JP2013523376A - Inhaler used for delivery of drugs in dry powder form - Google Patents

Abstract

The present invention is suitable for delivering drugs in the form of dry powder used for the treatment of respiratory diseases, especially asthma, chronic obstructive pulmonary disease (COPD) and allergic rhinitis by the oral route. The present invention relates to an inhaler having a mechanism for preventing a problem caused by.
[Selection] Figure 5c

Description

  The present invention relates to an inhaler suitable for delivering drugs in dry powder form for use in the treatment of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD). Furthermore, the present invention relates to an inhaler having a blister package that is used to achieve effective inhalation and is suitable for the delivery of dry powder medicaments.

  The use of inhalers is very common for the delivery of drugs used for the treatment and prevention of respiratory diseases. For these diseases, inhalation therapy is the most commonly preferred treatment. This is because the inhaler is easy to use, and as a result of being administered locally, the onset of the effect of the drug is rapid and side effects are reduced. Various inhalers have been designed to provide effective and sufficient delivery of drugs used in the treatment of respiratory diseases, particularly asthma and chronic obstructive pulmonary disease. These inhalers vary depending on their operating mechanism and the physical form of the drug being delivered.

  In an inhaler used to deliver a drug in dry powder form, the drug is carried in a container, capsule or blister pack. Since the doses of drug required for inhalation are very small, it is very important to deliver each dose to the patient with accurate accuracy and precision.

  In an inhaler used to deliver a drug in dry powder form, at least 98% of the drug in dry powder form encapsulated in a blister pocket or capsule must be delivered to the patient. In this dry powder drug to be inhaled, drug particles called “microparticles” whose size ranges from 1 μm to 6 μm can be absorbed in the lungs. The active agent particles contained in the drug in dry powder form are also fine particles. The proportion of dry powder drug measurements in the blister or capsule is at least 25% by weight, preferably more than 30% by weight. In this regard, in order to achieve effective inhalation, it is desirable that more than 25% of the drug in dry powder form delivered to the patient be composed of microparticles.

  Ventilation resistance of inhalers used to deliver drugs in dry powder form is one of the most important factors affecting the amount of microparticles and hence the amount of dry powder drug active agent delivered to the patient's lungs. One. This is because the pressure drop and the flow rate achieved by the patient depend on the inhaler ventilation resistance and the patient inhalation volume. When the ventilation resistance of the inhaler is low, the airflow speed is high, and when the ventilation resistance of the inhaler is high, the airflow speed is low.

  If the ventilation resistance of the inhaler is very high, the inhaler cannot be used effectively in most patients, especially children, or in any case, because the patient must breathe deeply. Because the inhaler has very low airflow resistance, the drug in dry powder form is delivered to the patient without having to breathe deeply. However, if the patient achieves inhalation without breathing deeply, most of the drug in dry powder form accumulates in the patient's mouth and cannot reach the lungs. Furthermore, when the patient breathes, some of the drug in dry powder form accumulates in the mouthpiece of the device during the inhalation process and cannot be delivered to the patient. Therefore, the amount of active agent delivered to the patient's lung is inadequate and the inhalation achieved is ineffective.

  The inhaler device sold by GlaxoSmithKlein under the trademark Diskus® is one of the best known inhalers on the market. In these inhalers, a dry powder form of the drug is carried in a single dose in each blister pocket of the blister pack. This device cannot achieve effective inhalation. This is because if the inhaler is activated during inhalation of a drug in dry powder form, the ventilation resistance of the device is so low that a large portion of the dry powder drug delivered to the patient remains in the patient's mouth, leaving a sufficient amount This is because the active agent is not delivered to the patient's lungs.

  Considering inhalers that have been developed or marketed, there are inhalers that ensure that all of the above requirements are met and that sufficient quantities of the active agent are inhaled for effective inhalation. It seems to be needed.

  The inventor of the present invention surprisingly found that when the ratio of the manifold outlet cross-section to the mouthpiece outlet cross-section was within a certain range of values, the resulting ventilation resistance was inhaled into the patient's lungs. It has been discovered that the required amount of active agent contained in a drug in dry powder form can be delivered to achieve effective inhalation. Accordingly, the present invention relates to an inhaler that is suitable for delivery of a drug in dry powder form and that allows the required amount of active agent contained in the drug in dry powder form to be delivered to a patient's lungs.

