Patent Application
20080236579
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.
Inhalation devices are known for use with blister packs in which the medicament is held in powder form in the blisters thereof. Such devices include a puncturing member which punctures each blister in turn, thus enabling the medicament to be inhaled therefrom.
It is an object of the present invention to provide an inhalation device the design of which has the potential, if desired, to handle a medicament pack having a large number of discrete unit doses, without the device becoming unacceptably large.
The invention also provides a medicament pack for use in an inhalation device, the pack comprising an elongate strip formed from a base sheet having a plurality of recesses spaced along its length and a lid sheet hermetically but peelably sealed thereto to define a plurality of containers, each container having therein inhalable medicament in powder form. The strip is preferably sufficiently flexible to be wound into a roll.
a and 4b are an axial section and cross-section respectively, on a larger scale than
a to 12d show the fifth embodiment in successive stages of operation, and
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: v is the volumetric flow rate (L/min);
p is the pressure drop (kPa); and
R is the flow resistance.
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. This dosage inhalator is suitable for dispensing to a patient a micronized solid, pharmacologically active compound in dry powdered form having a particle size of less than 5 micrometers suspended in a gas.
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.
Among compound groups and specific compounds which are suitable for administering with a powder inhalator according to the present invention the following can be mentioned:
betareceptor stimulating agents such as adrenaline, isoprenaline, orciprenaline, salbutamol and terbutaline,
steroids for inhalation such as budesonide, and
substances intended for nasal administration.
Especially useful are terbutaline and budesonide.
The active compound can be administered in micronized form without additional ingredients or in pharmaceutically modified micronized form in order to obtain improved flow properties. The micronized particles may be covered with a film functioning for example by masking bitter taste of the active compound, or by providing slow release of the active compound in the respiratory tract.
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.
Referring now to
The strip 101 is shown as having elongate pockets which run transversely with respect to the length of the strip. This is convenient in that it enables a large number of pockets to be provided in a given strip length. The strip may, for example, be provided with sixty or one hundred pockets, but it will be understood that the strip may have any suitable number of pockets.
The inhalation device comprises a body 110 defining three storage chambers, namely a chamber 111 in which the strip 101 is initially housed and from which it is dispensed, a chamber 112 for receiving the used portion of the base sheet 103, and a chamber 113 within which the used portion of the lid sheet can be wound up on a wheel 114. The chambers 111 and 112 contain respective curved leaf springs 128 and 129, the purpose of which is described below. The body defines a further chamber 115 which houses an index wheel 116. This has a plurality of grooves 117 extending parallel to the axis of the wheel 116. The grooves are spaced at a pitch which is equal to the distance between the centre lines of adjacent pocket 102. The chambers 111, 112, 113 and 115 are closed by a lid 130. The chamber 115 communicates with the chambers 111, 112 and 113 via passages 131, 133 and 132 respectively.
The chamber 115 communicates via a slit 118 which, in turn, extends upwardly within a mouthpiece 120. The slot 118 also communicates with air inlets, as will be described below with reference to the specific mouthpiece shown in
A means is provided by which the user can rotate the index wheel and the lid wheel in steps of a predetermined size. This means comprises a ratchet wheel 122 and a gear wheel 123, both connected to rotate in unison with the index wheel 116, a lever 124 arranged to rotate about the same axis as the ratchet wheel 122 and gear wheel 123, but independently thereof, and a gear wheel 125 which meshes with the gear wheel 123 and is arranged to rotate the lid wheel 114. The lever 124 carries a pusher arm 126, the end of which is arranged to engage the teeth of the ratchet wheel 122. The teeth of the ratchet wheel are also engaged by a pawl 127 fixedly secured to the body 110. For reasons which will become apparent from the description below of the operation of this embodiment, the gear wheel 125 is not connected directly to the lid wheel 114, but is connected via a slipping clutch 150 which is housed within the lid wheel 114. The effect of the provision of this clutch is that slipping occurs between the lid wheel and the gear wheel 125 when the force required to rotate the lid wheel exceeds a predetermined amount.
