US20040228806A1 - Inhalable powder containing tiotropium - Google Patents

Inhalable powder containing tiotropium Download PDF

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Publication number
US20040228806A1
US20040228806A1 US10/729,543 US72954303A US2004228806A1 US 20040228806 A1 US20040228806 A1 US 20040228806A1 US 72954303 A US72954303 A US 72954303A US 2004228806 A1 US2004228806 A1 US 2004228806A1
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Prior art keywords
excipient
inhalable powder
particle size
tiotropium
average particle
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US10/729,543
Inventor
Karoline Bechtold-Peters
Michael Walz
Georg Boeck
Rolf Doerr
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Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim Pharma GmbH and Co KG
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/007Pulmonary tract; Aromatherapy
    • A61K9/0073Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/08Bronchodilators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to powdered preparations containing tiotropium for inhalation, processes for preparing them as well as their use for preparing a pharmaceutical composition for treating respiratory complaints, particularly for treating COPD (chronic obstructive pulmonary disease) and asthma.
  • COPD chronic obstructive pulmonary disease
  • Tiotropium bromide is known from European Patent Application EP 418 716 A1 and has the following chemical structure:
  • Tiotropium bromide is a highly effective anticholinergic with a longa-lasting activity which can be used to treat respiratory complaints, particularly COPD (chronic obstructive pulmonary disease) and asthma.
  • COPD chronic obstructive pulmonary disease
  • tiotropium refers to the free ammonium cation.
  • the active substance With active substances which have a particularly high efficacy, only small amounts of the active substance are needed per single dose to achieve the desired therapeutic effect. In such cases, the active substance has to 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 critically influenced by the choice of excipient. When choosing the excipient its particle size is particularly important. As a rule, the finer the excipient, the poorer its flow properties. However, good flow properties are a prerequisite for highly accurate metering when packing and dividing up the individual doses of preparation, e.g.
  • the particle size of the excipient is very important for the emptying characteristics of capsules when used in an inhaler. It has also been found that the particle size of the excipient has a considerable influence on the proportion of active substance in the inhalable powder which is delivered for inhalation.
  • the term inhalable proportion of active substance refers to the particles of the inhalable powder which are conveyed deep into the branches of the lungs when inhaled with a breath. The particle size required for this is between 1 and 10 ⁇ m, preferably less than 6 ⁇ m.
  • 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 substance and powder mixture packed into each capsule by the manufacturer as well as the quantity of active substance released and delivered to the lungs from each capsule by the inhalation process) with only slight variations between batches, enables the active substance to be administered in a large inhalable proportion.
  • a further aim of the present invention is to prepare an inhalable powder containing tiotropium which ensures good emptying characteristics of the capsules, whether it is administered to the patient using an inhaler, for example, as described in WO 94/28958, or in vitro using an impactor or impinger.
  • a further aim of the present invention is to prepare an inhalable powder containing tiotropium which is characterised by a high degree of homogeneity and uniformity of dispersion.
  • the present invention also sets out to provide an inhalable powder which allows the inhalable proportion of active substance to be administered with the lowest possible variability.
  • the present invention relates to inhalable powders containing 0.04 to 0.8% of tiotropium mixed with a physiologically acceptable excipient, characterised in that the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 ⁇ m and finer excipient with an average particle size of 1 to 9 ⁇ m, the proportion of finer excipient representing 1 to 20% of the total amount of excipient.
  • Inhalable powders which contain 0.08 to 0.64%, most preferably 0.16 to 0.4% of tiotropium, are preferred according to the invention.
  • tiotropium is meant the free ammonium cation.
  • the counter-ion (anion) may be chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate. Of these anions, the bromide is preferred.
  • the present invention preferably relates to inhalable powders which contain between 0.048 and 0.96% of tiotropium bromide.
  • inhalable powders which contain 0.096 to 0.77%, most preferably 0.19 to 0.48% of tiotropium bromide.
  • the tiotropium bromide which is preferably contained in the inhalable powders according to the invention may include solvent molecules during crystallisation.
  • the hydrates of tiotropium bromide are used to prepare the tiotropium-containing inhalable powder according to the invention.
  • the present invention relates to powders for inhalation which contain between 0.05 and 1% of tiotropium bromide monohydrate.
  • inhalable powders which contain 0.1 to 0.8%, most preferably 0.2 to 0.5% of tiotropium bromide monohydrate.
  • the inhalable powders according to the invention are preferably characterised in that the excipient consists of a mixture of coarser excipient with an average particle size of 17 to 50 ⁇ m, most preferably 20 to 30 ⁇ m, and finer excipient with an average particle size of 2 to 8 ⁇ m, most preferably 3 to 7 ⁇ m.
  • the phrase average particle size used here denotes the 50% value from the volume distribution measured with a laser diffractometer using the dry dispersion method.
  • Inhalable powders in which the proportion of finer excipient in the total amount of excipient is from 3 to 15%, most preferably 5 to 10%, are preferred.
  • the coarser and finer excipient fractions may consist of chemically identical or chemically different substances, while inhalable powders in which the coarser excipient fraction and the finer excipient fraction consist of the same chemical compound are preferred.
  • physiologically acceptable excipients which may be used to prepare the inhalable powders according to the invention include, for example, monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another.
  • mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates.
  • lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred.
  • the inhalable powders according to the invention 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 U.S. Pat. No. 4,570,630A) or by other means (e.g. according to DE 36 25 685 A).
  • a measuring chamber e.g. according to U.S. Pat. No. 4,570,630A
  • DE 36 25 685 A e.g. according to DE 36 25 685 A
  • 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, for example.
  • the inhalable powder according to the invention is to be packed into capsules (inhalettes) in accordance with the preferred application mentioned above, it is advisable to fill the capsules with amounts of from 3 to 10 mg, preferably from 4 to 6 mg of inhalable powder per capsule. These will then contain between 1.2 and 80 ⁇ g of tiotropium. With a preferred filling of 4 to 6 mg of inhalable powder per capsule, the content of tiotropium per capsule is between 1.6 and 48 ⁇ g, preferably between 3.2 and 38.4 ⁇ g, most preferably between 6.4 and 24 ⁇ g. A content of 18 ⁇ g of tiotropium, for example, corresponds to a content of about 21.7 ⁇ g of tiotropium bromide.
  • capsules containing 3 to 10 mg of powder for inhalation preferably hold between 1.4 and 96.3 ⁇ g of tiotropium bromide, according to the invention.
  • each capsule contains between 1.9 and 57.8 ⁇ g, preferably between 3.9 and 46.2 ⁇ g, most preferably between 7.7 and 28.9 ⁇ g of tiotropium bromide.
  • a content of 21.7 ⁇ g of tiotropium bromide for example, corresponds to a content of about 22.5 ⁇ g of tiotropium bromide monohydrate.
  • capsules containing 3 to 10 mg of powder for inhalation preferably hold between 1.5 and 100 ⁇ g of tiotropium bromide monohydrate.
  • each capsule contains between 2 and 60 ⁇ g, preferably between 4 and 48 ⁇ g, most preferably between 8 and 30 ⁇ g of tiotropium bromide monohydrate.
  • the inhalable powders according to the invention are characterised, in accordance with the objective on which the present invention is based, by a high degree of homogeneity in terms of the accuracy of metering of single doses. This is in the range of ⁇ 8%, preferably ⁇ 6%, most preferably ⁇ 4%.
  • the inhalable powders according to the invention may be obtained by the method described hereinafter.
  • the excipient mixture is prepared from the defined fractions of the coarser excipient and finer excipient. Then the inhalable powder according to the invention is prepared from the excipient mixture and the active substance. If the inhalable powder is to be administered using inhalettes in suitable inhalers, the preparation of the inhalable powders is followed by the manufacture of the powder-filled capsules.
  • the powders for inhalation according to the invention are prepared by mixing the coarser excipient fractions with the finer excipient fractions and subsequently mixing the resulting excipient mixtures with the active substance.
  • the coarser and finer excipient fractions are placed in a suitable mixing container.
  • the two components are preferably added using a granulating sieve with a mesh size of 0.1 to 2 mm, preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.
  • the coarser excipient is put in first and then the finer excipient fraction is added to the mixing container.
  • the two components are preferably added in batches, with some of the coarser excipient being put in first and then finer and coarser excipient being added alternately. It is particularly preferred when producing the excipient mixture to sieve in the two components in alternate layers.
