Patent Grant
8022082
The invention relates to a method for the administration of powdered preparations containing tiotropium by inhalation.
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 long-lasting activity which can be used to treat respiratory complaints, particularly chronic obstructive pulmonary disease (COPD) 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 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.
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 for powder inhalation or when the patient is metering the individual dose before using a multi-dose 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 μm and 10 μm, preferably less than 5 μm.
Finally, it has been found that the intended therapeutic effect upon the administration of a pharmaceutical composition via inhalation can be decisively influenced by the inhalation device.
Accordingly, the aim of the invention is to provide for a therapeutically efficient method for the administration of inhalable powders containing tiotropium. Another object of the invention is to provide for an inhalation kit comprising a tiotropium containing powder and an inhalation device, the kit being applicable in the method for administration mentioned before.
In the method according to the invention an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient is administered.
Of particular interest for the method according to the invention is an inhalable powder containing 0.01% to 2%, preferably 0.04% to 0.8%, more preferably 0.08% to 0.64% tiotropium in admixture with a physiologically acceptable excipient is administered.
More preferably in the method according to the invention an inhalable powder containing 0.1% to 0.4% tiotropium in admixture with a physiologically acceptable excipient is administered.
By tiotropium is meant the free ammonium cation. The counter-ion (anion) may be chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, or methylsulfate. Of these anions, the bromide is preferred.
Accordingly, the method according to the present invention preferably relates to inhalable powders which contain tiotropium in form of tiotropium bromide in an amount of 0.0012% to 6.02%, in admixture with a physiologically acceptable excipient. Of particular interest for the method according to the invention is an inhalable powder containing 0.012% to 2.41%, preferably 0.048% to 0.96%, more preferably 0.096% to 0.77%, tiotropium bromide in admixture with a physiologically acceptable excipient is administered.
More preferably in the method according to the invention an inhalable powder containing 0.12% to 0.48% tiotropium bromide in admixture with a physiologically acceptable excipient is administered.
Tiotropium bromide is, depending on the choice of reaction conditions and solvents, obtainable in different crystalline modifications. Most preferred according to the invention are those powder preparations, that contain tiotropium in form of the crystalline tiotropium bromide monohydrate. Accordingly, the powdered preparations obtainable according to the invention preferably contain 0.0012% to 6.25% crystalline tiotropium bromide monohydrate in admixture with a physiologically acceptable excipient is administered. Of particular interest for the method according to the invention is an inhalable powder containing 0.0125% to 2.5%, preferably 0.05% to 1%, more preferably 0.1% to 0.8%, crystalline tiotropium bromide monohydrate in admixture with a physiologically acceptable excipient is administered.
More preferably in the method according to the invention an inhalable powder containing 0.12% to 0.5% crystalline tiotropium bromide monohydrate in admixture with a physiologically acceptable excipient is administered.
Examples of physiologically acceptable excipients which may be used to prepare the inhalable powders applicable according to the invention include, for example, monosaccharides (e.g., glucose or arabinose), disaccharides (e.g., lactose, saccharose, or maltose), oligo- and polysaccharides (e.g., dextrane), polyalcohols (e.g., sorbitol, mannitol, or xylitol), salts (e.g., sodium chloride or 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, preferably in the form of their monohydrates.
In the method according to the invention, the average particle size of the physiologically acceptable excipient is preferably between 10 μm to 500 μm, more preferably between 15 μm to 200 μm, most preferably between 20 μm to 100 μm. If not otherwise emphasized, the term average particle size according to the invention is to be understood as the Mass Median Aerodynamic Diameter (MMAD). Methods for the determination thereof are known in the art.
Besides the coarser particle fraction of the excipient mentioned hereinbefore, the excipient can optionally additionally contain a specifically added fraction of excipient of finer particle size. This finer particle size fraction is characterized by an average particle size of 1 μm to 9 μm, preferably 2 μm to 8 μm, more preferably 3 μm to 7 μm.
If a finer particle fraction is present, the proportion of finer excipient in the total amount of excipient is 1% to 20%, preferably 3% to 15%, more preferably 5% to 10%. 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.
The percentages given within the scope of the present invention are always percent by weight.
In the method according to the invention, the inhalable powders mentioned hereinbefore may efficiently be administered using inhalers that are characterized by a specific flow resistance (R).