The clutch 150 comprises a disc 151 provided with radially extending serrations 152, or other surface roughness, which is held in engagement with a similarly serrated or roughened surface 153 provided on an end face of the lid wheel 114 by a compression spring 154. The spring 154 bears at one end against an inwardly directed surface 155 of the lid wheel and at the other end against a nut 156 threaded on a bolt 157.
The device described above can be made so as to be reusable after the doses of medicament contained in the pocket 102 have all been dispensed. In that case, provision can be made for the user to gain access to the interior of the device, for example by removing the lid 130, so as to insert therein a fresh strip 101, for example in a cassette. Alternatively, however, the device may be made to be disposable once the strip 101 with which it is supplied has been used up.
In either event, when the device is first used the bulk of the strip 101 is within the chamber 111, kept in a relatively tight reel by the leaf spring 128, with a short portion at the leading end thereof passing out of the chamber 111 through the passage 131 to the index wheel 116. The foremost part of the leading end of the strip is peeled apart so that the leading end of the lid sheet 104 can be secured to the lid wheel 114, and so that the leading end of the base sheet 103 can enter the passage 133. The end of the lid sheet 104 is held in place on the lid wheel 114 by means of a key 134 which is a force fit in a slot 135 in the wheel 114.
A user desiring to use the device pushes the lever 124 in an anticlockwise direction, as viewed in
When the user inhales through the mouthpiece 120 the flow of air which this produces entrains powder from the opened pocket, so that the powder is inhaled by the user. One way in which this can occur is explained in more detail below with reference to the embodiment of mouthpiece shown in
One effect of winding up the lid sheet on the lid wheel 114 is that the external diameter of the wheel plus the sheet wound thereon gradually increases. Were it not for the use of a slipping clutch to connect the gear wheel 125 to the lid wheel 114 this would have the result that successive operations of the lever 124 would try to cause a progressively longer length of lid sheet to be wound on to the lid wheel. The slipping clutch 150, however, avoids this effect, the clutch slipping each time by an amount sufficient to ensure that for every operation of the lever the amount of lid sheet wound on is precisely equal to the pitch of the pocket 102.
a and 4b show a portion of the index wheel 116 with a pocket 102 therein, in conjunction with a mouthpiece which differs slightly from the mouthpiece 120 shown in
When a user inhales through the mouthpiece 120 this causes air to flow in through the inlets 140 and thence through the pocket 102, into the powder outlet 119, and out through the mouthpiece 120. By thus directing the flow of air through the pocket 102, efficient entrainment of powder in the airflow is achieved, with consequent efficient emptying of the pocket. The mouthpiece 120 is provided with additional air inlets 121, shown here by way of example as being four in number, which open tangentially into the mouthpiece. When the user inhales air is drawn into the mouthpiece not only through the air inlets 140 but also through the air inlets 121, and the air entering through the inlets 121 produces a swirling airflow which helps to distribute powder effectively within the airflow and reduce the extent to which powder is deposited on the inside of the mouthpiece. This also helps to break up any aggregates of powder which may be present in the blister.
A third embodiment of the inhalation device according to the invention is shown in
It will be appreciated that, as in the case of the second embodiment, the diameter of the lid wheel 214 with the lid sheet thereon gradually increases during operation. Since a slipping clutch cannot be used in this embodiment the effect just described is compensated by having the spacing of the pocket 202 gradually increasing towards the rear end of the strip.
One other difference which will be noted between the second and third embodiments, is that in the latter the chambers 211 and 212 form a single composite chamber, unlike the separate chambers 111 and 112 in the second embodiment. However, this need not be so, and the second embodiment could use a single composite chamber and the third embodiment could use separate chambers.