An inhaler suitable for delivery of a medicament in dry powder form according to the present invention is
A blister package comprising a plurality of equally spaced blister pockets each containing a drug in dry powder form;
A mouthpiece that allows the patient to inhale the drug in dry powder form from the opened blister;
A rotating mouthpiece cover covering the mouthpiece;
A gear mechanism that allows to index the blister package and to prepare for inhalation of the drug in dry powder form;
A housing located between the upper housing member and the lower housing member and enclosing the blister package and the gear mechanism;
A manifold through which air entering the device from the air inlet passes;
A flow path interconnecting the manifold outlet and the mouthpiece outlet;
With
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.

Whether a sufficient amount of the active agent contained in the dry powder drug contained in the blister package opened by the operation of the device according to the present invention is sufficiently delivered to the patient's lungs depends on the resistance of the inhaler. It depends heavily. On the other hand, the resistance of the inhaler affects the flow rate and pressure drop of external air entering the device. The approximate value for the pressure drop is ΔP = K. ρ. v is calculated by the formula ^2/2. The pressure drop can be calculated for each component of the device through which external air entering the inhaler passes. In this equation, the K value is a geometric factor, 0.5 if the cross section instantaneously shrinks and 1 if the cross section instantaneously expands, and ρ represents the air density, approximately 1.3 kg / m ³ where the v (m / s) value is the average velocity of the air. The resistance value of each component is obtained by dividing the square root of the ΔP (unit: kPa) value obtained from the above equation by the flow rate (min / liter) of the external air entering the inhaler. The airflow velocity provided is obtained by dividing the total pressure drop induced in the inhaler by the resistance value.

  The inventor of the present invention believes that the resistance in the mouthpiece and manifold outlet of the inhaler has a significant effect on the pressure drop and hence the air flow rate, and 4 kPa is required in the inhaler to achieve effective inhalation. I found that there must be a pressure drop above. Manifold outlet and mouthpiece outlet resistance and air flow velocity are directly proportional to the average air velocity. On the other hand, the average air velocity is determined according to the cross section of the manifold outlet and mouthpiece outlet. The pressure drop above 4 kPa required to achieve effective inhalation is such that the ratio of the manifold outlet cross section to the mouthpiece outlet cross section is in the range of 1:10 to 1:50, preferably from 1:15. Provided in the range of 1:40, more preferably in the range of 1:20 to 1:30. Therefore, it is possible to deliver to the patient's lungs the requisite amount of active agent contained in the dry powder drug by the breath that the patient does to deliver the drug in dry powder form to the lungs. it can. In addition, the change in air flow rate induced when the ratio of the manifold outlet cross-section to the mouthpiece outlet cross-section is in the range of 1:10 to 1:50 indicates that a large amount of residual dry powder drug is present in the mouthpiece and Prevent accumulation in the patient's mouth.

  An inhaler according to the present invention in which 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 suitable for use in delivering a drug in the form of a dry powder and is a blister pack. A manual device having

  The inhaler according to the present invention has a mechanism that is preferably activated by rotation of the mouthpiece cover. Therefore, the housing of the device according to the present invention is designed so that the components of the blister package and the gear mechanism, which play an important role in enabling the device to work properly, are located accurately and work in harmony. Has been. For this purpose, the housing is divided into several compartments. Used and unused parts of blister packs are separated into separate compartments to prevent spillage of dry powder form drug remaining in the opened blister pockets on other components of the housing. Be contained. In addition, the housing also includes a beak that allows the blister package to peel and a manifold through which the dry powder drug in the opened blister passes before reaching the mouthpiece during inhalation. Also, the housing can be any suitable shape, but is preferably oval or circular.

  The upper housing member and the lower housing member are interconnected to enclose the housing in order to keep the housing and gear mechanism fixed together. The mouthpiece cover that hides the mouthpiece rotates by sliding on the upper and lower housing members. Grids on the surfaces of the lower and upper housing members provide effective actuation by preventing the fingers from slipping while the mouthpiece cover rotates. The upper and lower housing members can be any suitable shape that provides ease of use.

  The mouthpiece cover that hides the mouthpiece of the device according to the present invention is designed to also provide operation of the device. Prior to each inhalation, one of the blister pockets is opened as a result of the mouthpiece cover preferably being manually rotated along a path restricted by engagement of protrusions on the upper and lower housing members Thus, the mouthpiece cover is removed and ready for inhalation of a single dose of dry powder drug. The rotation path along which the cover moves is limited at both ends by the protrusions of the upper housing member and the lower housing member.

