: 110. Omg * the excipient is characterised by the following parameters: average particle size: 21.6 um; % fine content: 2.5 umg3 specific surface: 0.59 m¥gz

Example 17: tiotropium bromide monohydrate: 0.0125 mg lactose monohydrate®: 9.9875 mg polyethylene capsules: 100-0 mg

Total: 110-0 mg * the excipient is characterised by the followling parameters: average particle size: 17.9 pm ; 10 % fine content: 2.3 ym; specific surface: 0.61 m%g ;

Example 18: tiotropium bromide monohydrate: 0.01225 mg lactose monohydrate®: 9.9875 mg polyethylene capsules: 100.0 mg

Total: 110.0 mg * the excipient is characterised by the follow ing parameters: average particle size: 18.5 um ; 10 % fine content; 22 um ; specific surface: 0.83 mia;

Coe 22

Example 19: tiotropium bromide monohydrate: 0.0125 mg lactose monohydrate: 9.9875 mg polyethyleme capsules: 100.0 mg

Total: 110.0 mg * the excipient i s characterised by the following parameters: average particle size: 21.6 ym; % fine «content: 2.5 um, specific suarface: 0.59 m¥/q;

Example 20: tiotropium bromide monohydrate: 0.0125 mg lactose monohydrate®: 9.9875 mg polyethyle ne capsules: 100.0 mg

Total: 110.0 mg * the excipient is characterised by the following parameters: average p article size: 16.0 pm; 10 % fine content: 2.0 um; specific surface: 0.79 m?/g;

Claims

Coes 23 Patent Claims

1) Inhalable powder containing 0.001 to 3% of tiotropium in admixture with a physiologically acceptable excipient, characterised in that the excipient has an average particle size of 10 - 50 1am, a 10 % fine content of 0.5 to 6 ym and & specific surface of 0.1 to 2 m?/g.

2) Inhalable powder according to cl aim 1, characterised in that the tiotropium i s present in the form of the chloride, bromide, iodide, methanesulphonate or para-toluenesulphonate thereof.

3) Inhalable powder according to c laim 1 or 2, characterised in that the physiologically acceptable excip ient is selected from among the monosaccharides, disaccharides, oligo- and polysaccharides, polyalcohols or salts.

4) Inhalable powder according to claim 3, characterised in that the physiologiecally acceptable excipient is selected from among glucose, arabinose, lactose, saccharose, maltose and trehalose, optionally in the form of the hydrates thereof.

5) Use of an inhalable powder according to one of claims 1 to 4 for preparing a pharmaceutical composition for treating respiratory complaints, particularly for treating COPD and/or asthma.

6) Capsule containing an inhalable powder according to one of claims 1 to 4.

7) Capsule according to claim 6, characterised in that the capsule material consists of synthetic plastics.

8) Capsule according to claim 7, characterised in that the capsule material iss selected from among polyethylene, polycarbonate, polyester, polypropyleme and polyethylene terephthalate.

Lt WO 2004/047796 PCT/EP2003/01 2911

Poe. 24 9) Capsule according to one of claims 6 to 8, characterised in that it contains about 1 to 20 mg of the powder for inhalation according to one of claims 1 te 4. 10) Inhalation kit consisting of a capsule according to one of claims 6 to 9 and an inhaler which can be used for administering inhalable powders from powder filled capsules. 11) Inhalation kit according to claim 10, characterised in that the inhaler is characterised by a housing 1 containing two windows 2, a deck 3 in which t here are air inlet ports arned which is provided with a screen 5 secured via a scree=n housing 4, an inhalation chamber 6 connected to the deck 3 on which there= is a push button 9 provided with two sharpened pins 7 and movable counter to & spring 8, and a mouthpiece 12 which is connected to the housing 1, the deck 3 and a cover 11 via a spindle 10 to enable it to be flipped open or shut and airholes 13 for adjusting the flow resistance.