One difference which will be observed between the third and fourth embodiments is that in place of the lid wheel 114 a pair of wheels 314a and 314b are employed, with the lid sheet being gripped in the nip between the wheels 314a and 314b, which act as a mangle. These wheels are knurled or otherwise roughened to improve the grip between the wheels and the lid sheet. The used lid sheet is not wound up but is fed into a chamber 313, so that no problem arises, as it does in the second and third embodiments, with the lid wheel attempting to wind up progressively longer lengths of lid as operation of the device continues.
As in the second embodiment, the device receives a flexible strip, here denoted as 401, comprising a base sheet 403 in which pocket 402 are defined and a lid sheet 404. The strip 401, is shown most clearly in
The body 410 comprises a base 410a and a top 410b both of generally circular shape. When the device is assembled the base and top are snap-fitted together. The body defines a single internal chamber within which the strip 401 is housed and within which are also housed a wheel 414 for winding up the used portion of the lid sheet 404, a base winding wheel 470 and an index wheel 416. The index wheel 416 is hollow and an index ratchet wheel 422 is housed within it. All the wheels just mentioned are mounted in the chamber defined by the body, for rotational movement with respect thereto. A pawl 470b is attached to the body 410 and engages the teeth of the base winding wheel 470 to prevent the wheel moving anticlockwise, thus ensuring that the strip 401 can only proceed forwards through the device.
The lid winding wheel 414 is formed in two parts, namely a toothed wheel 471 having teeth 472 and a shaft 473, and a collapsible wheel 474 having a hollow central shaft 475 and a plurality of resilient arms 476, for example, as shown, eight such arms, extending from the central shaft 475 each at an angle to a radius. The toothed wheel 471 has a lug 477 which engages in a corresponding notch in the shaft 475 so that the wheels 471 and 474 rotate in unison.
The hollow index wheel 416 has external teeth 478 which mesh with the teeth of the base winding wheel 470 and the teeth of the wheel 471. Ratchet teeth 479 are formed on the internal walls of the index wheel 416, and the index ratchet wheel 422 has two pawls 480 which engage the ratchet teeth 479.
The device further comprises a lever 424 which comprises an arcuate wall 481 with a finger tab 482, and an arm 483 which extends inwardly from the wall 481 and carries an arcuate array of teeth 484 at its distal end. The lever is pivotally mounted to the centre of the base 410a for movement about an axis which is at the centre of the pitch circle of the teeth 484, the teeth 484 mesh with the teeth 485 on the index ratchet wheel 422.
A manifold 486 provides communication between the chamber within the body 410 and a mouthpiece 420. The manifold has a powder outlet 419 and also has a passageway 487 to allow used lid strip 404 to pass to the collapsible wheel 474. Optionally, a roller 488 may be provided to guide the strip 404 into the passageway 487.
A dose monitor ring 489 having teeth 490 is arranged to be rotatable within the body base 410a. On its lower surface this bears indicia (not visible in the drawings) which can be viewed by the user through a window 494 in the body 410. It will be noted from
The device is provided under a cover 491 which is pivotally mounted on the body 410 by means of a lug 492 on the body top 410b and a corresponding lug 493 on the body base 410a. The cover is pivotal between an open position (shown in
In operation, the user moves the cover 491 to its open position and then presses on the finger tab 482 of the lever 424 to cause it to move as the lever pivots. This makes the index ratchet wheel 422 rotate which, via the pawls 480, causes the index wheel 416 also to rotate. Rotation of the index wheel 416 produces rotation of both the base winding wheel 470 and the lid winding wheel 414, thus peeling the base sheet and lid sheet apart over a distance sufficient to expose a previously unopened pocket 402 opposite the end of the powder outlet 419 in the manifold 486. The patient can then inhale through the mouthpiece, as in the preceding embodiments.