  • the two components are preferably sieved in alternately in 15 to 45, most preferably 20 to 40 layers each.
  • the mixing of the two excipients may take place while the two components are still being added. Preferably, however, mixing is only done once the two components have been sieved in layer by layer.
  • the excipient mixture has an average particle size of 0.5 to 10 ⁇ m, preferably 1 to 6 ⁇ m, most preferably 2 to 5 ⁇ m.
  • the two components are preferably added using a granulating sieve with a mesh size of 0.1 to 2 mm, preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm.
  • the excipient mixture is put in first and then the active substance is added to the mixing container. During this mixing process the two components are preferably added in batches. It is particularly preferred when producing the excipient mixture to sieve in the two components in alternate layers.
  • the two components are preferably sieved in alternately in 25 to 65, most preferably 30 to 60 layers.
  • the mixing of the excipient mixture with the active substance may take place while the two components are still being added. Preferably, however, mixing is only done once the two components have been sieved in layer by layer.
  • the powder mixture thus obtained may optionally be added once or repeatedly using a granulating sieve and then subjected to another mixing process.
  • One aspect of the present invention relates to an inhalable powder containing tiotropium, which may be obtained by the methods described hereinbefore.
  • any reference to tiotropium which is the free ammonium cation, corresponds to a reference to tiotropium in the form of a salt (tiotropium salt) which contains an anion as the counter-ion.
  • Tiotropium salts which may be used within the scope of the present invention are those compounds which contain chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate, in addition to tiotropium as counter-ion (anion).
  • tiotropium bromide is preferred of all the tiotropium salts.
  • References to tiotropium bromide within the scope of the present invention should always be taken as references to all possible amorphous and crystalline modifications of tiotropium bromide. These may, for example, include molecules of solvent in their crystalline structure. Of all the crystalline modifications of tiotropium bromide, those which also include water (hydrates) are preferred according to the invention. It is particularly preferable to use tiotropium bromide monohydrate within the scope of the present invention.
  • tiotropium bromide which may be prepared as disclosed in EP 418 716 A1
  • different crystal modifications are obtained. These modifications may be told apart, for example, by DSC (Differential Scanning Calorimetry).
  • DSC Different Scanning Calorimetry
  • Table summarises the melting points of different crystal modifications of tiotropium bromide depending on the solvent, which are determined by DSC. solvent DSC methanol 228° C. ethanol 227° C. ethanol/water 229° C. water 230° C. isopropanol 229° C. acetone 225° C. ethyl acetate 228° C. tetrahydrofuran 228° C.
  • Tiotropium bromide monohydrate has proved particularly suitable for preparing the formulation according to the invention.
  • the DSC diagram of tiotropium bromide monohydrate shows two characteristic signals. The first, relatively broad, endothermic signal between 50-120° C. can be attributed to the dehydration of the tiotropium bromide monohydrate to produce the anhydrous form. The second, relatively sharp endothermic peak at 230 ⁇ 5° C. can be put down to the melting of the substance.
  • lactose-monohydrate (200M) is used as the coarser excipient. It may be obtained, for example, from Messrs DMV International, 5460 Veghel/NL under the product name Pharmatose 200M.
  • lactose-monohydrate is used as the finer excipient. It may be obtained from lactose-monohydrate 200M by conventional methods (micronising). Lactose-monohydrate 200M may be obtained, for example, from Messrs DMV International, 5460 Veghe/NL under the product name Pharmnatose 200M.
  • the apparatus is further cooled to 10-15° C. using cold water and crystallisation is completed by stirring for at least one hour.
  • the crystals are isolated using a suction drier, the crystal slurry isolated is washed with 9 litres of cold water (10-15° C.) and cold acetone (10-15° C.)
  • the crystals obtained are dried in a nitrogen current at 25° C. over 2 hours. Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory)
  • the crystalline tiotropium bromide monohydrate thus obtained is micronised by known methods, to bring the active substance into the average particle size which meets the specifications according to the invention.
  • the equipment is operated according to the manufacturer's instructions.
  • Measuring equipment HELOS Laser-diffraction spectrometer, (SympaTec) Dispersing unit: RODOS dry disperser with suction funnel, (SympaTec) Sample quantity: from 100 mg Product feed: Vibri Vibrating channel, Messrs. Sympatec Frequency of vibrating 40 rising to 100% channel: Duration of sample feed: 1 to 15 sec.
  • At least 100 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 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 from about 40% up to 100% (towards the end of the measurement). The time taken to feed in the entire sample is 10 to 15 sec.
  • the equipment is operated according to the manufacturer's instructions.
  • Measuring equipment Laser diffraction spectrometer (HELOS), Sympatec Dispersing unit: RODOS dry disperser with suction funnel, Sympatec Sample quantity: 50 mg-400 mg Product feed: Vibri Vibrating channel, Messrs. Sympatec Frequency of vibrating 40 rising to 100% channel: Duration of sample feed: 15 to 25 sec.
  • HELOS Laser diffraction spectrometer
  • Sympatec Dispersing unit RODOS dry disperser with suction funnel
  • Sympatec Sample quantity 50 mg-400 mg
  • Product feed Vibri Vibrating channel
  • Sympatec Frequency of vibrating 40 rising to 100% channel Duration of sample feed: 15 to 25 sec.
  • the equipment is operated according to the manufacturer's instructions.
  • Measuring equipment Laser diffraction spectrometer (HELOS), Sympatec Dispersing unit: RODOS dry disperser with suction funnel, Sympatec Sample quantity: 500 mg Product feed: VIBRI Vibrating channel, Messrs.
  • Measuring time 10 s Cycle time: 10 ms Start/stop at: 1% on channel 19 Pressure: 3 bar Vacuum: maximum Evaluation method: HRLD
  • Mixing container or powder mixer Gyrowheel mixer 200 L; type: DFW80N-4; made by:
  • Granulating sieve Quadro Comil; type: 197-S; made by: Messrs Joisten & Kettenbaum, D-51429 Bergisch-Gladbach.
  • lactose monohydrate for inhalation 200M
  • lactose monohydrate for inhalation 200M
  • lactose monohydrate for inhalation 200M
  • lactose monohydrate for inhalation 200M
  • lactose monohydrate 5 ⁇ m
  • excipient mixture (1.1) About 1.1 to 1.7 kg of excipient mixture (1.1) are added to a suitable mixing container through a suitable granulating sieve with a mesh size of 0.5 mm. Then alternate layers of tiotropium bromide monohydrate in batches of about 0.003 kg and excipient mixture (1.1) in batches of 0.6 to 0.8 kg are sieved in. The excipient mixture and the active substance are added in 46 or 45 layers, respectively (tolerance: ⁇ 9 layers). The ingredients sieved in are then mixed together (mixing at 900 rpm). The final mixture is passed through a granulating sieve twice more and then mixed (mixing at 900 rpm).
  • Inhalation capsules having the following composition were produced using the mixture obtained according to Example 1: tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate (200 M): 5.2025 mg lactose monohydrate (5 ⁇ m): 0.2750 mg hard gelatine capsule: 49.0 mg Total: 54.5 mg
  • the mean particle size denotes the value in ⁇ m at which 50% of the particles from the volume distribution have a particle size which is smaller than or equal to the value specified.
  • Laser diffraction/dry dispersion is used as the method of measurement for determining the total distribution of the particle size distribution.

Abstract

The invention relates to powdered preparations containing tiotropium for inhalation, processes for preparing them as well as their use in preparing a pharmaceutical composition for the treatment of respiratory complaints, particularly for the treatment of COPD (chronic obstructive pulmonary disease) and asthma.