  The mouthpiece cover that activates the gear mechanism of the device can only be seen in two positions. When the mouthpiece cover is in the first position, the mouthpiece cover is on a protrusion at one end of the rotation path. When the first position is on, the mouthpiece cover is fully covered and the device is in standby mode. When the mouthpiece cover is in the second position, the mouthpiece cover is on a protrusion at the other end of the rotational path and is ready for inhalation of a single dose of dry powder medicament when the device is activated.

  The mouthpiece cover of the device is joined to the gear mechanism via a connection point. One end of the drive gear passes through the center of the lower housing member and is firmly joined to the mouthpiece cover at one connection point, and the other end passes through the center of the upper housing member and is connected to the mouthpiece at the other connection point. Join the cover. One side cover is used for each end of the drive gear so that each end of the drive gear is stably connected between the connection points of the mouthpiece cover. Therefore, the end of the drive gear is curved so that it can be securely engaged with the end of the side cover from the inside. The shape of the inner surface of these curved portions at both ends of the drive gear matches the shape of the end of the side cover that fits into it.

  There is a stabilizing elastic cover at each connection point of the mouthpiece cover. Stabilized elastic covers on both sides of the inhaler prevent movement of the mouthpiece cover on both sides. Prior to inhalation, raise the nail to operate the mouthpiece cover to activate the device and press down on the elastic part of each stabilizing elastic cover that matches the shape of the finger to release the mouthpiece cover.

  According to the invention, the gears of the gear mechanism of the device engage directly or indirectly with each other. Prior to inhalation, press the stabilizing elastic covers on both sides of the device and operate the device by rotating the mouthpiece cover along the rotation path and connect both of the mouthpiece covers via the side cover A drive gear joined to the point indexes the movement of the mouthpiece cover by the side cover during operation of the device and accurately transmits it to the ratchet wheel. The indexing wheel can be rotated by an indexing ratchet wheel connected to the indexing wheel from the inside by an arm. When the indexing wheel is activated, the blister pack is indexed and peeled off by the beak present in the housing. Since the indexing wheel is engaged with the take-up wheel gear and the pinion gear, when the indexing wheel operates, these gears also operate. Since the mechanical gear is engaged with the winding wheel gear and the winding wheel, when the winding wheel gear rotates, the winding wheel operates and the cover sheet of the blister package is tightly coiled on the winding wheel. The The pinion gear engages with the base gear, while the small gear under the base gear engages with the counter gear. Therefore, the rotation of the indexing wheel activated by the operation of the device is transmitted to the counter gear via a small gear just below the base gear.

  The counter gear of the device according to the present invention displays the number of unused blister pockets remaining in the device. In response to operation of the device with the mouthpiece cover, the mouthpiece cover is removed, the blister pack is indexed, and a single dose of dry powder medication is prepared for inhalation, while the counter gear also rotates. . Therefore, when the mouthpiece cover operates, the mouthpiece cover is removed, and after the blister pocket is opened, the unit is ready for inhalation of a dry dose of dry powder medicine, and the counter gear is rotated and the remaining unused Displays the new value of the blister pocket.

  On the counter gear there are numbers equal to the number of blister pockets present in the device, which are spaced at equal angles. For devices with 60 doses, the angle between the numbers is about 5 °. As a result of reflecting the rotation of the indexing wheel via the pinion gear and the base gear, the counter gear rotates. In response to each operation of the device, the movement of the mouthpiece is accurately transmitted to the gear mechanism via the drive gear, so that the indexing wheel rotates by the same angle each time, so that the counter wheel is also approximately the same angle. The numbers on the counterwheel are clearly visible through rotation and display openings in the upper housing member. Thus, the patient is ascertained how many unused blister pockets remain in the device.

  The inhaler according to the present invention further comprises a blister package comprising a plurality of blister pockets each having a medicament in the form of a dry powder and spaced apart at equal intervals. The blister package carries the drug in dry powder form in a single dose portion, which is preferably a blister strip and is preferably peelable. The blister pockets contained in the blister package are equally spaced and each carry a single dose of drug in dry powder form.

  While the blister package is being indexed on the indexing wheel, the beak on the housing peels off the blister. Thus, after each blister pack is peeled and opened with each operation of the device, a single dose of dry powder medicament is ready for inhalation.