Successive stages in the operation of the device are shown in
The user continues to rotate the body 410 from the position shown in
After use, the body 410 is rotated clockwise, the lever 424 moving in unison with the body, to bring the device back to the position of
It will be noted that the collapsible wheel 474 in effect assumes the function of the clutch in the first embodiment. As more lid sheet is wound onto the wheel 474 the arms 476 gradually flex inwardly, and the effect is to keep the external diameter of the reel of wound up lid sheet substantially constant, while the internal diameter thereof gradually decreases.
Although in the embodiment of
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.
U.S. Pat. No.4,627,432 relates to devices by which a medicament can be administered to or by patients inhaling through the devices. The medicaments may be in solid finely divided form or fluid form. Such devices are now quite well known for administering medicaments contained in capsules to patients suffering from bronchial conditions such as, for example, bronchial asthma.
It is well known for medicament in powder or other finely divided form to be supplied in capsules which are loaded by a patient into such a device which is sometimes called an “insufflator”. The medicament is then released from the capsule and inhaled by the patient, usually through the mouth, but sometimes through the nose.
There are disadvantages in the use of capsules, which are made of gelatin, to contain medicaments. Gelatin is relatively unstable and is lacking in physical strength so that the capsules need to be protected by packaging, for example in glass bottles. Environmental degradation of both the capsules and their contents may occur in a relatively short time.
An object of the present invention is to provide a more convenient way of administering medicament to such patients than has been possible hitherto and which avoids the need to pack medicaments in capsules. The device of the present invention makes use of the technique of packing medicaments by loading them in blister packs, that is to say, packs comprising a sheet, which may be laminated, of foil or plastics material which acts as a carrier and which is provided with a number of breakable or openable containers called “blisters” incorporating a sheet secured on a first sheet to form a cover or lid. Such blister packs are in common use with tablets of one kind or another, but we have discovered that they can also be used with medicaments in finely divided solid form.
The device of the invention is suitable for administering a variety of medicaments such as, for example, salbutamol, beclomethasone dipropionate and disodium cromoglycate.
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.
In the embodiment of the invention illustrated in
A mouthpiece outlet 505 projects outwardly from the cylindrical wall of the housing 501 and communicates with the interior of the chamber 502. A perforated guard not shown, is provided in the mouthpiece to prevent any solid particles of an undesirably large size being inhaled by a patient inhaling through the mouthpiece.
A rim or shoulder 506 runs round the inside wall of the chamber 502 to provide an annular support on which a blister pack 507 may be located.
The blister pack 507 can conveniently be a foil laminate with a plurality of frangible containers or “blisters” 508 arranged in a circle. The blisters 508 are filled with medicament in particulate form, having a particle size in the range of 0.5-10 microns. The medicament may be with a pharmaceutically acceptable carrier such as lactose or starch in particulate form. Alternatively, the medicament may be in liquid form. The blister pack is of circular disc form, and is removably fitted inside the chamber so that it is replaceable when the individual doses of medicament contained in the blisters have been discharged.
