Patent Grant
10842952
It is rather common to use inhalers for delivering medicaments utilized in the treatment and prophylaxis of respiratory diseases. Inhalation treatment is the most commonly preferred treatment method in these diseases as the inhalers provide ease of use; the medicaments have rapider onset of time resulting from local administration and they have fewer side effects. Various inhalers have been designed in order to provide effective and sufficient delivery of the medicaments used in the treatment of respiratory diseases, particularly in asthma and chronic obstructive pulmonary disease. These inhalers vary according to their operating mechanisms and the physical form of the medicament to be delivered.
In the inhalers used to deliver the medicaments in dry powder form, the medicament is carried in reservoirs, capsules or blisters packages. It is highly significant to deliver each dose to the patient with exact accuracy and preciseness since the required medicament dose in the inhalation is very low.
In general, one blister pocket containing medicament in dry powder form is opened in response to each actuation of the device in inhalers comprising blister packages. One blister pocket containing one dose of dry powder medicament is usually opened by peeling the blister package indexed upon the actuation of the device or piercing the blister pocket by the piercing means in the inhaler. The inhalers comprising peelable blister packs enable the sufficient amount of the dry powder medicament contained in the opened blister to be easily inhaled as the airflow enters the opened blister pocket more easily in the inhalers comprising peelable blister packs than the inhalers comprising pierceable blister packs. Therefore, the blister package should be indexed enough to enable the blister pocket to be opened completely so as to realize an effective inhalation in response to each actuation of the inhaler. However, it is quite difficult to enable the blister package to be indexed properly to the same extent in each actuation of the device so as to realize a safe inhalation in the inhaler comprising peelable blister packages. In the case that the blister package that is indexed upon the actuation of the device is indexed less than the required extent, the blister pocket may not be opened completely while more than one blister pocket may be opened in the case that the blister package is indexed more than the required extent. The fact that one blister pocket cannot be opened completely and an effective inhalation cannot be realized as the sufficient amount of the active agent comprised in the dry powder medicament cannot be delivered to the patient or more than the required amount of the active agent is delivered to the patient as one blister pockets are opened lead to dangerous consequences. Therefore, controlled dosing of the medicament in dry powder form cannot be achieved when the blister package is not indexed properly to the same extent in response to each actuation of the inhaler.
The inhalation device marketed under the trade mark Diskus® by GlaxoSmithKline is one of the most well-known inhalers on the market. This device operates with a slide mechanism and a blister strip package in which the dry powder medicament is carried. However, this device needs to be improved in terms of specifications to enable the blister package to be properly indexed to the same extent in response to each actuation of the device.
The inventor has surprisingly found that the force of attraction imposed by the winding wheel on the lid sheet is balanced, and thus the blister package is properly indexed to the same extent in response to each actuation of the device in the case that each of the preferably polyoxymethylene resilient wings of the winding wheel, on which the lid sheet of the blister package peeled upon the actuation of the inhaler is coiled, is composed of three parts in the inhaler comprising peelable blister package.
To this respect, the present invention relates to an inhaler comprising peelable blister package appropriate for delivering dry powder medicament which enables the blister package to be indexed properly to the same extent in response to each actuation of the inhaler.
An inhaler suitable for delivery of the medicament in dry powder form according to the present invention comprising;
a blister package composed of a plurality of blister pockets each of which comprises medicament in dry powder form and which are spaced at equal intervals;
a mouthpiece enabling the patient to inhale the medicament in dry powder form from the opened blister;
a rotatable mouthpiece cover covering the mouthpiece;
a gear mechanism enabling the blister package to be indexed and the medicament in dry powder form to become ready for inhalation;
a housing situated between the upper housing member and the lower housing member in which the blister package and the gear mechanism are enclosed;
a manifold through which the air entering the device from the air inlet passes and
a channel interconnecting the manifold outlet and the mouthpiece outlet
is characterized in that the ratio of the cross-section of the manifold outlet to the cross-section of the mouthpiece outlet is in the range of 1:10 to 1:50.
Delivery of sufficient quantity of the active agent comprised in the dry powder medicament contained in the blister package which is opened by the actuation of the device pertaining to the present invention to the patient's lungs substantially depends on the inhaler's resistance. The resistance of the inhaler, on the other hand, affects the flow velocity and the pressure decrease of the external air entering the device. Approximate value of the pressure decrease is calculated with the equation of ΔP=K·ρ·υ2/2. Pressure decrease can be calculated for each component of the device through which the external air entering the inhaler passes. In this equation, K value is a geometric factor and it is 0.5 in the case that the cross-section instantaneously contracts while it is 1 in the case that the cross-section instantaneously expands; p represents air density and it is approximately 1.3 kg/m3; υ (m/s) value is the average velocity of air. The resistance value for each components is obtained dividing the square root of ΔP (in kPa) value obtained from the abovementioned equation by the flow velocity (minutes/liter) of the external air entering the inhaler. Flow velocity of provided airflow is obtained by dividing the total pressure decrease induced in the inhaler by the resistance value.