The flow resistance of inhalers can be calculated via the following formula:
wherein:
In the method according to the invention, the flow resistance R characterizing the inhaler is in a range of about 0.01 to 0.1 √{square root over (kPa)} min/L preferably in the range of about 0.02 to 0.06 √{square root over (kPa)} min/L.
Accordingly, the invention relates to a method for the administration of an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, and further characterized in that the tiotropium containing powder is administered by an inhaler displaying a flow resistance of about 0.01 to 0.1 √{square root over (kPa)} min/L.
In another embodiment, the invention relates to a method for the treatment of airway diseases, particularly chronic obstructive pulmonary disease (COPD) and asthma, characterized in that an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, is administered via inhalation by an inhaler displaying a flow resistance of about 0.01 to 0.1 √{square root over (kPa)} min/L.
In another embodiment, the invention relates to the use of an inhaler for the administration of a tiotropium containing inhalable powder via inhalation, characterized in that the inhalable powder contains tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, and further characterized in that the inhaler displays a flow resistance of about 0.01 to 0.1 √{square root over (kPa)} min/L.
In yet another embodiment the invention relates to an inhalation kit consisting of an inhaler displaying a flow resistance of about 0.01 to 0.1 √{square root over (kPa)} min/L and an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm.
In another preferred embodiment according to the invention, the inhaler described in
The inhaler according to
The main air flow enters the inhaler between deck 3 and base 1 near to the hinge. The deck has in this range a reduced width, which forms the entrance slit for the air. Then the flow reverses and enters the capsule chamber 6 through the inlet tube. The flow is then further conducted through the filter and filter holder to the mouthpiece. A small portion of the flow enters the device between mouthpiece and deck and flows then between filter holder and deck into the main stream. Due to production tolerances, there is some uncertainty in this flow because of the actual width of the slit between filter holder and deck. In case of new or reworked tools, the flow resistance of the inhaler may therefore be a little off the target value. To correct this deviation, the deck has in the central region around the capsule chamber 6 and underneath the screen housing 4 and screen 5 three holes 13 with diameters below 1 mm. Through these holes 13 flows air from the base into the main air stream and reduces such slightly the flow resistance of the inhaler. The actual diameter of these holes 13 can be chosen by proper inserts in the tools so that the mean flow resistance can be made equal to the target value.
Accordingly, in a preferred embodiment the invention relates to a method for the administration of an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, by means of the inhaler according to
In another embodiment, the invention relates to a method for treatment of airway diseases, particularly chronic obstructive pulmonary disease and asthma, characterized in that an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, is administered via inhalation by the inhaler according to
In another preferred embodiment, the invention relates to the use of the inhaler according to
In yet another preferred embodiment, the invention relates to an inhalation kit consisting of an inhalable powdered containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, and the inhaler according to
In another preferred embodiment according to the invention the inhaler according to U.S. Pat. No. 4,524,769 is applied. This inhaler (or inhalator) is activated by the air flow generated at inhalation. The disclosure of U.S. Pat. No. 4,524,769 is incorporated herein by reference in its entirety.
Accordingly, in a preferred embodiment, the invention relates to a method for the administration of an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, by means of the inhaler according to U.S. Pat. No. 4,524,769, comprising a nozzle, a conduit connected to the nozzle, a storage chamber adjacent the conduit for storing the inhalable powder to be dispensed by the inhalator, a perforated membrane having a plurality of preselected perforated portions each holding and dispensing a reproducible unit dose of less than 50 mg of the inhalable powder, the membrane being mounted for movement between the conduit and the storage chamber so that one of the preselected portions is positioned across the conduit whereby the active compound held in the perforation thereof can be dispensed into the conduit and another of the preselected portions thereof is disposed within the storage chamber, dose loading means for introducing the inhalable powder in the storage chamber into the perforation of the preselected portion of the membrane disposed within the storage chamber, and maneuvering means for displacing the perforated membrane through a plurality of positions whereby successive preselected portions of the perforated membrane holding the inhalable powder are positioned across the conduit for dispensing the inhalable powder.