  The base sheet of the blister package with the blister cavities spaced apart on itself is stored in a separate compartment of the housing. On the other hand, a lid sheet that provides impermeability to the blister pack is coiled onto a winding wheel that is one of the components of a gear mechanism positioned on the other side of the housing.

  The blister opened by the beak is located directly under the manifold. When inhaled by the patient, an air flow, preferably entering the device through at least one air inlet on the upper housing member, entrains the mouthpiece through the manifold with the dry powder drug in the opened blister pocket. To allow delivery of the drug to the patient. The air inlet of the upper housing member that allows air ingress may be of any suitable shape and size that also allows external air to enter the device at an easy and convenient rate.

  The mouthpiece is designed to fit in the mouth so that the patient can comfortably inhale the drug in dry powder form. Depending on the shape of the device, the mouthpiece may be any suitable shape or size, and may be fixed or movable. Further, it may or may not be attached to the upper and / or lower cover.

  The air inlet through which the external air flow passes is preferably designed so that it does not close if the patient holds the device so as not to obstruct the air flow. In addition, the air inlet is designed so that the air flow can enter at a convenient angle through the air inlet to deliver the required amount of dry powder drug from the opened blister to the patient.

  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 patient breathing, external air passes through the air inlet and enters the manifold. When the patient inhales, the air entering the inhaler through the air inlet passes through one of the openings having four partial openings at the end of the manifold and enters the opened blister, giving a single dose of dry powder. Entrained in the form of drug, it passes through another opening with four partial openings at the end of the manifold to reach the manifold. The air that entrains the drug in dry powder form to the other end of the manifold that is closed to the mouthpiece, i.e. to the outlet of the manifold, is a flow path that preferably interconnects the mouthpiece and manifold. And then reach the mouthpiece. The angle of the peak point of the tapered channel is in the range of 30 ° to 150 °, preferably 45 ° to 135 °, and most preferably 50 ° to 125 °. Furthermore, the distance between the manifold outlet and the mouthpiece outlet, i.e. 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 considered as one of the factors affecting the ventilation resistance in the inhaler.

  In order to achieve effective inhalation using the inhaler according to the present invention, the ratio of the manifold outlet cross section and the mouthpiece outlet cross section provides a pressure drop in the inhaler of more than 4 kPa, The range is from 1:10 to 1:50, preferably from 1:15 to 1:40, and more preferably from 1:20 to 1:30. Therefore, the amount of active agent required for treatment in the dry powder medicament contained in the blister pocket that is opened when the inhaler is activated is delivered to the lungs.

  The term “effective inhalation” as used throughout this text refers to the desired result elicited as a result of the amount of active agent necessary for inhalation therapy being delivered to the patient's lungs.

  Each component of the device according to the present invention can be made of any suitable material, but is preferably made of plastic. These plastic materials include styrene-acrylonitrile, polyoxymethylene (commonly referred to as POM, also known as polyacetal or polyformaldehyde), acrylic-polymethyl methacrylate, cellulose acetate, polyetheretherketone, It is selected from the group comprising the types of polyvinyl chloride, polyethylene, polypropylene, acrylonitrile butadiene styrene, polycarbonate, polyamide, polystyrene, polyurethane or fluoropolymer, more preferably polyoxymethylene. Components made of plastic can be produced by methods such as injection molding. Further, each component of the device may be any suitable color.

  The lid sheet and base sheet constituting the blister package are preferably composed of a plurality of layers. Each of these layers is preferably selected from the group comprising polymer layers made of various polymer materials, aluminum foils and fluoropolymer films.

  According to the present invention, the cover sheet and the base sheet constituting the blister package are provided with impermeable properties such as cold forming fastening, high temperature metal fastening, high temperature metal welding, high frequency welding, laser welding or ultrasonic welding. Is sealed very tightly by at least one of the following methods, more preferably by a cold forming fastening method. Since these cold forming fastening methods can be performed at lower temperatures than hot sealing methods, this is the most appropriate method to use when the drug carried in the blister is heat sensitive. is there.

  Fluoropolymer films are polymer films that are used in blister packs and provide an excellent moisture barrier. This scientifically inert polymer film does not change the taste of the formulation when contacted with a dry powder formulation. Furthermore, it easily constitutes a layered structure with other polymer layers composed of various polymers. It is appropriate to treat with heat.