The inventor has found that the resistance in the mouthpiece and the manifold outlet of the inhaler affects the pressure decrease, therefore the flow velocity of the air to a substantial extent and there should be a pressure decrease higher than 4 kPa in the inhaler for an effective inhalation to be realized. The resistance and the airflow velocity in the manifold outlet and mouthpiece outlet are directly proportional to the average velocity of air. The average velocity of air, on the other hand, is determined according to the cross-section of the manifold outlet and the mouthpiece outlet. A pressure decrease higher than 4 kPa which is required for an effective inhalation to be realized is provided in the case that the ratio of the cross-section of the manifold outlet to cross-section of the mouthpiece outlet is in the range of 1:10 to 1:50, preferably in the range of 1:15 to 1:40, more preferably in the range of 1:20 to 1:30. Thus, the breath that the patient takes to deliver the medicament in dry powder form to his lungs can enable the delivery of the required amount of the active agent with fine particle sizes comprised in the dry powder medicament to the patient's lungs. In addition, the change in the airflow velocity induced when the ratio the cross-section of the manifold outlet to the cross-section of the mouthpiece outlet is in the range of 1:10 to 1:50 prevents the large amounts of residual dry powder medicament to accumulate in the mouthpiece and the patient's mouth.
The inhaler pertaining to the present invention wherein the ratio of the cross-section of the manifold outlet to the cross-section of the mouthpiece outlet is in the range of 1:10 to 1:50 is preferably a manual device which is appropriate to be used for delivery of medicament in dry powder form and comprise blister package.
The inhaler pertaining to the present invention has a mechanism preferably triggered by the rotation of the mouthpiece cover. According to this, the housing of the device pertaining to the present invention has been designed such that each component of the blister package and the gear mechanism which have a significant role in enabling the device to work properly is situated accurately and works harmoniously. To this end, the housing is divided into several compartments. The used portion and the unused portion of the blister package are accommodated in separated compartments in order to prevent the medicament in dry powder form remained in the opened blister pocket to spill on the other components of the housing. Furthermore, the housing also comprises the beak which enables the blister package to be peeled and the manifold through which the dry powder medicament in the open blister passes before reaching the mouthpiece during the inhalation. In addition, the housing can be in any appropriate shape while it is preferably elliptic or circular.
The upper and the lower housing members interlock with each other and enclose the housing in order to keep the housing and the gear mechanism fixed together. The mouthpiece cover hiding the mouthpiece is rotated by being slid on the upper and lower housing members. The grids on the surface of the lower and the upper housing members provide an effective actuation by preventing the slipping of the finger while rotating the mouthpiece cover. The upper and the lower housing members can be in any appropriate shape which provides ease of use. The mouthpiece cover hiding the mouthpiece of the device pertaining to the present invention has been designed such that it also provides to actuate the device. Before each inhalation, both the mouthpiece is uncovered and one dose of the medicament in dry powder form becomes ready for inhalation as one of the blister pockets is opened as a result of the mouthpiece cover's preferably being manually rotated along the path restricted by the engagement of the protrusions on the upper and the lower housing members. The rotational path on which the cover moves is restricted on both ends by the protrusions of the upper and the lower housing members.
The mouthpiece cover that triggers the gear mechanism of the device can be found solely in two positions. When the mouthpiece cover is in the first position, the mouthpiece cover resides on the protrusion in one end of the rotational path. When the first position is on, the mouthpiece cover is completely covered and the device is in standby mode. When the mouthpiece cover is in the second position, the mouthpiece cover resides on the protrusion in the other end of the rotational path and one dose of the dry powder medicament becomes ready for inhalation upon the actuation of the device.
The mouthpiece cover of the device is joined with the gear mechanism via the connection points. One end of the drive gear passes through the center of the lower housing member and tightly joins with the mouthpiece cover in one connection point while the other end passes through the center of the upper housing member and joins with the mouthpiece cover in the other connection point. For each end of the drive gear to make a stable connection between the connection points of the mouthpiece cover, one side cover is used for each end of the drive gear. Thus, the ends of the drive gear are carved such that they can tightly engage with the ends of the side covers from inside. The shape of the inside faces of these carved parts on both ends of the drive gear match with the shape of the ends of the side covers that fit into its.
On each connection point of the mouthpiece cover, there is a stabilizing resilient cover. The stabilizing resilient covers on both sides of the inhaler prevent the mouthpiece cover to move on both sides. Before the inhalation, the resilient parts of each stabilizing resilient cover that match with the shape of the fingers are pressed on for raising the pawls and releasing the mouthpiece cover in order to move the mouthpiece cover which actuates the device.
According to the present invention, each gear of the gear mechanism in the device is directly or indirectly engages with each other. Before the inhalation, the device is actuated by pressing on the stabilizing resilient covers on both faces of the device and rotating the mouthpiece cover along the rotational path, and the drive gear which is joined with the both connection points of the mouthpiece cover via the side covers precisely transmits the movement of the mouthpiece cover to the indexing ratchet wheel owing to the side covers upon the actuation of the device. The indexing ratchet wheel which interlocks with the indexing wheel from inside thanks to its arms enables the indexing wheel to rotate. Upon the indexing wheel's movement, the blister package is indexed and it is peeled by means of the beak present in the housing. As the indexing wheel engages with the winding wheel gear and the pinion gear, these gears move upon the indexing wheel's move, too. Since the mechanism gear engages both with the winding wheel gear and the winding wheel, the rotation of the winding wheel gear causes the winding wheel to move and lid sheet of the blister package coils on the winding wheel tightly. Pinion gear engages with the base gear while the small gear under the base gear engages with the counter gear. Thus, the rotation of the indexing wheel triggered by the actuation of the device is transmitted to the counter gear via the small gear which is immediately under the base gear. The counter gear in the device pertaining to the present invention displays the number of the unused blister pockets remained in the device. In response to the actuation of the device by the mouthpiece cover, the mouthpiece is uncovered, the blister package is indexed and one dose of the dry powder medicament is prepared for inhalation while the counter gear rotates as well. Thus, the movement of the mouthpiece cover leads to the mouthpiece cover to be uncovered; one dose of the dry powder medicament to be ready for inhalation after the blister pocket is opened as well as providing the counter gear to rotate and display the new value of the unused blister pockets remained.