In another embodiment, the invention relates to a method for treatment of airway diseases, particularly chronic obstructive pulmonary disease and asthma, characterized in that an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, is administered via inhalation by the inhaler according to U.S. Pat. No. 4,524,769, comprising a nozzle, a conduit connected to the nozzle, a storage chamber adjacent the conduit for storing the inhalable powder to be dispensed by the inhalator, a perforated membrane having a plurality of preselected perforated portions each holding and dispensing a reproducible unit dose of less than 50 mg of the inhalable powder, the membrane being mounted for movement between the conduit and the storage chamber so that one of the preselected portions is positioned across the conduit whereby the active compound held in the perforation thereof can be dispensed into the conduit and another of the preselected portions thereof is disposed within the storage chamber, dose loading means for introducing the inhalable powder in the storage chamber into the perforation of the preselected portion of the membrane disposed within the storage chamber, and maneuvering means for displacing the perforated membrane through a plurality of positions whereby successive preselected portions of the perforated membrane holding the inhalable powder are positioned across the conduit for dispensing the inhalable powder.
In another preferred embodiment, the invention relates to the use of the inhaler according to U.S. Pat. No. 4,524,769 comprising a nozzle, a conduit connected to the nozzle, a storage chamber adjacent the conduit for storing the inhalable powder to be dispensed by the inhalator, a perforated membrane having a plurality of preselected perforated portions each holding and dispensing a reproducible unit dose of less than 50 mg of the inhalable powder, the membrane being mounted for movement between the conduit and the storage chamber so that one of the preselected portions is positioned across the conduit whereby the active compound held in the perforation thereof can be dispensed into the conduit and another of the preselected portions thereof is disposed within the storage chamber, dose loading means for introducing the inhalable powder in the storage chamber into the perforation of the preselected portion of the membrane disposed within the storage chamber, and maneuvering means for displacing the perforated membrane through a plurality of positions whereby successive preselected portions of the perforated membrane holding the inhalable powder are positioned across the conduit for dispensing the inhalable powder, for the administration of an inhalable powdered containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm.
In yet another preferred embodiment, the invention relates to an inhalation kit consisting of an inhalable powdered containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, and the inhaler according to U.S. Pat. No. 4,524,769, comprising a nozzle, a conduit connected to the nozzle, a storage chamber adjacent the conduit for storing the inhalable powder to be dispensed by the inhalator, a perforated membrane having a plurality of preselected perforated portions each holding and dispensing a reproducible unit dose of less than 50 mg of the inhalable powder, the membrane being mounted for movement between the conduit and the storage chamber so that one of the preselected portions is positioned across the conduit whereby the active compound held in the perforation thereof can be dispensed into the conduit and another of the preselected portions thereof is disposed within the storage chamber, dose loading means for introducing the inhalable powder in the storage chamber into the perforation of the preselected portion of the membrane disposed within the storage chamber, and maneuvering means for displacing the perforated membrane through a plurality of positions whereby successive preselected portions of the perforated membrane holding the inhalable powder are positioned across the conduit for dispensing the inhalable powder.
In another preferred embodiment according to the invention, the inhaler according to U.S. Pat. No. 5,590,645 is applied. The disclosure of U.S. Pat. No. 5,590,645 is incorporated herein by reference in its entirety.
Accordingly, in a preferred embodiment, the invention relates to a method for the administration of an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, by means of the inhaler according to U.S. Pat. No. 5,590,645, comprising a medicament pack having a plurality of containers for containing medicament in powder form wherein the containers are spaced along the length of and defined between two peelable sheets secured to each other, an opening station for receiving a container of the medicament pack being, means positioned to engage peelable sheets of a container which has been received in the opening station for peeling apart the peelable sheets, to open such a container, an outlet, positioned to be in communication with an opened container, through which a user can inhale medicament in powder form from such an opened container, and indexing means for indexing in communication with the outlet containers of a medicament pack in use with the inhalation device.
In another embodiment, the invention relates to a method for treatment of airway diseases, particularly chronic obstructive pulmonary disease and asthma, characterized in that an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, is administered via inhalation by the inhaler according to U.S. Pat. No. 5,590,645, comprising a medicament pack having a plurality of containers for containing medicament in powder form wherein the containers are spaced along the length of and defined between two peelable sheets secured to each other, an opening station for receiving a container of the medicament pack being, means positioned to engage peelable sheets of a container which has been received in the opening station for peeling apart the peelable sheets, to open such a container, an outlet, positioned to be in communication with an opened container, through which a user can inhale medicament in powder form from such an opened container, and indexing means for indexing in communication with the outlet containers of a medicament pack in use with the inhalation device.