Description

    RELATED APPLICATIONS
  • This application is a continuation of U.S. patent application Ser. No. 09/975,418, filed on Oct. 11, 2001, which claims benefit to U.S. Provisional Application Serial No. 60/252,683 filed on Nov. 22, 2000 and said applications are herein incorporated by reference.[0001]
  • FIELD OF THE INVENTION
  • The invention relates to powdered preparations containing tiotropium for inhalation, processes for preparing them as well as their use for preparing a pharmaceutical composition for treating respiratory complaints, particularly for treating COPD (chronic obstructive pulmonary disease) and asthma. [0002]
  • BACKGROUND OF THE INVENTION
  • Tiotropium bromide is known from European Patent Application EP 418 716 A1 and has the following chemical structure: [0003]
    Figure US20040228806A1-20041118-C00001
  • Tiotropium bromide is a highly effective anticholinergic with a longa-lasting activity which can be used to treat respiratory complaints, particularly COPD (chronic obstructive pulmonary disease) and asthma. The term tiotropium refers to the free ammonium cation. [0004]
  • For treating the abovementioned complaints, it is useful to administer the active substance by inhalation. In addition to the administration 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. [0005]
  • With active substances which have a particularly high efficacy, only small amounts of the active substance are needed per single dose to achieve the desired therapeutic effect. In such cases, the active substance has to 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 critically influenced by the choice of excipient. When choosing the excipient its particle size is particularly important. As a rule, the finer the excipient, the poorer its flow properties. However, good flow properties are a prerequisite for highly accurate metering when packing and dividing up the individual doses of preparation, e.g. when producing capsules (inhalettes) 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 important for the emptying characteristics of capsules when used in an inhaler. It has also been found that the particle size of the excipient has a considerable influence on the proportion of active substance in the inhalable powder which is delivered for inhalation. The term inhalable proportion of active substance refers to the particles of the inhalable powder which are conveyed deep into the branches of the lungs when inhaled with a breath. The particle size required for this is between 1 and 10 μm, preferably less than 6 μm. [0006]
  • 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 substance and powder mixture packed into each capsule by the manufacturer as well as the quantity of active substance released and delivered to the lungs from each capsule by the inhalation process) with only slight variations between batches, enables the active substance to be administered in a large inhalable proportion. A further aim of the present invention is to prepare an inhalable powder containing tiotropium which ensures good emptying characteristics of the capsules, whether it is administered to the patient using an inhaler, for example, as described in WO 94/28958, or in vitro using an impactor or impinger. [0007]
  • The fact that tiotropium, particularly tiotropium bromide, has a therapeutic efficacy even at very low doses imposes further conditions on an inhalable powder which is to be used with highly accurate metering. Because only a low concentration 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 fluctuations in the dispersion characteristics from one batch of capsules to the next are essential. The homogeneity of the powder mixture and minor fluctuations in the dispersion properties are crucial in ensuring that the inhalable proportion of active substance is released reproducibly in constant amounts and with the lowest possible variability. [0008]
  • Accordingly, a further aim of the present invention is to prepare an inhalable powder containing tiotropium which is characterised by a high degree of homogeneity and uniformity of dispersion. The present invention also sets out to provide an inhalable powder which allows the inhalable proportion of active substance to be administered with the lowest possible variability.[0009]
  • DETAILED DESCRIPTION OF THE INVENTION
  • It was found that, surprisingly, the objective outlined above can be achieved by means of the powdered preparations for inhalation (inhalable powders) according to the invention described hereinafter. [0010]
  • Accordingly, the present invention relates to inhalable powders containing 0.04 to 0.8% of tiotropium mixed with a physiologically acceptable excipient, characterised in that the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μm and finer excipient with an average particle size of 1 to 9 μm, the proportion of finer excipient representing 1 to 20% of the total amount of excipient. [0011]
  • Inhalable powders which contain 0.08 to 0.64%, most preferably 0.16 to 0.4% of tiotropium, are preferred according to the invention. [0012]
  • By tiotropium is meant the free ammonium cation. The counter-ion (anion) may be chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate. Of these anions, the bromide is preferred. [0013]
  • Accordingly, the present invention preferably relates to inhalable powders which contain between 0.048 and 0.96% of tiotropium bromide. Of particular interest according to the invention are inhalable powders which contain 0.096 to 0.77%, most preferably 0.19 to 0.48% of tiotropium bromide. [0014]
  • The tiotropium bromide which is preferably contained in the inhalable powders according to the invention may include solvent molecules during crystallisation. Preferably, the hydrates of tiotropium bromide, most preferably tiotropium bromide monohydrate, are used to prepare the tiotropium-containing inhalable powder according to the invention. Accordingly the present invention relates to powders for inhalation which contain between 0.05 and 1% of tiotropium bromide monohydrate. Of particular interest according to the invention are inhalable powders which contain 0.1 to 0.8%, most preferably 0.2 to 0.5% of tiotropium bromide monohydrate. [0015]
  • The inhalable powders according to the invention are preferably characterised in that the excipient consists of a mixture of coarser excipient with an average particle size of 17 to 50 μm, most preferably 20 to 30μm, and finer excipient with an average particle size of 2 to 8 μm, most preferably 3 to 7μm. The phrase average particle size used here denotes the 50% value from the volume distribution measured with a laser diffractometer using the dry dispersion method. Inhalable powders in which the proportion of finer excipient in the total amount of excipient is from 3 to 15%, most preferably 5 to 10%, are preferred. [0016]
  • The percentages given within the scope of the present invention are always percent by weight. [0017]
  • When reference is made to a mixture within the scope of the present invention, this always means a mixture obtained by mixing together clearly defined components. Accordingly, when an excipient mixture of coarser and finer excipients is mentioned, this can only denote mixtures obtained by mixing a coarser excipient component with a finer excipient component. [0018]
  • The coarser and finer excipient fractions may consist of chemically identical or chemically different substances, while inhalable powders in which the coarser excipient fraction and the finer excipient fraction consist of the same chemical compound are preferred. [0019]
  • Examples of physiologically acceptable excipients which may be used to prepare the inhalable powders according to the invention include, for example, monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred. [0020]
  • The inhalable powders according to the invention 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 U.S. Pat. No. 4,570,630A) or 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, for example. [0021]
  • If the inhalable powder according to the invention is to be packed into capsules (inhalettes) in accordance with the preferred application mentioned above, it is advisable to fill the capsules with amounts of from 3 to 10 mg, preferably from 4 to 6 mg of inhalable powder per capsule. These will then contain between 1.2 and 80 μg of tiotropium. With a preferred filling of 4 to 6 mg of inhalable powder per capsule, the content of tiotropium per capsule is between 1.6 and 48 μg, preferably between 3.2 and 38.4 μg, most preferably between 6.4 and 24 μg. A content of 18 μg of tiotropium, for example, corresponds to a content of about 21.7 μg of tiotropium bromide. [0022]
  • Consequently, capsules containing 3 to 10 mg of powder for inhalation preferably hold between 1.4 and 96.3 μg of tiotropium bromide, according to the invention. When the filling is from 4 to 6 mg of inhalable powder per capsule, as is preferred, each capsule contains between 1.9 and 57.8 μg, preferably between 3.9 and 46.2 μg, most preferably between 7.7 and 28.9 μg of tiotropium bromide. A content of 21.7 μg of tiotropium bromide, for example, corresponds to a content of about 22.5 μg of tiotropium bromide monohydrate. [0023]
  • Consequently, capsules containing 3 to 10 mg of powder for inhalation preferably hold between 1.5 and 100 μg of tiotropium bromide monohydrate. When the filling is from 4 to 6 mg of inhalable powder per capsule, as is preferred, each capsule contains between 2 and 60 μg, preferably between 4 and 48 μg, most preferably between 8 and 30 μg of tiotropium bromide monohydrate. [0024]
  • The inhalable powders according to the invention are characterised, in accordance with the objective on which the present invention is based, by a high degree of homogeneity in terms of the accuracy of metering of single doses. This is in the range of <8%, preferably <6%, most preferably <4%. [0025]