  In order to maintain the stability of the dry powder formulation stored in the blister package, at least one of the polymer layers has a gas and moisture permeability of the layer, such as silica gel, zeolite, alumina, bauxite, anhydrous calcium sulfate, activated carbon and viscosity. It is preferable to include at least one desiccant having water-absorbing properties in order to reduce

  According to the present invention, the thickness of the lid of the blister package and the aluminum foil of the base sheet is preferably selected to be in the range of 5 μm to 80 μm, more preferably in the range of 15 μm to 65 μm.

  According to the invention, the blister pack lid sheet and the base sheet polymer layer are made of the same polymer or different polymers. The thickness of these polymer layers varies according to the type of polymer material used and its properties, but is preferably in the range of 5-100 μm, more preferably in the range of 15-60 μm.

  The polymer constituting the polymer layer is preferably selected from thermoplastics such as polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane or synthetic polymer.

  The blister pockets of the blister package may be any suitable shape. The plurality of blister pockets equally spaced on the base sheet of the blister package may be the same or different shapes, structures or volumes.

  The drawings attached to illustrate the invention and the reference numerals of the detailed description of the invention with these drawings are given below, but the scope of the invention is not limited to these drawings.

It is a perspective view of the inhaler by the inhaler demonstrated by this invention. It is an exploded view of the inhaler concerning the present invention. It is a perspective view of the blister pack used with the inhaler concerning the present invention. 1 is a perspective view of an inhaler housing according to the present invention. FIG. 1 is a perspective view of an inhaler housing according to the present invention. FIG. FIG. 6 is a perspective view of an upper housing member of an inhaler according to the present invention. FIG. 6 is a perspective view of a lower housing member of an inhaler according to the present invention. It is a longitudinal cross-sectional view of the inhaler based on this invention. It is a perspective view of the mouthpiece cover of the inhaler concerning the present invention. It is an exploded view of the communication between the mouthpiece cover, the drive gear and the stabilizing elastic cover of the inhaler according to the present invention. It is sectional drawing of the communication between the mouthpiece cover of the inhaler which concerns on this invention, a drive gear, and the stabilization elastic cover. It is sectional drawing of the communication between the mouthpiece cover of the inhaler which concerns on this invention, a drive gear, and the stabilization elastic cover. It is an exploded view of the communication between the drive gear and the side cover of the inhaler according to the present invention. It is sectional drawing of the connection of the stabilization elastic cover and lower housing member of the inhaler concerning this invention. It is sectional drawing of engagement with the mutual of the gear provided with the gear mechanism of the inhaler which concerns on this invention. It is sectional drawing of engagement with the mutual of the gear provided with the gear mechanism of the inhaler which concerns on this invention. It is sectional drawing of engagement with the mutual of the gear provided with the gear mechanism of the inhaler which concerns on this invention. It is sectional drawing of the blister package which peels in the process of the operation | movement of the inhaler concerning this invention. It is a perspective view of the counter gear used with the inhaler concerning the present invention.

  As shown in FIGS. 1 and 2, the inhaler (1) according to the present invention has an upper housing member (4a) for allowing inhalation of a dry powder medicine carried in a blister package (15). And a lower housing member (4b) with a gear mechanism located in the housing (10). Each component of the inhaler (1) is positioned at the appropriate spot on the device to ensure proper and accurate operation.

  The inhaler (1) according to the invention shown in FIG. 1 is ready for inhalation. In this case, the mouthpiece cover (2) is in the second position, and the entire mouthpiece (14) is exposed. The mouthpiece cover (2) holds the curved portion (2a) at one end of the mouthpiece cover (2) in order to switch from the first position where the mouthpiece is completely covered to the second position. Must rotate. In this way, when the mouthpiece cover (2) is switched from the first position to the second position and the gear mechanism is activated by the drive gear (12), the mouthpiece (14) is completely exposed. The drive gear (12) indexes the movement of the mouthpiece cover (2) and accurately transmits it to the ratchet wheel (3).

  The indexing wheel (8) that engages the indexing ratchet wheel (3) allows indexing of the blister pack (15) shown in FIG. When the indexing wheel (8) rotates, the blister pocket (15a) constituting the blister package is received by the recess (8a) on the indexing wheel, and the blister package (15) is indexed. In the inhaler according to the present invention, the shape of the depression (8a) of the indexing wheel (8) is such that the blister pocket (15) constituting the blister package (15) is properly indexed. Designed to match the shape.