On the counter gear, there exist numerals equal to the number of the blister pockets present in the device and they are spaced by equal angles. In a device comprising 60 doses, the angle between the numerals is approximately 5°. The counter gear rotates as a result of the reflection of the rotation of the indexing wheel via the pinion gear and the base gear. In response to the each actuation of the device, rotation of the indexing wheel by the same angle each time due to the accurate transmission of the movement of the mouthpiece to the gear mechanism via the drive gear results in the rotation of the counter wheel approximately by the same angle as well and each numeral on the counter wheel is clearly seen through the display aperture on the upper housing member. Therefore, the patient makes sure about the number of the unused blister pockets remained in the device.
The inhaler according to according to the present invention, further comprises a blister package composed of a plurality of blister pockets each of which comprises medicament in dry powder form and which are spaced at equal intervals. The blister package carries the medicament in dry powder form in one-dose portions and it is preferably a blister strip and it is preferably peelable. The blister pockets comprised in the blister package are spaced in equal intervals and each of them carries one dose of the medicament in dry powder form.
While the blister package is indexed on the indexing wheel, the beak on the housing peels the blister. Therefore, one dose dry powder medicament becomes ready for inhalation after the blister package is peeled to be opened in each actuation of the device.
The base sheet of the blister package on which the blister cavities are spaced is accumulated in the separated compartment of the housing. The lid sheet that provides impermeability of the blister package, on the other hand, is coiled on the winding wheel which is one of the components of the gear mechanism positioned in the other side of the housing. The blister opened by the beak is situated immediately under the manifold. Upon the inhalation of the patient, the airflow that preferably enters the device through at least one air inlet on the upper housing member entrains the dry powder medicament in the opened blister pocket via the manifold to the mouthpiece and enables the delivery of said medicament to the patient. The air inlet on the upper housing member that allows the entry of air can be in any suitable shape and size that also enable external air to enter the device easily and at convenient speed.
The mouthpiece is designed to fit the mouth for the patient to comfortably inhale the medicament in dry powder form. According to the shape of the device, the mouthpiece can be in any suitable shape or size as well as being fixed or movable. Furthermore, it could be attached or unattached to the upper and/or the lower cover.
The air inlet that the external airflow passes through is preferably designed not to be close where the patient holds the device in order not to prevent the air flow. Furthermore, in order to deliver the required amount of the dry powder medicament in the opened blister to the patient, the air inlet has been designed such that it allows the entry of the airflow through the air inlet by a convenient angle.
One end of the manifold between the opened blister and the mouthpiece communicates with the opened blister while the other end communicates with the mouthpiece. During the respiration of the patient, the external air passes through the air inlet and enters the manifold. The air which enters the inhaler through the air inlet upon the inhalation of the patient passes through one of the apertures with four sub-apertures on the end of the manifold, enters the opened blister, entrains the one dose of medicament in dry powder form; passes it through the other aperture with four sub-apertures on the end of the manifold and reaches the manifold. The air entraining the medicament in dry powder form to the other end of the manifold which is close to the mouthpiece, namely to the outlet of the manifold, passes through preferably the tapered channel interconnecting the mouthpiece and the manifold, then reaches the mouthpiece. The angle of the peak point of the tapered channel is in the range of 30° to 150°, preferably 45° to 135°, most preferably 50° to 125°. In addition, the distance between the manifold outlet and the mouthpiece outlet, namely the length of the tapered channel, is at least 2 mm, preferably in the range of 2 mm to 5 mm. This length can be counted as one of the factors influencing the airflow resistance in the inhaler.
In order to realize an effective inhalation using the inhaler pertaining to the present invention, the ratio of the cross-section of the manifold outlet to the cross-section of the mouthpiece outlet is in the range of 1:10 to 1:50, preferably in the range of 1:15 to 1:40, more preferably in the range of 1:20 to 1:30 so as to provide the pressure decrease higher than 4 kPa in the inhaler. Thus, the required amount of the active agent for the treatment in the dry powder medicament contained in the blister pocket that is opened upon the actuation of the inhaler is delivered to the lungs.
The term “an effective inhalation” used throughout the text refers to the desired result which is induced as a result of the delivery of the active agent in quantities required for inhalation treatment to the patient's lungs.
Each component of the device pertaining to the present invention can be made of any appropriate substance while it is preferably made of plastics. These plastic substances are selected from a group comprising styrene-acrylonitrile, polyoxymethylene (it is generally named as POM and it is also known as polyacetal or polyformaldehyde), acrylic-polymethylmetacrylate, cellulose acetate, polyetheretherketone, polyvinyl choloride, polyethylene, polypropylene, acrylonitrile butadiene styrene, polycarbonate, polyamide, polystyrene, polyurathane or fluoropolymer types while it is more preferably polyoxymethylene. The components made of plastics can be produced by methods such as injection molding. Furthermore, each component of the device can be in any appropriate color.
The lid and the base sheets constituting the blister package preferably consist of a plurality of layers. Each of these layers are preferably chosen from a group comprising polymeric layers that are made of various polymeric substances; aluminum foil and fluoropolymer film.
According to the present invention, the lid and base sheets composing the blister package are sealed very tightly by at least one of the methods comprising cold formed bonding, hot metal bonding, hot metal welding, radio frequency welding, laser welding or ultrasonic welding in order to provide impermeability, more preferably by cold formed bonding method. Since these cold formed bonding methods can be carried out at lower temperatures than hot sealing methods, they are the most appropriate methods to use in the case that the medicament carried in the blister is heat sensitive.