  • The inhalable powders according to the invention may be obtained by the method described hereinafter. [0026]
  • After the starting materials have been weighed out, first of all the excipient mixture is prepared from the defined fractions of the coarser excipient and finer excipient. Then the inhalable powder according to the invention is prepared from the excipient mixture and the active substance. If the inhalable powder is to be administered using inhalettes in suitable inhalers, the preparation of the inhalable powders is followed by the manufacture of the powder-filled capsules. [0027]
  • In the preparation processes described hereinafter, the abovementioned components are used in the amounts by weight described in the abovementioned compositions of the inhalable powders according to the invention. [0028]
  • The powders for inhalation according to the invention are prepared by mixing the coarser excipient fractions with the finer excipient fractions and subsequently mixing the resulting excipient mixtures with the active substance. [0029]
  • To prepare the excipient mixture, the coarser and finer excipient fractions are placed in a suitable mixing container. The two components are preferably added using a granulating sieve with a mesh size of 0.1 to 2 mm, preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm. Preferably, the coarser excipient is put in first and then the finer excipient fraction is added to the mixing container. During this mixing process the two components are preferably added in batches, with some of the coarser excipient being put in first and then finer and coarser excipient being added alternately. It is particularly preferred when producing the excipient mixture to sieve in the two components in alternate layers. The two components are preferably sieved in alternately in 15 to 45, most preferably 20 to 40 layers each. The mixing of the two excipients may take place while the two components are still being added. Preferably, however, mixing is only done once the two components have been sieved in layer by layer. [0030]
  • Once the excipient mixture has been produced, this and the active substance are placed in a suitable mixing container. The active substance used has an average particle size of 0.5 to 10 μm, preferably 1 to 6 μm, most preferably 2 to 5 μm. The two components are preferably added using a granulating sieve with a mesh size of 0.1 to 2 mm, preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm. Preferably, the excipient mixture is put in first and then the active substance is added to the mixing container. During this mixing process the two components are preferably added in batches. It is particularly preferred when producing the excipient mixture to sieve in the two components in alternate layers. The two components are preferably sieved in alternately in 25 to 65, most preferably 30 to 60 layers. The mixing of the excipient mixture with the active substance may take place while the two components are still being added. Preferably, however, mixing is only done once the two components have been sieved in layer by layer. [0031]
  • The powder mixture thus obtained may optionally be added once or repeatedly using a granulating sieve and then subjected to another mixing process. [0032]
  • One aspect of the present invention relates to an inhalable powder containing tiotropium, which may be obtained by the methods described hereinbefore. [0033]
  • When the term active substance is used within the scope of the present invention, this is intended as a reference to tiotropium. According to the invention, any reference to tiotropium, which is the free ammonium cation, corresponds to a reference to tiotropium in the form of a salt (tiotropium salt) which contains an anion as the counter-ion. Tiotropium salts which may be used within the scope of the present invention are those compounds which contain chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate, in addition to tiotropium as counter-ion (anion). Within the scope of the present invention, tiotropium bromide is preferred of all the tiotropium salts. References to tiotropium bromide within the scope of the present invention should always be taken as references to all possible amorphous and crystalline modifications of tiotropium bromide. These may, for example, include molecules of solvent in their crystalline structure. Of all the crystalline modifications of tiotropium bromide, those which also include water (hydrates) are preferred according to the invention. It is particularly preferable to use tiotropium bromide monohydrate within the scope of the present invention. [0034]
  • In order to prepare the formulations according to the invention, first of all tiotropium has to be prepared in a form which can be used for pharmaceutical purposes. For this, tiotropium bromide, which may be prepared as disclosed in EP 418 716 A1, is preferably subjected to another crystallisation step. Depending on the reaction conditions and solvent used, different crystal modifications are obtained. These modifications may be told apart, for example, by DSC (Differential Scanning Calorimetry). The following Table summarises the melting points of different crystal modifications of tiotropium bromide depending on the solvent, which are determined by DSC. [0035]
    solvent DSC
    methanol 228° C.
    ethanol 227° C.
    ethanol/water 229° C.
    water 230° C.
    isopropanol 229° C.
    acetone 225° C.
    ethyl acetate 228° C.
    tetrahydrofuran 228° C.
  • Tiotropium bromide monohydrate has proved particularly suitable for preparing the formulation according to the invention. The DSC diagram of tiotropium bromide monohydrate shows two characteristic signals. The first, relatively broad, endothermic signal between 50-120° C. can be attributed to the dehydration of the tiotropium bromide monohydrate to produce the anhydrous form. The second, relatively sharp endothermic peak at 230±5° C. can be put down to the melting of the substance. These data were obtained using a Mettler DSC 821 and evaluated with the Mettler STAR software package. [0036]
  • These data, like the other values given in the above Table, were obtained at a heating rate of 10 K/min. [0037]
  • The following Examples serve to illustrate the present invention further without restricting its scope to the embodiments provided hereinafter by way of example. [0038]
  • Starting Materials [0039]
  • In the Examples which follow, lactose-monohydrate (200M) is used as the coarser excipient. It may be obtained, for example, from Messrs DMV International, 5460 Veghel/NL under the product name Pharmatose 200M. [0040]
  • In the Examples which follow, lactose-monohydrate (5μ) is used as the finer excipient. It may be obtained from lactose-monohydrate 200M by conventional methods (micronising). Lactose-monohydrate 200M may be obtained, for example, from Messrs DMV International, 5460 Veghe/NL under the product name Pharmnatose 200M. [0041]
  • Preparation of Tiotropium Bromide Monohydrate: [0042]
  • 15.0 kg of tiotropium bromide are added to 25.7 kg of water In a suitable reaction vessel. The mixture is heated to 80-90° C. and stirred at constant temperature until a clear solution is formed. Activated charcoal (0.8 kg), moistened with water, is suspended in 4.4 kg of water, this mixture is added to the solution containing the tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 min at 80-90° C. and then filtered through a heated filter into an apparatus which has been preheated to an outer temperature of 70° C. The filter is rinsed with 8.6 kg of water. The contents of the apparatus are cooled at 3-5° C. every 20 minutes to a temperature of 20-25° C. The apparatus is further cooled to 10-15° C. using cold water and crystallisation is completed by stirring for at least one hour. The crystals are isolated using a suction drier, the crystal slurry isolated is washed with 9 litres of cold water (10-15° C.) and cold acetone (10-15° C.) The crystals obtained are dried in a nitrogen current at 25° C. over 2 hours. Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory) [0043]
  • The crystalline tiotropium bromide monohydrate thus obtained is micronised by known methods, to bring the active substance into the average particle size which meets the specifications according to the invention. [0044]
  • The method of determining the average particle size of the various ingredients of the formulation according to the invention is described as follows. [0045]
  • A) Determining the Particle Size of Finely Divided Lactose: [0046]
  • Measuring Equipment and Settings: [0047]
  • The equipment is operated according to the manufacturer's instructions. [0048]
    Measuring equipment: HELOS Laser-diffraction spectrometer,
    (SympaTec)
    Dispersing unit: RODOS dry disperser with suction funnel,
    (SympaTec)
    Sample quantity: from 100 mg
    Product feed: Vibri Vibrating channel, Messrs. Sympatec
    Frequency of vibrating 40 rising to 100%
    channel:
    Duration of sample feed: 1 to 15 sec. (in the case of 100 mg)
    Focal length: 100 mm (measuring range: 0.9-175 μm)
    Measuring time: about 15 s (in the case of 100 mg)
    Cycle time:  20 ms
    Start/stop at:  1% on channel 28
    Dispersing gas: compressed air
    Pressure:  3 bar
    Vacuum: maxmium
    Evaluation method: HRLD
  • Sample Preparation/Product Feed: [0049]
  • At least 100 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 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 from about 40% up to 100% (towards the end of the measurement). The time taken to feed in the entire sample is 10 to 15 sec. [0050]
  • B) Determining the Particle Size of Micronised Tiotropium Bromide Monohydrate: [0051]
  • Measuring Equipment and Settings: [0052]
  • The equipment is operated according to the manufacturer's instructions. [0053]
    Measuring equipment: Laser diffraction spectrometer (HELOS),
    Sympatec
    Dispersing unit: RODOS dry disperser with suction funnel,
    Sympatec
    Sample quantity:  50 mg-400 mg