  The blister package (15) shown in FIG. 3 includes a lid sheet (15b) that provides impermeability, and a base sheet (15c) on which blister pockets (15a) are spaced apart at equal intervals. Each blister pocket contains a drug in dry powder form containing one or more active agents.

  The rotational movement performed by the mouthpiece cover (2) of the device during switching from the first position to the second position is determined via the indexing ratchet wheel (3) via the drive gear (12) engaged with the mouthpiece cover (2). ). As shown in FIG. 2, the arm (3a) of the index ratchet wheel is connected to the protrusion inside the index wheel (8) to rotate the index wheel (8) in one direction. Therefore, the blister package (15) is indexed forward while the indexing wheel (8a) rotates. This is because the blister pocket (15a) constituting the blister package (15) is received by the index wheel depression (8a). In response to each actuation of the device (1), the blister pack (15) is indexed and opened by the beak (16) of the housing (10) while opening one blister pocket (15a). 15) is peeled off.

  The winding wheel gear (6), which is another component of the gear mechanism, engages with the indexing wheel (8) as shown in FIG. The mechanism gear (5) connected to the winding wheel (13) from the inside has an arm (5a) connected to the internal teeth of the winding wheel gear (6). When the indexing wheel (12) rotates the winding wheel gear (6), the winding wheel rotates in one direction by the arm of the mechanism gear (5a) connected to the internal teeth of the winding wheel gear (6). The lid sheet (15b) peeled off while the blister package is indexed is tightly coiled around the wing (13a) of the winding wheel. The base sheet (15c) of the blister package (15), where the blister pockets are spaced, is stored in a separate part (18a) of the device.

  Various perspective views of the housing (10) in which the gear mechanism and other components of the inhaler (1) according to the present invention are arranged are shown in FIGS. 4a and 4b. Furthermore, as seen in FIGS. 4a and 4b, the housing (10) plays an important role in the operation of the device, such as the beak (16), manifold (20), opening with four partial openings (20a, 20b). The other component which has is also provided. Each component contained in the housing is located in a suitable part of the housing (10) to allow proper operation of the inhaler (1). The drive gear (12) passes through the center (21) of the housing and joins the mouthpiece cover (2) at two points. The blister pack (15) is in the lower part (17) of the housing in a coiled state. In response to each actuation of the device (1), the blister pack (15) is indexed by the indexing wheel (8) located in the upper part (19) of the housing, while the beak ( 16). The lid sheet (15b) of the blister pack (15) providing impermeability is indexed on the beak (16) and coiled on the winding wheel (13) located on the side (18) of the housing. Is done. On the other hand, the base sheet (15c) of the blister pack (15), on which the blister pocket (15a) is spaced, accumulates in the separated compartment (18a) of the housing (10). As the patient inhaled, air passed under the manifold (20) through the air inlet with four partial openings (20a) into the opened blister pocket and opened in response to each actuation of the device. The dry powder drug contained in the blister pocket (15a) is entrained and passed through the other opening with four partial openings (20b) to reach the mouthpiece via the manifold (20).

  Since the upper housing member (4a) and the lower housing member (4b) shown in FIGS. 5a and 5b are joined together, the housing (10) and other components of the inhaler (1) according to the present invention are: Maintained together in a stable state. The engagement tab (28) on the inner surface of the lower housing member (4b) engages with the engagement recess (27) on the inner surface of the upper housing member (4a), so that the upper and lower housing members are firmly fixed. Therefore, the protrusions (23a, 23b) of the upper housing member (4a) and the protrusions (24a, 24b) of the lower housing member (4b) are joined at the ends, thereby providing a path for limiting the rotational movement of the mouthpiece cover (2). Define. The mouthpiece cover (2) can move along this path. When the mouthpiece cover (2) is in the first position, the mouthpiece is completely covered and the device is in the standby mode, and the mouthpiece cover (2) has a first protrusion (23a) on the upper housing member. And the first protrusion (24a) on the lower housing member. The mouthpiece (2) manually slides along the rotation path using the curved portion and switches to the second position. The mouthpiece is fully exposed when the cover is in this position and is ready for inhalation of a single dose of dry powder medicament, the mouthpiece cover (2) is connected to the second protrusion (23b) of the upper housing member and It leans against the second protrusion (24b) on the lower housing member.