Fluoropolymer film is a polymeric film which is used in blister packs and provides excellent moisture barrier. This chemically inert polymeric film does not cause any change in the taste of the formulation when it is in contact with the dry powder formulation. In addition, it easily constitutes a layered structure with the other polymeric layers which are composed of various polymers. It is appropriate to be transacted with heat.
For preserving the stability of the dry powder formulation stored in the blister package, preferably at least one of the polymeric layers comprises at least one desiccant agent including silica gel, zeolite, alumina, bauxite, anhydrous calcium sulfate, activated carbon and clay which has the property of water absorption in order to decrease gas and moisture permeability of the layer.
According to the invention, the thickness of the aluminum foil in the lid and the base sheets of the blister package are preferably chosen to be in the range of 5 to 80μπι, more preferably in the range of 15 to 65μιη.
According to the invention, the polymeric layers in the lid and the base sheets of the blister pack are made of the same or different polymers. The thickness of these polymeric layers varies according to the type of the polymeric substance used and its properties while they are preferably in the range of 5 to 100μιη, more preferably in the range of 15 to 60μιη.
The polymers composing the polymeric layer are preferably selected from thermoplastics such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane or synthetic polymers.
The blister pockets in the blister package can be in any appropriate shape. The plurality of blister pockets spaced at equal intervals on the base sheet of the blister package can be in the same or different shape, structure or volume.
The dry powder inhaler in accordance with the present invention, which is devised to achieve an effective inhalation, consists of the mechanical components. Said dry powder inhaler comprises a housing on which the mechanical components which are required to achieve an effective inhalation of the dry powder medicament, are located. These mechanical components constitute the dispensing mechanism which is actuated as a result of the movement of the mouthpiece cover.
All the mechanical components of the dispensing mechanism is located in the housing which can be in any suitable shape, preferably circle or oval, to provide for working of these mechanical components properly and for interaction of the mechanical components with one another properly.
According to the invention, the dispensing mechanism which causes the advancement of the blister strip, interacts with directly to the mouthpiece cover through the center of the dry powder inhaler and comprises the gear mechanism of the dry powder inhaler. The dispensing mechanism is actuated by the fact that the movement of the mouthpiece cover is transmitted to the dispensing mechanism via a central hub gear of the dispensing mechanism. So that, before the inhalation of the dry powder inhaler, the single movement which is the movement of the mouthpiece cover from one position to another position, results in that the mouthpiece is completely uncovered, the peelable blister strip is advanced by working of the dispensing mechanism for inhaling the dry powder medicament from the blister and the dose counter shows the number of doses left to be taken. Therefore, the patients from every age, can use the dry powder inhaler in accordance with the present invention easily and inhale the dry powder medicament fastly and effectively.
The inhaler (1) pertaining to the present invention comprises a gear mechanism situated in the housing (10) between the upper housing member (4a) and the lower housing member (4b) in order to enable the inhalation of the dry powder medicament carried in a blister package (15) as displayed in
Another aspect of the invention, the mouthpiece cover is present in only two positions: the first position in which the mouthpiece is completely covered for protection of this mouthpiece, the second position in which the mouthpiece is completely uncovered, the mouthpiece can be cleaned easily and the dry powder medicament can be inhaled through the mouthpiece.
The dry powder inhaler in accordance with the present invention has a holder on the movable mouthpiece cover. This holder can be in any suitable form which makes the patients move the mouthpiece cover easily. Therefore, the mouthpiece cover can be moved easily by holding this holder on the mouthpiece cover.
The inhaler (1) pertaining to the present invention shown in
According to the invention, the indexing/advancement of the peelable blister strip is achieved by a rotatable index wheel. This rotatable index wheel having recesses therein, is engageable with the peelable blister strip in use with said dry powder inhaler such that said recesses each receive a respective cavity of the base sheet of a blister strip in use with said dry powder inhaler. The index gear interacting with the index wheel can be provided with a stopper or a lock shaft to provide irreversible rotation of the peelable blister strip. Because of the fact that the stopper engages the index gear interacting with the index wheel after the advancement of the peelable blister strip, the peelable blister strip is present at a certain position wherein one blister is opened completely and the dry powder medicament in this blister can be inhaled by the patient. In each actuation of the dispensing mechanism, the index wheel rotates irreversibly with the same angle, so that, open blister of the blister strip is situated in correct and accurate position for inhaling the effective amount of the dry powder medicament from open blister with high discharging capacity.
According to the present invention, the dry powder inhaler in which the index gear and the other gears interacting with the index gear directly or indirectly engage with one another correctly so that the dispensing mechanism works properly for delivering effective amount of the dry powder medicament to the lungs in each inhalation. It is important that the engagement especially between the gear of the index wheel and central hub gear is proper and tight because of the fact that the movement of the mouthpiece cover, which causes the actuation of the dispensing mechanism, is transmitted to the index gear in the dispensing mechanism via central hub gear.
The peelable blister strip, which consists of the blisters wherein each of the blisters has one dose of the dry powder medicament, is hold as winding up around itself in the blister strip chamber of the dry powder inhaler and is in elongate form. A base sheet and lid sheet of the peelable blister strip are peeled apart from each other to open a blister for inhaling the dry powder medicament contained by it. The actuation of the dispensing mechanism as a result of the movement of the mouthpiece cover leads to advancement of the blister. While the peelable blister strip is advanced by actuating the dispensing mechanism, the base sheet and the lid sheet of the peelable blister strip are peeled apart from each other to open one blister and the dry powder medicament in open blister become ready for inhalation in the opening station.