    Product feed: Vibri Vibrating channel, Messrs. Sympatec
    Frequency of vibrating 40 rising to 100%
    channel:
    Duration of sample feed: 15 to 25 sec. (in the case of 200 mg)
    Focal length: 100 mm (measuring range: 0.9-175 μm)
    Measuring time: about 15 s (in the case of 200 mg)
    Cycle time:  20 ms
    Start/stop at:  1% on channel 28
    Dispersing gas: compressed air
    Pressure:  3 bar
    Vacuum: maximum
    Evaluation method: HRLD
  • Sample Preparation/Product Feed: [0054]
  • 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 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 from about 40% up to 100% (towards the end of the measurement). The sample should be fed in as continuously as possible. However, the amount of product should not be so great that adequate dispersion cannot be achieved. The time over which the entire sample is fed in is about 15 to 25 seconds for 200 mg, for example. [0055]
  • C) Determining the Particle Size of Lactose 200M: [0056]
  • Measuring Equipment and Settings: [0057]
  • The equipment is operated according to the manufacturer's instructions. [0058]
    Measuring equipment: Laser diffraction spectrometer (HELOS),
    Sympatec
    Dispersing unit: RODOS dry disperser with
    suction funnel, Sympatec
    Sample quantity: 500 mg
    Product feed: VIBRI Vibrating channel, Messrs. Sympatec
    Frequency of vibrating 18 rising to 100%
    channel:
    Focal length (1): 200 mm (measuring range: 1.8-350 μm)
    Focal length (2): 500 mm (measuring range: 4.5-875 μm)
    Measuring time:  10 s
    Cycle time:  10 ms
    Start/stop at: 1% on channel 19
    Pressure:  3 bar
    Vacuum: maximum
    Evaluation method: HRLD
  • Sample Preparation/Product Feed: [0059]
  • About 500 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 is then transferred into the funnel of the vibrating channel. A gap of 1.2 to 1.4 mm is set between the vibrating channel and funnel. After the start of the measurement the amplitude setting of the vibrating channel is increased from 0 to 40% until a continuous flow of product is obtained. Then it is reduced to an amplitude of about 18%. Towards the end of the measurement the amplitude is increased to 100%. [0060]
  • Apparatus [0061]
  • The following machines and equipment, for example, may be used to prepare the inhalable powders according to the invention: [0062]
  • Mixing container or powder mixer: Gyrowheel mixer 200 L; type: DFW80N-4; made by: [0063]
  • Messrs Engelsmann, D-67059 Ludwigshafen. [0064]
  • Granulating sieve: Quadro Comil; type: 197-S; made by: Messrs Joisten & Kettenbaum, D-51429 Bergisch-Gladbach. [0065]
  • EXAMPLE 1
  • 1.1: Excipient Mixture: [0066]
  • 31.82 kg of lactose monohydrate for inhalation (200M) are used as the coarser excipient component. 1.68 kg of lactose monohydrate (5 μm) are used as the finer excipient component. In the resulting 33.5 kg of excipient mixture the proportion of the finer excipient component is 5%. [0067]
  • About 0.8 to 1.2 kg of lactose monohydrate for inhalation (200M) are added to a suitable mixing container through a suitable granulating sieve with a mesh size of 0.5 mm. Then alternate layers of lactose monohydrate (5 μm) in batches of about 0.05 to 0.07 kg and lactose monohydrate for inhalation (200M) in batches of 0.8 to 1.2 kg are sieved in. Lactose monohydrate for inhalation (200M) and lactose monohydrate (5 μm) are added in 31 and 30 layers, respectively (tolerance: ±6 layers). [0068]
  • The ingredients sieved in are then mixed together (mixing at 900 rpm). [0069]
  • 1.2: Final Mixture: [0070]
  • To prepare the final mixture, 32.87 kg of the excipient mixture (1.1) and 0.13 kg of micronised tiotropium bromide monohydrate are used. The content of active substance in the resulting 33.0 kg of inhalable powder is 0.4%. [0071]
  • About 1.1 to 1.7 kg of excipient mixture (1.1) are added to a suitable mixing container through a suitable granulating sieve with a mesh size of 0.5 mm. Then alternate layers of tiotropium bromide monohydrate in batches of about 0.003 kg and excipient mixture (1.1) in batches of 0.6 to 0.8 kg are sieved in. The excipient mixture and the active substance are added in 46 or 45 layers, respectively (tolerance: ±9 layers). The ingredients sieved in are then mixed together (mixing at 900 rpm). The final mixture is passed through a granulating sieve twice more and then mixed (mixing at 900 rpm). [0072]
  • EXAMPLE 2
  • Inhalation capsules (inhalettes) having the following composition were produced using the mixture obtained according to Example 1: [0073]
    tiotropium bromide monohydrate: 0.0225 mg
    lactose monohydrate (200 M): 5.2025 mg
    lactose monohydrate (5 μm): 0.2750 mg
    hard gelatine capsule:  49.0 mg
    Total:  54.5 mg
  • EXAMPLE 3
  • Inhalation Capsules Having the Composition: [0074]
    tiotropium bromide monohydrate: 0.0225 mg
    lactose monohydrate (200 M): 4.9275 mg
    lactose monohydrate (5 μm): 0.5500 mg
    hard gelatine capsule:  49.0 mg
    Total:  54.5 mg
  • The inhalable powder needed to prepare the capsules was obtained analogously to Example 1. [0075]
  • EXAMPLE 4
  • Inhalation Capsules Having the Composition: [0076]
    tiotropium bromide monohydrate: 0.0225 mg
    lactose monohydrate (200 M): 5.2025 mg
    lactose monohydrate (5 μm): 0.2750 mg
    polyethylene capsule:  100.0 mg
    Total: 105.50 mg
  • The inhalable powder needed to prepare the capsules was obtained analogously to Example 1. [0077]
  • For the purposes of the present invention the mean particle size denotes the value in μm at which 50% of the particles from the volume distribution have a particle size which is smaller than or equal to the value specified. Laser diffraction/dry dispersion is used as the method of measurement for determining the total distribution of the particle size distribution. [0078]

Claims (57)

We claim:
1. An inhalable powder comprising 0.04 to 0.8% of tiotropium in admixture with a physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μm and finer excipient with an average particle size of 1 to 9 μm, the proportion of the finer excipient constituting 1 to 20% of the total amount of excipient.
2. An inhalable powder according to claim 1, wherein the tiotropium is present in the form of the chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate thereof.
3. An inhalable powder comprising between 0.048 and 0.96% of tiotropium bromide in admixture with a physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μm and finer excipient with an average particle size of 1 to 9 μm, the proportion of the finer excipient constituting 1 to 20% of the total amount of excipient.
4. An inhalable powder comprising between 0.05 and 1% of tiotropium bromide monohydrate in admixture with a physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 15 to 80 μm and finer excipient with an average particle size of 1 to 9 μm, the proportion of the finer excipient constituting 1 to 20% of the total amount of excipient.
5. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 17 to 50 μm and finer excipient with an average particle size of 2 to 8 μm.
6. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein the proportion of finer excipient in the total amount of excipient is 3 to 15%.
7. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein the tiotropium used has an average particle size of 0.5 to 10 μm.
8. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein one or more monosaccharides, disaccharides, oligo- or polysaccharides, polyalcohols, salts thereof, or mixtures thereof are used as the excipients.
9. An inhalable powder according to claim 8, wherein glucose, arabinose, lactose, saccharose, maltose, dextrane, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate or mixtures thereof are used as the excipients.
10. An inhalable powder according to claim 9, wherein glucose or lactose or mixtures thereof are used as the excipients.
11. A process for preparing an inhalable powder according to one of claims 1 to 4, comprising: (a) mixing coarser excipient fractions with finer excipient fractions to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium.
12. A method of treating a disease that is responsive to the administration of tiotropium, comprising administering to a host in need thereof an inhalable powder according to one of claims 1 to 4.
13. A method according to claim 12, wherein the disease is asthma or COPD.
14. An inhalette capsule containing an inhalable powder according to one of claims 1 to 4.
15. An inhalette capsule containing from 3 to 10 mg of inhalable powder according to one of claims 1 to 4.
16. An inhalette capsule according to claim 15, containing between 1.2 and 80 μg of tiotropium.
17. An inhalable powder according to claim 4 comprising 0.1 to 0.8% of tiotropium bromide monohydrate.
18. An inhalable powder according to claim 4 comprising 0.2 to 0.5% of tiotropium bromide monohydrate.
19. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 20 to 30 μm and finer excipient with an average particle size of 3 to 7 μm.
20. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein the proportion of finer excipient in the total amount of excipient is 5 to 10%.
21. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein the tiotropium used has an average particle size of 1 to 6 μm.
22. An inhalable powder according to one of claims 1, 2, 3 or 4, wherein the tiotropium used has an average particle size of 2 to 5 μm.
23. An inhalable powder according to claim 10, wherein lactose monohydrate is used as the excipient.
24. An inhalable powder comprising between 0.2 and 0.5% of tiotropium bromide monohydrate in admixture with lactose monohydrate as the physiologically acceptable excipient, wherein the excipient consists of a mixture of coarser excipient with an average particle size of 20 to 30 μm and finer excipient with an average particle size of 3 to 7 μm, the proportion of the finer excipient constituting 5 to 10% of the total amount of excipient.