  As shown in FIGS. 5a and 5b, one half (25a) of the tapered channel interconnecting the manifold (20) present in the housing (10) with the mouthpiece (14) is connected to the upper housing member (4a). The other half (25b) is included in the lower housing member (4b). The flow path is configured as a whole when the upper housing member (4a) and the lower housing member (4b) are joined together. When the patient inhales, air entering the device through an air inlet (22) located in the upper housing member (4a) passes through an opening having four partial openings (20a) and opens the blister (15a) ) And entrain it to the manifold (20) by passing the dry powder drug through the other opening with four partial openings (20b). The air entraining the dry powder drug into the manifold (20) causes the dry powder form of drug to flow from the manifold outlet (20c) through the tapered channels (25a and 25b) as shown in FIG. 14a), enabling delivery of the drug in dry powder form to the patient.

The grids (23e, 23f) on the upper housing member and the grids (24e, 24f) on the lower housing member prevent finger slipping when the mouthpiece cover is rotated.

  A mouthpiece cover (2) of an inhaler according to the invention is illustrated in FIG. 6a. The curved part (2a) at one end of the device allows the mouthpiece cover to be easily moved manually. The mouthpiece cover (2) is joined to the gear mechanism via a connection point. 6b, 6c and 6d clearly showing the communication between the mouthpiece cover (2), the drive gear (12), the side covers (31a, 31c) and the stabilizing elastic covers (32, 33). Thus, the drive gear (12) is joined to the connection point (29, 30) of the mouthpiece cover via the side cover (31a, 31c). Each of these side covers (31a, 31c) passes through the center (4d) of the upper housing member or the center (4e) of the lower housing member and is joined to the end (12a; 12b) of the drive gear. It can be clearly seen in FIG. 6d that both ends (12a; 12b) of the drive gear are curved so that the end of the side cover (31b; 31d) can pass. Each end (31d; 31b) of the side cover passes through one of the connection points (29; 30) of the mouthpiece cover and is received by a recess (12b; 12a) at one end of the drive gear, and thus the mouthpiece. The cover (2) and the drive gear (12) are interconnected tightly and stably. It is defined that the mouthpiece cover (2) is synchronized with the drive gear (12). This is because the connection point (29; 30) of the mouthpiece cover having a shape coinciding with the end (31d; 31b) of the side cover passing through itself on both sides of the device and the end of the drive gear with which it communicates This is because the part (12b; 12d) is on the same component.

  6a to 6e, the shape of the end portion (31b; 31d) of the side cover received in the curved portion of the end portion of the drive gear, and the shape of the connection point (29, 30) of the mouthpiece cover Are not identical. This is because the two ends (12a, 12b) of the drive gear are not identical.

  As shown in FIGS. 2, 6a to 6d and 6f, there is one stabilizing elastic cover (33; 32) on each connection point (29; 30) of the mouthpiece and on each side cover. When the mouthpiece cover (2) is in the first position, as clearly seen in FIGS. 6c and 6d, the nails (32a) under the stabilizing elastic cover on the connection point (29, 30) of the mouthpiece 33a) are connected to the mouthpiece cover (2) on both sides. The claw (33a) under the stabilizing elastic cover on the first connection point (29) connects with the mouthpiece cover on one side (FIG. 6c). Exactly the same, the claw (32a) under the stabilizing elastic cover on the second connection point (30) of the mouthpiece cover connects with the mouthpiece cover (2) on the other side (FIG. 6d).

  The extension (32b, 32c; 33b, 33c) under the stabilizing elastic cover passes through the openings (23c, 23d; 24c, 24d) on the upper and lower housing members shown in FIGS. Keep the elasticized cover stable. That is, the extension (33b; 33c) below the stabilizing elastic cover on the first connection point (29) of the mouthpiece cover passes through the opening (23c; 23d) on the upper housing member, and stabilizes the elasticity. The cover (33) is bonded to the device in a stable state. Exactly the extension (32b, 32c) under the stabilizing elastic cover on the second connection point (30) of the mouthpiece cover is on the lower housing member as clearly shown in FIG. 6f. The stabilized elastic cover (32) is bonded to the device in a stable state through the openings (24c, 24d).

  Prior to inhalation, the elastic portion (32d, 33d) of each stabilizing elastic cover shown in FIGS. 6c and 6d activates the gear mechanism of the device to prepare a single dose of dry powder drug prior to inhalation. Then, the fingernail (32a, 33a) is pushed up to release the mouthpiece cover (2). Therefore, when the elastic part (32d, 33d) of the stabilizing elastic cover is pressed and the mouthpiece cover (2) is switched from the first position to the second position at the same time, the gear mechanism of the device is activated and used for inhalation. One blister pocket (15a) is opened so that a single dose of dry powder medicament is ready.