Another aspect of the present invention, the base sheet and the lid sheet of the peelable blister, which are peeled apart from each other while the peelable blister strip is advanced, gather in separate parts of the inhaler. The lid take-up mechanism comprises a wheel around which the lid sheet is wound tightly and it uses torsional force on the lid sheet for pulling apart the lid sheet from the base sheet of the blister that has been received at the opening station in which the dry powder medicament is inhaled from open blister. The base sheet, in which blisters are formed to define blister pockets (cavities) therein for containing distinct medicament dose portions, is wound around the base sheet take-up spindle which is hold in another part of the housing.
Various known techniques can be employed to join the lid and base sheet and hence to seal the blisters of the peelable blister strip. Such methods include adhesive bonding, hot metal bonding, hot metal welding, radio frequency welding, laser welding, ultrasonic welding and hot bar sealing. The lid sheet and base sheet of the peelable blister strip are particularly sealable by ‘cold form’ sealing methods, which are conducted at lower temperatures than conventional heat sealing methods. Such ‘cold form’ sealing methods are of particular utility where the medicament or medicament formulation for containment within the blister is heat sensitive.
The lid sheet and the base sheet of the peelable blister strip, consists of many layers which constitute the lid sheet and the base sheet of the blister strip such as polymeric layer, aluminum foil and optionally Aclar® fluoropolimer film.
Aclar® fluoropolymer film is a polymeric film which is used for production of the blister strip and provides high moisture protection. This chemically inert film does not cause any change in taste of the formulation when it is in contact with the dry powder formulation. It easily forms a lamellar structure with other polymeric layers which are made from various polymers. It is suitable for treatment with heat.
Desiccant agents are optionally added to the polymeric layers in order to reduce moisture and gas permeability of the polymeric layers for protection of stability of the dry powder formulation contained in the blisters which are juxtaposed on the peelable blister strip. Some examples of the desiccant agents are silica gel, zeolite, alumina, baucsite, anhydrous calcium sulfate, activated carbon, clay capable of absorbing water.
According to the invention, aluminium foil is used both in the lid sheet and in the base sheet of the peelable blister strip to provide high humidity and gas protection because of that aluminium foil is conventionally used in both the lid sheet and the base sheet of the blister strip for high humidty and gas protection. These layers must have the sufficient thickness which provides the protection for the stability of humidity sensitive dry powder formulation which is carried in the blister cavity. Because of this reason, the thickness of aluminium foil that is used in the lid sheet and the base sheet of the blister strip is in the range of 10 to 40 μm, preferably of 15 to 30 μm.
The polymeric layers which are contained in the lid sheet and the base sheet of the peelable blister strip in accordance with the present invention may be made from either same or different polymers. The thickness of these polymeric layers depends on the type of polymeric substance used and its properties. Therefore, the thickness of each polymeric layer which is used in the lid sheet and the base sheet of said blister strip is in the range of 15 to 60 μm, preferably of 20 to 35 μm depending on the type of polymer used.
The inside layer of blister cavity of said blister strip which is in contact with dry powder formulation is polymeric layer because of the fact that aluminium foil causes adhesion of a part of dry powder formulation to inside layer of the cavity due to electrostatic forces, and hence cause uncontrolled dosing.
According to the present invention, the polymers used for forming polymeric layers are preferably selected from a group comprising thermo-plastic polymers such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane, or synthetic polymers.
Moreover, said blisters which are placed on the peelable blister strips mentioned above, can be in any appropriate shape. Blisters that are placed to the bottom sheet of the blister strip can be in the same or different shapes and volumes and depending on the type of treatment can comprise dry powder medicament in the same or different amounts.
The indexing wheel (8) which engages with the indexing ratchet wheel (3) enables the blister package (15) shown in
The blister package (15) shown in
The rotational movement that the mouthpiece cover (2) of the device executes while switching from the first position to the second is transmitted to the indexing ratchet wheel (3) via the drive gear (12) that the mouthpiece cover (2) engages with. As displayed in
The winding wheel gear (6), which is another component of the gear mechanism, engages with the indexing wheel (8) as displayed in
As illustrated in
Different views of the housing (10) wherein the gear mechanism and the other components of the inhaler (1) pertaining to the present invention are arranged are displayed in
The housing (10) and the other components of the inhaler (1) pertaining to the present invention are stably kept together as the upper housing member (4a) and the lower housing member (4b) displayed in
In opening station of the dry powder inhaler in accordance with the invention, there is a beak, and the lid sheet and the base sheet are separable by peeling to open a blister cavity about this beak. After the blister cavities passes through the opening station, because of the engagement between recesses of the index wheel and blister cavities, the blister strip, which has been advanced as a result of the actuation of the dispensing mechanism, is positioned correctly and accurately in the dispensing station for achieving the effective inhalation of the dry powder formulation. An airflow, which enters to the dry powder inhaler throughout at least an airflow inlet during the inhalation of the patient through the dry powder inhaler, reaches to the dry powder medicament in the cavity of open blister in the dispensing station. Said dry powder medicament is drawn out through manifold of the dry powder inhaler and then it is delivered to the patient by the airflow. The airflow inlet can be in any suitable shape which provide for entering of airflow to the dry powder inhaler easily.
According to the invention, the manifold through which the dry powder medicament is drawn out by the airflow, can be in any suitable form which enables delivery of the dry powder medicament to the patient in an effective way.