25. An inhalette capsule containing from 3 to 10 mg of inhalable powder according to claim 24.
26. An inhalette capsule containing from 4 to 6 mg of inhalable powder according to one of claims 1 to 4 or 24.
27. An inhalette capsule according to claim 26, containing between 1.6 and 48 μm of tiotropium.
28. An inhalette capsule according to claim 26, containing between 2 and 60 μm of tiotropium bromide monohydrate.
29. An inhalette capsule according to claim 26, containing between 4 and 48 μg of tiotropium bromide monohydrate.
30. An inhalette capsule according to claim 26, containing between 8 and 30 μg of tiotropium bromide monohydrate.
31. An inhalable powder comprising 0.04 to 0.8% of tiotropium in admixture with a physiologically acceptable excipient, said inhalable powder prepared by a process comprising: (a) mixing coarser excipient having an average particle size of 15 to 80 μm and finer excipient having an average particle size of 1 to 9 μm, wherein the proportion of the finer excipient constitutes 1 to 20% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium.
32. An inhalable powder according to claim 31, wherein the tiotropium is present in the form of the chloride, bromide, iodide, methanesulphonate, para-toluenesulphonate or methyl sulphate thereof.
33. An inhalable powder comprising between 0.048 and 0.96% of tiotropium bromide in admixture with a physiologically acceptable excipient, said inhalable powder prepared by a process comprising: (a) mixing coarser excipient having an average particle size of 15 to 80 μm and finer excipient having an average particle size of 1 to 9 μm, wherein the proportion of the finer excipient constitutes 1 to 20% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium bromide.
34. An inhalable powder comprising between 0.05 and 1% of tiotropium bromide monohydrate in admixture with a physiologically acceptable excipient, said inhalable powder prepared by a process comprising: (a) mixing coarser excipient having an average particle size of 15 to 80 μm and finer excipient having an average particle size of 1 to 9 μm, wherein the proportion of the finer excipient constitutes 1 to 20% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium bromide monohydrate.
35. An inhalable powder according to claim 34 comprising 0.1 to 0.8% of tiotropium. bromide monohydrate.
36. An inhalable powder according to claim 34 comprising 0.2 to 0.5% of tiotropium bromide monohydrate.
37. An inhalable powder according to one of claims 31, 32, 33 or 34, wherein the coarser excipient has an average particle size of 17 to 50 μm and the finer excipient has an average particle size of 2 to 8 μm.
38. An inhalable powder according to one of claims 31, 32, 33 or 34, wherein the coarser excipient has an average particle size of 20 to 30 μm and the finer excipient has an average particle size of 3 to 7 μm.
39. An inhalable powder according to one of claims 31, 32, 33 or 34, wherein the proportion of finer excipient in the total amount of excipient is 3 to 15%.
40. An inhalable powder according to one of claims 31, 32, 33 or 34, wherein the proportion of finer excipient in the total amount of excipient is 5 to 10%.
41. An inhalable powder according to one of claims 31, 32, 33 or 34, wherein the tiotropium used has an average particle size of 0.5 to 10 μm.
42. An inhalable powder according to one of claims 31, 32, 33 or 34, wherein the tiotropium used has an average particle size of 1 to 6 μm.
43. An inhalable powder according to one of claims 31, 32, 33 or 34, wherein the tiotropium used has an average particle size of 2 to 5 μm.
44. An inhalable powder according to one of claims 31, 32, 33 or 34, wherein one or more monosaccharides, disaccharides, oligo- or polysaccharides, polyalcohols, salts thereof, or mixtures thereof are used as the excipients.
45. An inhalable powder according to claim 44, wherein glucose, arabinose, lactose, saccharose, maltose, dextrane, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate or mixtures thereof are used as the excipients.
46. An inhalable powder according to claim 45, wherein glucose or lactose or mixtures thereof are used as the excipients.
47. An inhalable powder according to claim 46, wherein lactose monohydrate is used as the excipient.
48. An inhalable powder comprising between 0.2 and 0.5% of tiotropium bromide monohydrate in admixture with lactose monohydrate as a physiologically acceptable excipient, said inhalable powder prepared by a process comprising: (a) mixing coarser lactose monohydrate excipient having an average particle size of 20 to 30 μm and finer lactose monohydrate excipient having an average particle size of 3 to 7 μm, wherein the proportion of the finer lactose monohydrate excipient constitutes 5 to 10% of the total amount of excipient, to obtain an excipient mixture, and (b) mixing the excipient mixture thus obtained with the tiotropium bromide monohydrate.
49. A method of treating a disease that is responsive to the administration of tiotropium, comprising administering to a host in need thereof an inhalable powder according to one of claims 31, 32, 33, 34 or 48.
50. A method according to claim 49, wherein the disease is asthma or COPD.
51. An inhalette capsule containing an inhalable powder according to one of claims 31, 32, 33, 34 or 48.
52. An inhalette capsule containing from 3 to 10 mg of inhalable powder according to one of claims 31, 32, 33, 34 or 48.
53. An inhalette capsule containing from 4 to 6 mg of inhalable powder according to one of claims 31, 32, 33, 34 or 48.
54. An inhalette capsule according to claim 53, containing between 1.6 and 48 μg of tiotropium.
55. An inhalette capsule according to claim 53, containing between 2 and 60 μg of tiotropium bromide monohydrate.
56. An inhalette capsule according to claim 53, containing between 4 and 48 μg of tiotropium bromide monohydrate.
57. An inhalette capsule according to claim 53, containing between 8 and 30 μg of tiotropium bromide monohydrate.
US10/729,543 2000-10-12 2003-12-05 Inhalable powder containing tiotropium Abandoned US20040228806A1 (en)

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DEDE10050635.6 2000-10-12
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030185766A1 (en) * 2002-03-28 2003-10-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg HFA suspension formulations of an anhydrate

Families Citing this family (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU757008B2 (en) * 2000-10-12 2003-01-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel tiotropium-containing inhalation powder
ATE517607T1 (en) 2000-11-30 2011-08-15 Vectura Ltd METHOD FOR PRODUCING PARTICLES FOR USE IN A PHARMACEUTICAL COMPOSITION
AU2002220857A1 (en) 2000-11-30 2002-06-11 Vectura Limited Particles for use in a pharmaceutical composition
US20030055026A1 (en) 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
US20030070679A1 (en) * 2001-06-01 2003-04-17 Boehringer Ingelheim Pharma Kg Capsules containing inhalable tiotropium
DE10128779A1 (en) * 2001-06-13 2003-01-02 Boehringer Ingelheim Pharma Process for cleaning hard gelatin capsules
US20030008001A1 (en) * 2001-06-13 2003-01-09 Boehringer Ingelheim Pharma Kg Process for cleaning hard gelatine capsules
DE10141376A1 (en) * 2001-08-23 2003-03-13 Boehringer Ingelheim Pharma Process for the preparation of inhalable powders
DE10141377A1 (en) 2001-08-23 2003-03-13 Boehringer Ingelheim Pharma Scattering process for the production of powder formulations
DE10212264A1 (en) 2002-03-20 2003-10-02 Boehringer Ingelheim Pharma Crystalline micronisate, process for its preparation and its use for the manufacture of a medicament
US7309707B2 (en) * 2002-03-20 2007-12-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Crystalline micronisate, process for the manufacture thereof and use thereof for the preparation of a medicament
JP2005526103A (en) * 2002-04-04 2005-09-02 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト Powder formulation suitable for inhalation
US20030235538A1 (en) * 2002-04-09 2003-12-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Method for the administration of an anticholinergic by inhalation