In another preferred embodiment, the invention relates to the use of the inhaler according to U.S. Pat. No. 5,590,645, comprising a medicament pack having a plurality of containers for containing medicament in powder form wherein the containers are spaced along the length of and defined between two peelable sheets secured to each other, an opening station for receiving a container of the medicament pack being, means positioned to engage peelable sheets of a container which has been received in the opening station for peeling apart the peelable sheets, to open such a container, an outlet, positioned to be in communication with an opened container, through which a user can inhale medicament in powder form from such an opened container, and indexing means for indexing in communication with the outlet containers of a medicament pack in use with the inhalation device, for the administration of an inhalable powdered containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm.
In yet another preferred embodiment, the invention relates to an inhalation kit consisting of an inhalable powdered containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, and the inhaler according to U.S. Pat. No. 5,590,645, comprising a medicament pack having a plurality of containers for containing medicament in powder form wherein the containers are spaced along the length of and defined between two peelable sheets secured to each other, an opening station for receiving a container of the medicament pack being, means positioned to engage peelable sheets of a container which has been received in the opening station for peeling apart the peelable sheets, to open such a container, an outlet, positioned to be in communication with an opened container, through which a user can inhale medicament in powder form from such an opened container, and indexing means for indexing in communication with the outlet containers of a medicament pack in use with the inhalation device.
In another preferred embodiment according to the invention, the inhaler according to U.S. Pat. No. 4,627,432 is applied. The disclosure of U.S. Pat. No. 4,627,432 is incorporated herein by reference in its entirety.
Accordingly, in a preferred embodiment, the invention relates to a method for the administration of an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, by means of the inhaler according to U.S. Pat. No. 4,627,432, being characterized by a housing with a chamber therein, an air inlet into the chamber, a circular disc having an axis substantially coaxial to the chamber axis and rotatable inside the chamber and provided with a plurality of apertures therethrough arranged in a circle, the apertures being sized and positioned so that each aperture is adapted to be aligned with a different container, the disc being arranged so that the carrier can be placed in contact with one face of the disc with one of the containers located in each one of the apertures, an outlet through which a patient may inhale leading out of the chamber, an opening in the housing alignable with respective ones of the apertures in the disc as the disc is rotated, a plunger operatively connected to the housing and having a penetrating member, the penetrating member being displaceable to pass through the opening and the corresponding aperture in the disc registered with it thereby to penetrate and open a container located in the aperture so that the medicament will be released from the container and entrained in the air flow produced by a patient inhaling through the outlet, and means between the disc and the housing for rotatably indexing the disc to register each of the apertures in turn with the housing opening.
In another embodiment, the invention relates to a method for treatment of airway diseases, particularly chronic obstructive pulmonary disease and asthma, characterized in that an inhalable powder containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm, is administered via inhalation by the inhaler according to U.S. Pat. No. 4,627,432, being characterized by a housing with a chamber therein, an air inlet into the chamber, a circular disc having an axis substantially coaxial to the chamber axis and rotatable inside the chamber and provided with a plurality of apertures therethrough arranged in a circle, the apertures being sized and positioned so that each aperture is adapted to be aligned with a different container, the disc being arranged so that the carrier can be placed in contact with one face of the disc with one of the containers located in each one of the apertures, an outlet through which a patient may inhale leading out of the chamber, an opening in the housing alignable with respective ones of the apertures in the disc as the disc is rotated, a plunger operatively connected to the housing and having a penetrating member, the penetrating member being displaceable to pass through the opening and the corresponding aperture in the disc registered with it thereby to penetrate and open a container located in the aperture so that the medicament will be released from the container and entrained in the air flow produced by a patient inhaling through the outlet, and means between the disc and the housing for rotatably indexing the disc to register each of the apertures in turn with the housing opening.