The chamber 502 contains a central open cylindrical support column 509 upstanding from the bottom wall 503 of the chamber. A clamp disc member 510 is removably fitted inside the chamber 502 and has on its underside a plurality of locating pegs, not shown, which pass through the blister pack by an appropriate method and engage inside the support column. The clamp member 510 is rotatable inside the chamber. In use, the clamp member is placed on top of a blister pack 507 which has already been loaded into the chamber and is located on the support shoulder 506. The blister pack 507 is preferably a circular disc of foil laminate material with blisters or containers 508. The clamp member 510 has a plurality of apertures 511 which are arranged in a circle and so spaced from each other that each of them will receive one of the blisters 508 of the blister pack 507. A knob 512 is upstanding from the clamp member 510 and when the lid 504 is fitted on the housing 501 the knob 512 will project through an aperture 513 in the top of the lid 504. This knob can be turned by the patient to rotate the clamp member 510 and since the blisters 508 of the blister pack 507 are located in the apertures 511 in the clamp plate 510 rotation of the clamp member will also rotate the blister pack. A plurality of protuberances or pips 514 are provided on the top of the clamp member 510 and engage in a recess 515,
The cover 504 also has an aperture 516 in which a plunger 517 contained in a plunger housing 518 can be received. The plunger has an annular shoulder 519 and a spring 520 can bear between the shoulder 519 and the bottom of the plunger housing 518 to urge the plunger into an upper or inoperative position. The plunger may be provided with a knife edge 521 or other means to enable the blister to be opened. When the plunger 517 is depressed against the action of the spring 520, the lower edge portion 521 of the plunger will pass through an aperture 522 in the plunger housing to pass through a blister 508 located in register with the plunger. Such engagement will open the blister, and permit the release of medicament therefrom. This action will so open the blister that when a patient inhales air will pass through the blister, the medicament being entrained in the air flow and exiting through the mouthpiece 505 via a transfer cavity 523 inside the chamber in communication with the mouthpiece 505. By rotation of the knob 512 the clamp member 510 and the blister pack 507 can be rotated to bring each blister in turn into location beneath the plunger. The various protuberances or pips 14 will in turn engage in the recess 515 to make sure that the blister pack is correctly registered with the plunger.
It is not essential that the plunger have a knife 521 to open the blister. If desired a needle can be used to perforate the blister or the plunger may have a pointed end or even a blunt end or any other convenient opening means may be used.
In use, the patient needing a dose of medicament may hold the device with the mouthpiece in his mouth. The patient then depresses the plunger to open the blister and give access to the medicament therefrom and inhales through the mouthpiece so that the medicament will be entrained in the air flow and will enter the lungs of the patient. If desired, the mouthpiece can be provided with air inlet apertures 525 to improve the air flow as the patient inhales.
In a modification not illustrated the underside of the blister pack can be supported on another clamp plate instead of the support rim or shoulder 506.
The blister pack is conveniently arranged to provide a sufficient number of individual doses for a patient for use during a convenient period such as one day or more. The housing can be modified by providing an additional chamber, not visible, at the bottom, this additional chamber being closed by a removable cover 526. This additional chamber can be used to store replacement blister packs.
The mouthpiece may, if desired, be arranged so that a patient may use it to inhale through the nose.
A modified device which does not use the clamp member 510 is illustrated in
The hole 552 is so positioned that each hole 538 in the support member 535 will register with this hole as the support member 535 is rotated.
When one of the holes 538 is in register with the hole 552 the trigger 550 can be depressed so that its plunger 551, which may be in the form of a needle, will pierce through the blister 537 located in that hole (i.e. pierce the top and the bottom of the blister) thereby to permit powder to exit from the blister. Some powder will fall into a tray-like compartment 554 inside the chamber 531. When the patient inhales, air passes through the pierced blister so that powder will be entrained in the airflow and will, with powder from the compartment 554, be withdrawn through the guard 533 and the mouthpiece 532. When the device is not in use, the mouthpiece 532 can be enclosed in a mouthpiece cover or sheath 555 which has a channel-like extension 556 which will engage with the bracket 549 to prevent the plunger 551 being depressed to enter through the hole 537.
When the device is in use and the patient inhales through the mouthpiece 532 it is, of course, essential for air to be able to enter the interior of the chamber 531. Any suitable air inlets can be provided. Conveniently, however, air can enter through the hole 552 the plunger or needle 551 being smaller in diameter than the diameter of the hole 552 so that it serves as an air inlet.
The following Examples serve to illustrate the present invention further without restricting its scope to the embodiments provided hereinafter by way of example.
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=102.6910°, V=2096.96 Å3.
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 claims benefit of U.S. Ser. No. 60/386,794, filed Jun. 7, 2002.
| Number | Date | Country | |
|---|---|---|---|
| 60386794 | Jun 2002 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10407019 | Apr 2003 | US |
| Child | 12053971 | US |