AU2003276837B2 (en) * 2002-06-12 2006-07-20 Epigenesis Pharmaceuticals, Llc. Combination of anti-muscarinic agents and non-glucocorticoid steroids
GB0219513D0 (en) 2002-08-21 2002-10-02 Norton Healthcare Ltd Inhalation compositions including coarse carrier
ATE520405T1 (en) * 2002-08-21 2011-09-15 Norton Healthcare Ltd INHALATION COMPOSITION
JP2006516531A (en) * 2002-08-21 2006-07-06 ノートン ヘルスケアー リミテッド Inhalation composition
GB0219511D0 (en) * 2002-08-21 2002-10-02 Norton Healthcare Ltd Method of preparing dry powder inhalation compositions
DE10255387A1 (en) * 2002-11-28 2004-06-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg New tiotropium-containing powder formulation for inhalation
US7763280B2 (en) 2002-11-28 2010-07-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium containing powder formulation for inhalation
US20050058606A1 (en) * 2002-12-16 2005-03-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium containing HFC solution formulations
US20040152720A1 (en) * 2002-12-20 2004-08-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Powdered medicaments containing a tiotropium salt and salmeterol xinafoate
DE10317461A1 (en) 2003-04-16 2004-10-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Preparing microparticles labeled with technetium, useful as powders for inhalation, e.g. to study deposition of pharmaceuticals, such as anticholinergic agents, involves incubation with solution of technetium salt
US20040226556A1 (en) 2003-05-13 2004-11-18 Deem Mark E. Apparatus for treating asthma using neurotoxin
US7954491B2 (en) 2003-06-13 2011-06-07 Civitas Therapeutics, Inc. Low dose pharmaceutical powders for inhalations
TWI359675B (en) 2003-07-10 2012-03-11 Dey L P Bronchodilating β-agonist compositions
US20050038004A1 (en) * 2003-07-31 2005-02-17 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with an anticholinergic bronchodilator for treatment of asthma or chronic obstructive pulmonary disease
EA012326B1 (en) 2003-11-03 2009-08-28 Бёрингер Ингельхайм Интернациональ Гмбх Method for producing tiotropium salts, tiotropium salts and pharmaceutical formulations containing the same
CN1875020B (en) 2003-11-03 2010-04-28 贝林格尔.英格海姆国际有限公司 Novel tiotropium salts, methods for the production thereof, and pharmaceutical formulations containing the same
PL1691783T3 (en) * 2003-12-03 2010-05-31 Boehringer Ingelheim Int Pre-metered dry powder inhaler for moisture-sensitive medicaments
SE0303269L (en) * 2003-12-03 2005-06-04 Microdrug Ag Medical product
SE0303570L (en) * 2003-12-03 2005-06-04 Microdrug Ag Moisture-sensitive medical product
CA2547782A1 (en) * 2003-12-03 2005-06-16 Microdrug Ag Medical product containing tiotropium
SE0303270L (en) * 2003-12-03 2005-06-04 Microdrug Ag Method of administration of tiotropium
DE102004048389A1 (en) 2004-10-01 2006-04-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Modification of surfaces of lactose as adjuvant for use with powder inhalants
RU2007133547A (en) 2005-02-10 2009-03-20 Глаксо Груп Лимитед (GB) METHODS FOR PRODUCING LACTOSES USING PRELIMINARY SORTING METHODS AND PHARMACEUTICAL COMPOSITIONS PRODUCED FROM IT
RU2417224C2 (en) * 2005-05-02 2011-04-27 Бёрингер Ингельхайм Интернациональ Гмбх New crystalline forms of tiotropium bromide
KR20080024532A (en) * 2005-06-15 2008-03-18 베링거 인겔하임 인터내셔날 게엠베하 Process for preparing new tiotropium salts, new tiotropium salts as such and pharmaceutical compositions thereof
TWI274641B (en) * 2005-08-30 2007-03-01 Rexon Ind Corp Ltd Cutting machine
JP5086267B2 (en) * 2005-12-19 2012-11-28 シコール インコーポレイティド Novel form of tiotropium bromide and process for producing it
RU2453547C2 (en) * 2005-12-19 2012-06-20 Сикор Инк. Novel forms of tiotropium bromide and synthesis methods thereof
MX2007009987A (en) * 2005-12-19 2007-10-02 Sicor Inc Pure and stable tiotropium bromide.
US9108962B2 (en) 2005-12-19 2015-08-18 Sicor, Inc. Forms of tiotropium bromide and processes for preparation thereof
US20070167480A1 (en) * 2005-12-19 2007-07-19 Sicor Inc. Pure and stable tiotropium bromide
US20080051582A1 (en) * 2006-07-10 2008-02-28 Sicor Inc. Process for the preparation of tiotropium bromide
GB0716026D0 (en) * 2007-08-16 2007-09-26 Norton Healthcare Ltd An inhalable medicament
EP2183262A1 (en) * 2007-07-27 2010-05-12 Cargill, Incorporated Micronization of polyols
US8483831B1 (en) 2008-02-15 2013-07-09 Holaira, Inc. System and method for bronchial dilation
EP2662046B1 (en) 2008-05-09 2023-03-15 Nuvaira, Inc. Systems and assemblies for treating a bronchial tree
EP2172190A1 (en) 2008-10-02 2010-04-07 Laboratorios Liconsa, S.A. Inhalable particles comprising tiotropium
WO2010106988A1 (en) 2009-03-17 2010-09-23 第一三共株式会社 Amide derivative
CN102639077B (en) 2009-10-27 2015-05-13 赫莱拉公司 Delivery devices with coolable energy emitting assemblies
EP4111995A1 (en) 2009-11-11 2023-01-04 Nuvaira, Inc. Device for treating tissue and controlling stenosis
US8911439B2 (en) 2009-11-11 2014-12-16 Holaira, Inc. Non-invasive and minimally invasive denervation methods and systems for performing the same
US8834931B2 (en) 2009-12-25 2014-09-16 Mahmut Bilgic Dry powder formulation containing tiotropium for inhalation
WO2011152804A2 (en) * 2010-06-03 2011-12-08 Mahmut Bilgic Process for dry powder formulations
TR201007251A2 (en) * 2010-09-01 2012-03-21 Bi̇lgi̇ç Mahmut Calcium channel blocker formulation.
GB201200525D0 (en) 2011-12-19 2012-02-29 Teva Branded Pharmaceutical Prod R & D Inc An inhalable medicament
WO2014007773A1 (en) * 2012-07-05 2014-01-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions comprising muscarinic receptor antagonist and sorbitol
WO2013127738A1 (en) 2012-02-28 2013-09-06 Boehringer Ingelheim International Gmbh Novel propellant-gas-containing tiotropium formulation
RU2522213C2 (en) * 2012-06-07 2014-07-10 Шолекс Девелопмент Гмбх, Pharmaceutical inhaled medication for treatment of bronchial asthma and chronic obstructive lung disease, containing micronised tiotropium bromide as active substance and method of its production
WO2014007781A2 (en) * 2012-07-05 2014-01-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Inhalation compositions
WO2014007768A1 (en) 2012-07-05 2014-01-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Dry powder inhaler compositions comprising long acting muscorinic antagonists
US20150165037A1 (en) * 2012-07-05 2015-06-18 Arven llac Sanayi Ve Ticaret A.S. Inhalation compositions comprising corticosteroid and sorbitol
WO2014007772A2 (en) * 2012-07-05 2014-01-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Inhalation compositions comprising glucose anhydrous
US10105316B2 (en) 2012-07-05 2018-10-23 Arven llac Sanayi Ve Ticaret A.S. Inhalation compositions comprising muscarinic receptor antagonist
WO2014007769A1 (en) * 2012-07-05 2014-01-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Compositions comprising muscarinic receptor antagonist and glucose anhydrous
EP2705838A1 (en) 2012-09-06 2014-03-12 Xspray Microparticles Ab Tiotropium preparations
US9398933B2 (en) 2012-12-27 2016-07-26 Holaira, Inc. Methods for improving drug efficacy including a combination of drug administration and nerve modulation
WO2015065222A1 (en) * 2013-10-28 2015-05-07 Шолекс Девелопмент Гмбх Pharmaceutical inhaled drug with micronized tiotropium bromide as active ingredient for the treatment of bronchial asthma and chronic obstructive pulmonary disease and method for producing same
EP2913332A1 (en) 2014-02-27 2015-09-02 Euticals S.P.A. Crystalline form of tiotropium bromide with lactose
US10034866B2 (en) 2014-06-19 2018-07-31 Teva Branded Pharmaceutical Products R&D, Inc. Inhalable medicament comprising tiotropium
EP3159277B1 (en) 2015-10-23 2019-05-29 Arven Ilac Sanayi Ve Ticaret A.S. Blister for inhalable formulation of tiotropium bromide
KR101728116B1 (en) * 2015-11-03 2017-04-18 한미약품 주식회사 Dry powder composition for inhalation comprising tiotropium or pharmaceutically acceptable salt thereof
MX2018007507A (en) 2015-12-24 2018-08-01 Philip Morris Products Sa Flavoured nicotine powder.