In another preferred embodiment, the invention relates to the use of the inhaler according to U.S. Pat. No. 4,627,432 being characterized by a housing with a chamber therein, an air inlet into the chamber, a circular disc having an axis substantially coaxial to the chamber axis and rotatable inside the chamber and provided with a plurality of apertures therethrough arranged in a circle, the apertures being sized and positioned so that each aperture is adapted to be aligned with a different container, the disc being arranged so that the carrier can be placed in contact with one face of the disc with one of the containers located in each one of the apertures, an outlet through which a patient may inhale leading out of the chamber, an opening in the housing alignable with respective ones of the apertures in the disc as the disc is rotated, a plunger operatively connected to the housing and having a penetrating member, the penetrating member being displaceable to pass through the opening and the corresponding aperture in the disc registered with it thereby to penetrate and open a container located in the aperture so that the medicament will be released from the container and entrained in the air flow produced by a patient inhaling through the outlet, and means between the disc and the housing for rotatably indexing the disc to register each of the apertures in turn with the housing opening, for the administration of an inhalable powdered containing tiotropium, preferably in an amount of 0.001% to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 μm to 500 μm.
In yet another preferred embodiment, the invention relates to an inhalation kit consisting of an inhalable powdered containing tiotropium, preferably in an amount of 0.001 to 5%, in admixture with a physiologically acceptable excipient with an average particle size of between 10 to 500 μm, and the inhaler according to U.S. Pat. No. 4,627,432, being characterized by a housing with a chamber therein, an air inlet into the chamber, a circular disc having an axis substantially coaxial to the chamber axis and rotatable inside the chamber and provided with a plurality of apertures therethrough arranged in a circle, the apertures being sized and positioned so that each aperture is adapted to be aligned with a different container, the disc being arranged so that the carrier can be placed in contact with one face of the disc with one of the containers located in each one of the apertures, an outlet through which a patient may inhale leading out of the chamber, an opening in the housing alignable with respective ones of the apertures in the disc as the disc is rotated, a plunger operatively connected to the housing and having a penetrating member, the penetrating member being displaceable to pass through the opening and the corresponding aperture in the disc registered with it thereby to penetrate and open a container located in the aperture so that the medicament will be released from the container and entrained in the air flow produced by a patient inhaling through the outlet, and means between the disc and the housing for rotatably indexing the disc to register each of the apertures in turn with the housing opening.
The following Examples serve to illustrate the present invention further without restricting its scope to the embodiments provided hereinafter by way of example.
Starting Materials
As a starting material for the synthesis of crystalline tiotropium bromide monohydrate tiotropium bromide obtained according to the disclosure of European patent application EP 418 716 A1 is be used.
Preparation of Crystalline Tiotropium Bromide Monohydrate
15.0 kg of tiotropium bromide as obtained according to the methods disclosed in EP 418 716 A1 are added to 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80° C. to 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 minutes at 80° C. to 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 is cooled at 3° C. to 5° C. every 20 minutes to a temperature of 20° C. to 25° C. The apparatus is further cooled to 10° C. to 15° C. using cold water and crystallization 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 liters of cold water (10° C. to 15° C.) and cold acetone (10° C. to 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 micronized by known methods, to bring the active substance into the average particle size which meets the specifications according to the invention.
The DSC diagram of crystalline tiotropium bromide monohydrate shows two characteristic signals. The first, relatively broad, endothermic signal between 50° C. to 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° C.±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. These data, like the other values given in the above Table, were obtained at a heating rate of 10 K/min.
The crystalline tiotropium bromide monohydrate thus obtained was characterized by IR spectroscopy. The data was obtained using a Nicolet FTIR spectrometer and evaluated with the Nicolet OMNIC software package, version 3.1. The measurement was carried out with 2.5 μmol of tiotropium bromide monohydrate in 300 mg of KBr. Table 1 shows some of the essential bands of the IR spectrum.
The crystalline tiotropium bromide monohydrate was characterized by X-ray structural analysis. The measurements of X-ray diffraction intensity were carried out on an AFC7R-4-circuit diffractometer (Rigaku) using monochromatic copper Kα radiation. The structural solution and refinement of the crystal structure were obtained by direct methods (SHELXS86 Program) and FMLQ-refinement (TeXsan Program). The X-ray structural analysis carried out showed that crystalline tiotropium bromide hydrate has a simple monoclinic cell with the following dimensions: a=18.0774 Å, b=11.9711 Å, c=9.9321 Å, β=102.691°, V=2096.96 Å3.
Apparatus
The following machines and equipment, for example, may be used to prepare the inhalable powders according to the invention:
Mixing Container or Powder Mixer: Gyrowheel mixer 200 L; type: DFW80N-4; made by: Messrs Engelsmann, D-67059 Ludwigshafen.