A view of the cross-section of the housing component (10) which illustrated as X in
Another cross-sectional view of the part of the housing which is shown as X in
The drive gear (12) passes through the aperture (4d) in the center of the upper housing member displayed in
The mouthpiece cover (2) of the inhaler pertaining to the present invention is displayed in
The mouthpiece cover (2) is joined with the gear mechanism via the connection points. The drive gear consists of two ends (12a, 12b) and a hole (12c) at the center of one end as seen in
The shape of one of the connection points of the mouthpiece cover (29) is different from the shape of the other connection point of the mouthpiece cover (30) as well as the shape of the end of the drive gear (12a) that is connected with one connection point of the mouthpiece cover (29) is different from shape of other end of the drive gear (12b) (
Each end of the side covers (31d, 31b) passes through one of the connection points (29, 30) of the mouthpiece cover and it is received in the recess in one end (12b, 12a) of the drive gear, thus it provides to tightly and stably interconnect the mouthpiece cover (2) with the drive gear (12). It is provided that the mouthpiece cover (2) synchronizes with the drive gear (12) as the connection point (29, 30) of the mouthpiece cover which has a matching shape with the ends (31d, 31b) of the side covers that passes through it on both sides of the device and the end (12b, 12d) of the drive gear that it communicates with are on the same component.
As is seen from
The mouthpiece cover (2) rotates by the same angle each time it is switched from the first position to the second position on the path restricted by the protrusions (29a, 29b, 30a, 30b) on the upper and the lower housing members (4a, 4b). The rotational angle of the mouthpiece cover (2) varies depending on the shape and the size of the device but is a fixed value between 30° and 160°. This angle is adjusted according to the shape and the size of the device such that the indexing wheel (12) having 8 recesses (8a) rotates 45 degrees in response to each actuation of the device. The mouthpiece cover (2) rotates by the same angle on its two ends in response to each actuation of the device and this rotational movement of the mouthpiece cover (2) is accurately transmitted to the indexing wheel (12) by the indexing ratchet wheel (3) because of the drive gear (12) which is tightly attached to the mouthpiece cover (2) and the indexing wheel is provided to rotate 45° each time the device is triggered.
The mouthpiece cover (2) can be rotated by holding from the front end (2a) or back end (2b) of its with the help of the thumb. Therefore, the front end (2a) or the back end (2b) of the mouthpiece cover (2) is in contact with the patient's finger while it is moved manually. According to
In addition, another variable contributing to the carved part in the front end (2a) of the mouthpiece cover to match with the shape of the thumb is the width of the mouthpiece cover (2) illustrated as D1 in
There are 8 recesses (8a) on the indexing wheel displayed in
There is one stabilizing resilient cover (33; 32) on each connection point (29; 30) of the mouthpiece and on each side cover (31c; 31a), as displayed in
The extensions (32b, 32c, 33b, 33c) under the stabilizing resilient covers pass through the apertures (23c, 23d, 24c, 24d) on the upper and the lower housing members illustrated in
Before the inhalation, the resilient parts (32d, 33d) of each stabilizing resilient cover illustrated in
Another aspect of the present invention, a stopper can attach to the top cover of said dry powder inhaler to engage the movable mouthpiece cover for providing irreversible movement of said mouthpiece cover as well as it also engages the index gear interacting with the index wheel after the advancement of the peelable blister strip. In each actuation of the dispensing mechanism, the movement of the mouthpiece cover from one position, in which the mouthpiece is completely uncovered, to another position, in which the mouthpiece is completely closed, results in the advancement of the peelable blister strip to the same extent. The stopper which engages the movable mouthpiece cover to prevent its reversible movement from the position in which the mouthpiece is completely uncovered and open blister of the peelable blister is situated correctly for an effective inhalation of the dry powder medicament from opened blister. Also, the stopper which is attached to the top cover of said dry powder inhaler, make it possible to prevent reversible rotation of the index wheel undirectly because of the fact that the movable mouthpiece cover is attached directly to the dispensing mechanism through the center of the dry powder inhaler.
The inhaler (1) of the present invention has a stopper (31) that is situated between the lower housing member (4b) and the housing (10) as engaging with the two holes on the lower housing member (4b) (
Because of the supporting part (31c) of the stopper, there is no need for a spring to enable the pressing button (31b) to be pressed. There is an end (31d) that is integrated with the supporting part and leans the housing of the inhaler. When the pressing button is pressed, the supporting part springs over the end of said supporting part (31d) and both of the pressing button (31b) and the pawl (31a) are advanced forward inside of the inhaler.
The inhaler has another stopper (26) in the lower housing member (4b) in order to provide the opened blister in the blister package (15) which is indexed by the indexing wheel (8) to be positioned precisely.
As can be seen in
The rotation of the indexing wheel (8) is transmitted to the base gear (7) engaging with the pinion gear (11) by the pinion gear (11). The small gear which is under the base gear (7) as attached engages with the counter gear (9) (
In use of the device described in
The medicament in dry powder form which is stored in blister cavities is manufactured according to the prior art. According to the present invention, the particle sizes of the active agents comprised in the dry powder medicament are smaller than 20 μm, preferably smaller than 10 μm.
The inhaler pertaining to the present invention has been designed so as to deliver the dry powder medicament used in monotherapy or combined therapy. The term “monotherapy” refers to inhalation treatments in which dry powder medicaments comprising a single active agent are used whereas the term “combined therapy” refers to inhalation treatments in which dry powder medicaments comprising more than one active agents are use used.
The dry powder medicament delivered via the device pertaining to the present invention comprises at least one excipient in addition to the active agent or agents. These excipients are generally chosen from a group comprising monosaccharides (glucose, arabinose, etc.), disaccharides (lactose, saccharose, maltose, etc.), oligo- and polysaccharides (dextran, etc.), polyalcohols (sorbite, mannite, xylite), salts (sodium chloride, calcium carbonate, etc.) or combinations thereof. According to the present invention, the medicament in dry powder form comprises lactose as the excipient. The medicament in dry powder form comprises fine or coarse excipients particles preferably having various particle size ranges in order to deliver the required amount to the lungs.