JP7016880B2 (en) 2017-03-23 2022-02-07 シンガポール ヘルス サービシーズ ピーティーイー リミテッド Myopia prophylaxis, myopia treatment and / or myopia progression inhibitor containing tiotropium as an active ingredient
EP4108230A1 (en) 2021-06-24 2022-12-28 Laboratoires SMB New dry powder composition of tiotropium for inhalation
GR1010358B (en) * 2021-09-14 2022-12-16 Elpen Ανωνυμος Εταιρεια Φαρμακευτικη Βιομηχανια, Stable orally inhaled pharmaceutical formulation containing tiotropium bromide

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3634582A (en) * 1967-08-08 1972-01-11 Fisons Pharmaceuticals Ltd Pharmaceutical compositions
US3860618A (en) * 1967-08-08 1975-01-14 Philip Saxton Hartley Chromone
US3957965A (en) * 1967-08-08 1976-05-18 Fisons Limited Sodium chromoglycate inhalation medicament
US5478578A (en) * 1991-12-10 1995-12-26 Boehringer Ingelheim Kg Powders for inhalation
US6183782B1 (en) * 1994-03-15 2001-02-06 Glaxo Group Limited Inhalation composition containing lactose pellets
US6221338B1 (en) * 1993-10-26 2001-04-24 Vectura Limited Method of producing particles for use in dry powder inhalers
US6228394B1 (en) * 1997-10-14 2001-05-08 Boehringer Ingelheim Pharmaceuticals, Inc. Supercritical fluid extraction of mould lubricant from hard shell capsules
US6235725B1 (en) * 1998-10-30 2001-05-22 Baker Norton Pharmaceuticals, Inc. Methods and compositions for the prevention of tolerance to medications

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2540633A1 (en) 1975-09-12 1977-04-28 Boehringer Sohn Ingelheim NEW QUARTERLY N-BETA-SUBSTITUTED BENZILIC ACID-N-ALKYL-NORTROPINESTER AND PROCESS FOR THE PREPARATION
DE3211185A1 (en) 1982-03-26 1983-09-29 Boehringer Ingelheim KG, 6507 Ingelheim NEW QUARTAERE 6,11-DIHYDRO-DIBENZO- (B, E) -THIEPIN-11-N-ALKYL-NORSCOPINETHER AND METHOD FOR THE PRODUCTION THEREOF
DE3215493A1 (en) 1982-04-26 1983-11-03 Boehringer Ingelheim KG, 6507 Ingelheim NEW INTERMEDIATE PRODUCTS, METHOD FOR THEIR PRODUCTION AND THEIR USE
JPS60172442A (en) 1984-02-20 1985-09-05 Fanuc Ltd Machining apparatus for copying work and nc work
US5610163A (en) 1989-09-16 1997-03-11 Boehringer Ingelheim Gmbh Esters of thienyl carboxylic acids and amino alcohols and their quaternization products
DE3931041C2 (en) 1989-09-16 2000-04-06 Boehringer Ingelheim Kg Esters of thienyl carboxylic acids with amino alcohols, their quaternization products, processes for their preparation and medicaments containing them
DE4108393A1 (en) 1991-03-15 1992-09-17 Boehringer Ingelheim Kg NEW ESTERS BI-AND TRICYCLIC AMINO ALCOHOLS, THEIR PREPARATION AND THEIR USE IN MEDICINAL PRODUCTS
EP0580861B1 (en) 1991-04-08 1998-09-09 Nippon Shinyaku Company, Limited Sustained release capsule for adhesion in the gastrointestinal tract
US5770738A (en) 1992-03-05 1998-06-23 Boehringer Ingelheim Kg Esters of bi- and tricyclic amino alcohols, their preparation and their use in pharmaceutical compositions
DE4318455A1 (en) 1993-06-03 1994-12-08 Boehringer Ingelheim Kg Capsule holder
GB9311892D0 (en) 1993-06-09 1993-07-28 Glaxo Wellcome Australia Ltd Device
EP1033128B2 (en) 1993-09-28 2011-11-23 R.P. Scherer GmbH Soft gelatin capsule manufacture
DE4425255A1 (en) 1994-07-16 1996-01-18 Asta Medica Ag Formulation for inhalation application
DE19515625C2 (en) 1995-04-28 1998-02-19 Boehringer Ingelheim Kg Process for the production of enantiomerically pure tropic acid esters
FR2757173A1 (en) 1996-12-17 1998-06-19 Warner Lambert Co POLYMERIC COMPOSITIONS OF NON-ANIMAL ORIGIN FOR FILM FORMATION
JP2002529498A (en) 1998-11-13 2002-09-10 ヤゴ・リサーチ・アクチェンゲゼルシャフト Dry powder for inhalation
GB9902689D0 (en) * 1999-02-08 1999-03-31 Novartis Ag Organic compounds
US20040002548A1 (en) 1999-05-12 2004-01-01 Boehringer Ingelheim Pharma Kg Medicament compositions containing anticholinergically-effective compounds and betamimetics
JP3931486B2 (en) 1999-06-24 2007-06-13 住友化学株式会社 Positive resist composition
US6908928B2 (en) * 2000-10-12 2005-06-21 Bi Pharma Kg. Crystalline tiotropium bromide monohydrate, processes for the preparation thereof, and pharmaceutical compositions
AU757008B2 (en) 2000-10-12 2003-01-30 Boehringer Ingelheim Pharma Gmbh & Co. Kg Novel tiotropium-containing inhalation powder
UA75375C2 (en) * 2000-10-12 2006-04-17 Boehringer Ingelheim Pharma Method for producing powdery preparations for inhaling
DE10064816A1 (en) 2000-12-22 2002-06-27 Boehringer Ingelheim Pharma Production of tiotropium bromide useful as an anticholinergic comprises oxidation of di-(2-thienyl)-glycolic acid tropenol ester and subsequent quaternisation
US6506900B1 (en) 2001-01-31 2003-01-14 Boehringer Ingelheim Pharma Ag Process for preparing a scopine ester intermediate
US20030070679A1 (en) 2001-06-01 2003-04-17 Boehringer Ingelheim Pharma Kg Capsules containing inhalable tiotropium
DE10126924A1 (en) 2001-06-01 2002-12-05 Boehringer Ingelheim Pharma Inhalation capsule contains powdered mixture of tiotropium and auxiliary, for treating asthma or chronic obstructive pulmonary disease, having capsule material of low moisture content to improve stability
US6482429B1 (en) 2001-06-20 2002-11-19 Boehringer Ingelheim Pharmaceuticals, Inc. Stable powder inhalation dosage formulation
DE10141377A1 (en) 2001-08-23 2003-03-13 Boehringer Ingelheim Pharma Scattering process for the production of powder formulations
DE10141376A1 (en) 2001-08-23 2003-03-13 Boehringer Ingelheim Pharma Process for the preparation of inhalable powders
US7309707B2 (en) * 2002-03-20 2007-12-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Crystalline micronisate, process for the manufacture thereof and use thereof for the preparation of a medicament
JP2005526103A (en) 2002-04-04 2005-09-02 ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト Powder formulation suitable for inhalation
US20030235538A1 (en) 2002-04-09 2003-12-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Method for the administration of an anticholinergic by inhalation
UA80123C2 (en) 2002-04-09 2007-08-27 Boehringer Ingelheim Pharma Inhalation kit comprising inhalable powder of tiotropium
US7763280B2 (en) 2002-11-28 2010-07-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tiotropium containing powder formulation for inhalation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3634582A (en) * 1967-08-08 1972-01-11 Fisons Pharmaceuticals Ltd Pharmaceutical compositions
US3860618A (en) * 1967-08-08 1975-01-14 Philip Saxton Hartley Chromone
US3957965A (en) * 1967-08-08 1976-05-18 Fisons Limited Sodium chromoglycate inhalation medicament
US5478578A (en) * 1991-12-10 1995-12-26 Boehringer Ingelheim Kg Powders for inhalation
US6221338B1 (en) * 1993-10-26 2001-04-24 Vectura Limited Method of producing particles for use in dry powder inhalers
US6183782B1 (en) * 1994-03-15 2001-02-06 Glaxo Group Limited Inhalation composition containing lactose pellets
US6228394B1 (en) * 1997-10-14 2001-05-08 Boehringer Ingelheim Pharmaceuticals, Inc. Supercritical fluid extraction of mould lubricant from hard shell capsules
US6235725B1 (en) * 1998-10-30 2001-05-22 Baker Norton Pharmaceuticals, Inc. Methods and compositions for the prevention of tolerance to medications

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030185766A1 (en) * 2002-03-28 2003-10-02 Boehringer Ingelheim Pharma Gmbh & Co. Kg HFA suspension formulations of an anhydrate
US7244415B2 (en) 2002-03-28 2007-07-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg HFA suspension formulations of an anhydrate

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