Granulating Sieve: Quadro Comil; type: 197-S; made by: Messrs Joisten & Kettenbaum, D-51429 Bergisch-Gladbach.
The following examples provide for inhalable powder mixtures applicable according to the invention.
5.2 kg of glucose monohydrate for inhalation (average particle size 25 μm) is used as the excipient. 22.5 g crystalline tiotropium bromide monohydrate (micronized; average particle size 1 μm to 3.5 μm) is used as the active ingredient.
The aforementioned components are sieved in in alternate layers of lactose monohydrate in batches of about 200 g and crystalline tiotropium bromide monohydrate in batches of about 1 g. The ingredients sieved in are then mixed together (mixing at 900 rpm).
According to the invention, preferably 5.2225 mg of the aforementioned powder is delivered per dose.
5.4775 kg of lactose monohydrate for inhalation (average particle size 25 μm) is used as the excipient. 22.5 g crystalline tiotropium bromide monohydrate (micronized; average particle size 1 to 3.5 μm) is used as the active ingredient.
The aforementioned components are sieved in in alternate layers of lactose monohydrate in batches of about 200 g and crystalline tiotropium bromide monohydrate in batches of about 1 g. The ingredients sieved in are then mixed together (mixing at 900 rpm).
According to the invention, preferably 5.5 mg of the aforementioned powder are delivered per dose.
1.1: Excipient Mixture
5.203 kg of lactose monohydrate for inhalation (average particle size 25 μm) is used as the coarser excipient component. 0.27 kg of lactose monohydrate (5 μm) is used as the finer excipient component. In the resulting 5,473 kg of excipient mixture, the proportion of the finer excipient component is 5%.
The aforementioned components are sieved in in alternate layers of lactose monohydrate (25 μm) in batches of about 200 g and lactose monohydrate (5 μm) in batches of about 10 g. The ingredients sieved in are then mixed together (mixing at 900 rpm).
1.2: Final Mixture
To prepare the final mixture, 5,473 kg of the excipient mixture (1.1) and 22.5 g crystalline tiotropium bromide monohydrate (micronized; average particle size 1 μm to 3.5 μm) are used. The content of active substance in the resulting powder is 0.4%.
The aforementioned components are sieved in in alternate layers of excipient mixture (1.1) in batches of about 200 g and crystalline tiotropium bromide monohydrate in batches of about 1 g. The ingredients sieved in are then mixed together (mixing at 900 rpm).
According to the invention preferably about 5.5 mg of the aforementioned powder are delivered per dose.
| Number | Date | Country | Kind |
|---|---|---|---|
| 02007868 | Apr 2002 | EP | regional |
This application is a continuation of U.S. application Ser. No. 10/407,019, filed Apr. 4, 2003, which claims benefit of U.S. provisional application No. 60/386,794, filed Jun. 7, 2002, the contents of which are herein incorporated by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 4042700 | Banholzer et al. | Aug 1977 | A |
| 4524769 | Wetterlin et al. | Jun 1985 | A |
| 4608377 | Banholzer et al. | Aug 1986 | A |
| 4627432 | Newell et al. | Dec 1986 | A |
| 4783534 | Banholzer et al. | Nov 1988 | A |
| 5301666 | Lerk et al. | Apr 1994 | A |
| 5544647 | Jewett et al. | Aug 1996 | A |
| 5590645 | Davies et al. | Jan 1997 | A |
| 5610163 | Banholzer et al. | Mar 1997 | A |