The active agent or the active agents comprised in the dry powder medicament which is stored in blister packages used in the device pertaining to the present invention can be selected from a group comprising cromolyns, anti-infectives, antihistamines, steroids, anti-inflammatories, bronchodilators, leukotirene inhibitors, PDE IV inhibitors, antitussives, diuretics, anticholinergics, hormones, xanthines and pharmaceutically acceptable combinations thereof.
The active agent comprised in the medicament in dry powder form delivered via the inhaler pertaining to the present invention is preferably selected from a group comprising tiotropium, oxitropium, flutropium, ipratropium, glicopironium, flunisolid, beclomethasone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, montelukast, methylcyclopropane acetic acid, sodium cromoglicat, nedocromil sodium, Npropylene, teophylline, roflumilast, ariflo (cilomilast), salmeterol, salbutamol, formoterol, terbutaline, carmoterol, indacaterol, cetirizine, levocetirizine, efletirizine, fexofenadine and their racemates, free base, enantiomers or diastereomers and their pharmaceutically acceptable salts, solvates and/or hydrates or a combination of said active agents.
The device pertaining to the present invention is used in the administration of the medicament in dry powder form which is utilized in the treatment of respiratory diseases, particularly in asthma, chronic obstructive pulmonary disorder (COPD) and allergic rhinitis. Accordingly, the respiratory diseases include, but not restricted to, allergic or non-allergic asthma at any phases, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airways hyperactivity, bronchiectasis, chronic obstructive pulmonary including emphysema and chronic bronchitis, airways or lung diseases (COPD, COAD or COLD), pneumoconiosis, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis. The device pertaining to the invention can be used in prophylactic or symptomatic treatment. In addition, the medicament in dry powder form which is preferably used in the symptomatic treatment of allergic asthma and COPD is administered to the patient via the device pertaining to the present invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2009/07917 | Oct 2009 | TR | national |
| 2010/02877 | Apr 2010 | TR | national |
| 2010/03091 | Apr 2010 | TR | national |
| 2010/03238 | Apr 2010 | TR | national |
| 2010/04307 | May 2010 | TR | national |
| 2010/04308 | May 2010 | TR | national |
| 2010/04310 | May 2010 | TR | national |
| 2010/04312 | May 2010 | TR | national |
| 2010/04313 | May 2010 | TR | national |
| 2010/04317 | May 2010 | TR | national |
This application is a continuation of U.S. patent application Ser. No. 14/695,726, filed Apr. 24, 2015, now U.S. Pat. No. 9,795,750, which is a divisional application of U.S. patent application Ser. No. 13/451,838, filed Apr. 20, 2012, now U.S. Pat. No. 9,345,848, which is a continuation-in-part of PCT application No. PCT/TR2010/000210, filed Oct. 20, 2010, and PCT application Nos. PCT/TR2011/000085, PCT/TR2011/000086, PCT/TR2011/000087, PCT/TR2011/000088, PCT/TR2011/000089, PCT/TR2011/000090, PCT/TR2011/000091, PCT/TR2011/000093, PCT/TR2011/000094, and PCT/TR2011/000095, filed Apr. 13, 2011, each of which is incorporated herein by reference in its entirety. This application also claims priority to Turkish patent applications TR2009/07917, filed Oct. 20, 2009, TR2010/02877, filed Apr. 13, 2010, TR2010/03091, filed Apr. 20, 2010, TR2010/03238, filed Apr. 26, 2010, TR2010/04307, TR2010/04308, TR2010/04310, TR2010/04312, TR2010/04313, and TR2010/04317, filed May 28, 2010.
| Number | Name | Date | Kind |
|---|---|---|---|
| 2625292 | Spender | Jan 1953 | A |
| 5113855 | Newhouse | May 1992 | A |
| D335029 | Gerding | Apr 1993 | S |
| 5619984 | Hodson et al. | Apr 1997 | A |
| 5657749 | Cox | Aug 1997 | A |
| 6092522 | Calvert et al. | Jul 2000 | A |
| 6234365 | Bougamont et al. | May 2001 | B1 |
| D450117 | Braithwaite et al. | Nov 2001 | S |
| D479689 | Altonen et al. | Sep 2003 | S |
| 6880555 | Brunnberg et al. | Apr 2005 | B1 |
| D505865 | Seizer et al. | Jun 2005 | S |
| D518171 | Anderson et al. | Mar 2006 | S |
| D590495 | Lulla et al. | Apr 2009 | S |
| D590938 | Lulla et al. | Apr 2009 | S |
| D613397 | Nakao et al. | Apr 2010 | S |
| 7694676 | Wachtel | Apr 2010 | B2 |
| D641890 | Nardo | Jul 2011 | S |
| D645734 | Eason et al. | Sep 2011 | S |
| D683844 | Andrade et al. | Jun 2013 | S |
| D710002 | Valentine et al. | Jul 2014 | S |
| 20020132001 | Garthwaite et al. | Sep 2002 | A1 |
| 20030172927 | Young et al. | Sep 2003 | A1 |
| 20040094152 | Harvey et al. | May 2004 | A1 |
| 20040173211 | Kladders et al. | Sep 2004 | A1 |
| 20040182387 | Steiner et al. | Sep 2004 | A1 |
| 20040244794 | Richards | Dec 2004 | A1 |
| 20050005934 | Harvey | Jan 2005 | A1 |
| 20050154491 | Anderson et al. | Jul 2005 | A1 |
| 20050172964 | Anderson et al. | Aug 2005 | A1 |
| 20050183723 | Pinon et al. | Aug 2005 | A1 |
| 20050268909 | Bonney et al. | Dec 2005 | A1 |
| 20050279357 | Wachtel | Dec 2005 | A1 |
| 20060196504 | Augustyn et al. | Sep 2006 | A1 |
| 20070062525 | Bonney | Mar 2007 | A1 |
| 20070137645 | Eason et al. | Jun 2007 | A1 |
| 20080196718 | Connell | Aug 2008 | A1 |
| 20080308102 | Davies et al. | Dec 2008 | A1 |
| 20090078252 | Anderson et al. | Mar 2009 | A1 |
| 20090139516 | Augustyn et al. | Jun 2009 | A1 |
| 20090165791 | Wendland | Jul 2009 | A1 |
| 20090188498 | Thoemmes et al. | Jul 2009 | A1 |
| 20090211576 | Lehtonen et al. | Aug 2009 | A1 |
| 20090314291 | Anderson | Dec 2009 | A1 |
| 20100000528 | Palmer et al. | Jan 2010 | A1 |
| 20100000529 | Prime et al. | Jan 2010 | A1 |
| 20100059052 | Davies et al. | Mar 2010 | A1 |
| 20110232637 | Kaemper et al. | Sep 2011 | A1 |
| 20110271958 | Sawant | Nov 2011 | A1 |
| 20120260917 | Bilgic | Oct 2012 | A1 |
| 20140318538 | Bilgic | Oct 2014 | A1 |
| 20150231345 | Bilgic | Aug 2015 | A1 |
| 20150231346 | Bilgic | Aug 2015 | A1 |
| Number | Date | Country |
|---|---|---|
| 2544745 | May 2005 | CA |
| 1175220 | Apr 2005 | EP |
| 2082759 | Jul 2009 | EP |
| 2082764 | Jul 2009 | EP |
| 1459426 | Dec 1976 | GB |
| 2407042 | Apr 2005 | GB |
| 2447560 | Sep 2008 | GB |
| WO-0033847 | Jun 2000 | WO |
| WO-0141770 | Jun 2001 | WO |
| WO-0192239 | Dec 2001 | WO |
| WO-0236189 | May 2002 | WO |
| WO-03095010 | Nov 2003 | WO |
| WO-2006066908 | Jun 2006 | WO |
| WO-2007012960 | Feb 2007 | WO |
| WO-2008074098 | Jun 2008 | WO |
| WO-2009003989 | Jan 2009 | WO |
| WO-2009139731 | Nov 2009 | WO |
| WO-2011049541 | Apr 2011 | WO |
| WO-2011129785 | Oct 2011 | WO |
| WO-2011129786 | Oct 2011 | WO |
| WO-2011129787 | Oct 2011 | WO |
| WO-2011129788 | Oct 2011 | WO |
| WO-2011129789 | Oct 2011 | WO |
| WO-2011129790 | Oct 2011 | WO |
| WO-2011129791 | Oct 2011 | WO |
| WO-2011129793 | Oct 2011 | WO |
| WO-2011129794 | Oct 2011 | WO |
| WO-2011129795 | Oct 2011 | WO |
| WO-2011133740 | Oct 2011 | WO |
| Entry |
|---|
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000085 dated Aug. 10, 2011 (10 pages). |
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000086, dated Oct. 6, 2011 (8 pages). |
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000087 dated Aug. 18, 2011 (8 pages). |
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000088 dated Oct. 6, 2011 (8 pages). |
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000089 dated Jul. 22, 2011 (9 pages). |
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000090 dated Aug. 22, 2011 (8 pages). |
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000091 dated Jul. 29, 2011 (9 pages). |
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000093 dated Jul. 21, 2011 (9 pages). |
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000094 dated Sep. 28, 2011 (9 pages). |
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000095 dated Aug. 4, 2011 (9 pages). |
| International Search Report and Written Opinion for International Application No. PCT/TR2011/000210 dated Mar. 7, 2012 (7 pages). |
| Number | Date | Country | |
|---|---|---|---|
| 20180264211 A1 | Sep 2018 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13451838 | Apr 2012 | US |
| Child | 14695726 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14695726 | Apr 2015 | US |
| Child | 15792245 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/TR2011/000091 | Apr 2011 | US |
| Child | 13451838 | US | |
| Parent | PCT/TR2011/000094 | Apr 2011 | US |
| Child | PCT/TR2011/000091 | US | |
| Parent | PCT/TR2011/000089 | Apr 2011 | US |
| Child | PCT/TR2011/000094 | US | |
| Parent | PCT/TR2011/000093 | Apr 2011 | US |
| Child | PCT/TR2011/000089 | US | |
| Parent | PCT/TR2011/000085 | Apr 2011 | US |
| Child | PCT/TR2011/000093 | US | |
| Parent | PCT/TR2011/000088 | Apr 2011 | US |
| Child | PCT/TR2011/000085 | US | |
| Parent | PCT/TR2011/000087 | Apr 2011 | US |
| Child | PCT/TR2011/000088 | US | |
| Parent | PCT/TR2011/000095 | Apr 2011 | US |
| Child | PCT/TR2011/000087 | US | |
| Parent | PCT/TR2011/000086 | Apr 2011 | US |
| Child | PCT/TR2011/000095 | US | |
| Parent | PCT/TR2011/000090 | Apr 2011 | US |
| Child | PCT/TR2011/000086 | US | |
| Parent | PCT/TR2010/000210 | Oct 2010 | US |
| Child | PCT/TR2011/000090 | US |