| 5647349 | Ohki et al. | Jul 1997 | A |
| 5654314 | Banholzer et al. | Aug 1997 | A |
| 5770738 | Banholzer et al. | Jun 1998 | A |
| 5785049 | Smith et al. | Jul 1998 | A |
| 5826633 | Parks et al. | Oct 1998 | A |
| 5947118 | Hochrainer et al. | Sep 1999 | A |
| 5952505 | Banholzer et al. | Sep 1999 | A |
| 6182655 | Keller et al. | Feb 2001 | B1 |
| 6270869 | Zeiter et al. | Aug 2001 | B1 |
| 6486321 | Banholzer et al. | Nov 2002 | B2 |
| 6506900 | Banholzer et al. | Jan 2003 | B1 |
| 6536427 | Davies et al. | Mar 2003 | B2 |
| 6537524 | Hassan et al. | Mar 2003 | B1 |
| 6608054 | Meade et al. | Aug 2003 | B2 |
| 6620438 | Pairet et al. | Sep 2003 | B2 |
| 6645466 | Keller et al. | Nov 2003 | B1 |
| 6696042 | Pairet et al. | Feb 2004 | B2 |
| 6881398 | Myrman et al. | Apr 2005 | B2 |
| 6884794 | Staniforth et al. | Apr 2005 | B2 |
| 6890517 | Drechsel et al. | May 2005 | B2 |
| 6908928 | Banholzer et al. | Jun 2005 | B2 |
| 7070800 | Bechtold-Peters et al. | Jul 2006 | B2 |
| 7776315 | Pairet et al. | Aug 2010 | B2 |
| 7854225 | Pasbrig et al. | Dec 2010 | B2 |
| 20020053344 | Davies et al. | May 2002 | A1 |
| 20020110529 | Bechtold-Peters et al. | Aug 2002 | A1 |
| 20020122773 | Pairet et al. | Sep 2002 | A1 |
| 20020137764 | Drechsel et al. | Sep 2002 | A1 |
| 20020151541 | Pairet et al. | Oct 2002 | A1 |
| 20020169181 | Pairet et al. | Nov 2002 | A1 |
| 20020183292 | Pairet et al. | Dec 2002 | A1 |
| 20020183347 | Meade et al. | Dec 2002 | A1 |
| 20020193393 | Pairet et al. | Dec 2002 | A1 |
| 20030070679 | Hochrainer et al. | Apr 2003 | A1 |
| 20030158196 | Jung et al. | Aug 2003 | A1 |
| 20030180227 | Staniforth et al. | Sep 2003 | A1 |
| 20030181478 | Drechsel et al. | Sep 2003 | A1 |
| 20030192540 | Myrman et al. | Oct 2003 | A1 |
| 20030203925 | Meade et al. | Oct 2003 | A1 |
| 20030212075 | Pairet et al. | Nov 2003 | A1 |
| 20040024007 | Pairet et al. | Feb 2004 | A1 |
| 20040151770 | Pairet et al. | Aug 2004 | A1 |
| 20040161386 | Pairet et al. | Aug 2004 | A1 |
| 20040176338 | Pairet et al. | Sep 2004 | A1 |
| 20040192675 | Pairet et al. | Sep 2004 | A1 |
| 20040266869 | Montague et al. | Dec 2004 | A1 |
| 20050055014 | Coppeta et al. | Mar 2005 | A1 |
| 20050147564 | Drechsel et al. | Jul 2005 | A1 |
| 20050148562 | Pairet et al. | Jul 2005 | A1 |
| 20060102511 | Pasbrig et al. | May 2006 | A1 |
| 20070208060 | Disse | Sep 2007 | A1 |
| 20100310477 | Pairet et al. | Dec 2010 | A1 |
| Number | Date | Country |
|---|---|---|
| 0 211 595 | Feb 1987 | EP |
| 0 237 507 | Sep 1987 | EP |
| 1 158 970 | Dec 2001 | EP |
| 2 135 690 | Nov 1999 | ES |
| 2 169 265 | Jul 1986 | GB |
| 8-059576 | Mar 1996 | JP |
| 8-322933 | Dec 1996 | JP |
| 9-140794 | Jun 1997 | JP |
| 9-140796 | Jun 1997 | JP |
| 9-206378 | Aug 1997 | JP |
| 9-206379 | Aug 1997 | JP |
| 9-206380 | Aug 1997 | JP |
| 9-206381 | Aug 1997 | JP |
| 11-299891 | Nov 1999 | JP |
| 9404210 | Mar 1994 | WO |
| WO 0028979 | May 2000 | WO |
| WO 0047200 | Aug 2000 | WO |
| 0224266 | Mar 2002 | WO |
| 0224268 | Mar 2002 | WO |
| 0236163 | May 2002 | WO |
| 0236591 | May 2002 | WO |
| 02069945 | Sep 2002 | WO |
| 03084502 | Oct 2003 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20060251586 A1 | Nov 2006 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60386794 | Jun 2002 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10407019 | Apr 2003 | US |
| Child | 11427173 | US |