  In FIG. 7a, it is illustrated that the stopper (26) connects with the teeth of the index ratchet wheel (3) and prevents its rotation. In response to each actuation of the device (1), the mouthpiece cover (2) is rotationally moved by the same angle, and this movement is indexed by the drive gear (12) engaging the mouthpiece cover (2) on both sides. Accurately transmitted to the wheel (3), the drive gear (12) can rotate by the same angle each time the device (1) is actuated. The blister package that is indexed by the indexing wheel (8) synchronized with the indexing ratchet wheel by the stopper component (26) of the lower housing member (4b) being maintained in a fixed position by the indexing ratchet wheel (3) The backward movement of (15) is prevented and the blister package (15) is positioned accurately.

  As can be seen in FIG. 7b, the indexing wheel (8) synchronized with the indexing ratchet wheel (3) engages with the take-up wheel gear (6) and the pinion gear (11) and rotates by the indexing wheel (8). The pinion gear (11) and the winding wheel gear (6) rotate. Therefore, the peeled lid sheet (15b) of the blister package (15) indexed by the rotation of the indexing wheel (8) is tightly placed on the winding wheel (13) engaged with the winding wheel gear (6). Further, the counter wheel (9) is provided to be operated by the pinion gear (11) and the base gear (7) as a result of the rotation of the indexing wheel (8).

  As seen in FIG. 8, the lid sheet (15b) and the base sheet (15c) of the blister package (15) peeled off by the beak (16) are enclosed in separate compartments. The lid sheet (15b) providing impermeability is indexed on the beak (16) and tightly coiled onto the wing (13a) of the winding wheel. The base sheet (15c) of the blister pack (15) is a separate compartment (18a) of the housing (10) when the blister pockets (15a) each carrying a single dose of dry powder medicament are spaced apart. Accumulated in. In response to each actuation of the device (1), a single dose of dry powder medicament is prepared for inhalation after the blister pocket (15a) has been opened and the device passes through the air inlet (22) as the patient inhales. The incoming air delivers it to the patient by entraining a single dose of dry powder drug from the blister pocket (15a) into the mouthpiece (14).

  The rotation of the indexing wheel (8) is transmitted by the pinion gear (11) to the base gear (7) engaged with the pinion gear (11). The small gear under the base gear (7) in the mounted state engages with the counter gear (9) (FIG. 7c). Therefore, the operation of the indexing wheel (8) is transmitted to the counter wheel (9) shown in FIG. 9 by the pinion gear (11) and the base gear. In the counter gear (9) shown in FIG. 9, there are numbers that increment from 1 to 60. The angles between these numbers are all equal and are about 5 °. In response to each actuation of the device, the counter gear rotates about 5 ° and the number of unused blister pockets remaining in the device is clearly visible through the display opening (4c) of the lower housing member (4b).

  When the mouthpiece cover (2) slides from the first position to the second position on the upper housing member (4a) and the lower housing member (4b) during use of the device described in FIGS. (14) is exposed, the gear mechanism is actuated by the drive gear (12) to prepare a single dose of dry powder medicine for inhalation, the counter gear (9) is indexed and the lower housing member (4b) ) Is incremented by the number visible through the display opening (4c).

  Drugs in dry powder form stored in blister cavities are manufactured by the prior art. According to the invention, the particle size of the active agent contained in the dry powder medicament is smaller than 20 μm, preferably smaller than 10 μm.

  The inhaler according to the present invention is designed to deliver dry powder drugs used in monotherapy or combination therapy. The term “monotherapy” refers to inhalation therapy using a dry powder drug containing a single active agent, and the term “combination therapy” refers to inhalation therapy using a dry powder drug containing multiple active agents. Point to.

  The dry powder medicament delivered via the device according to the invention comprises at least one excipient in addition to one or more active agents. These excipients are usually monosaccharides (such as glucose, arabinose), disaccharides (such as lactose, sucrose, maltose), oligosaccharides and polysaccharides (such as dextran), polyhydric alcohols (sorbitol, mannitol, xylitol), It is selected from the group comprising salts (sodium chloride, calcium carbonate, etc.), or combinations thereof. According to the invention, the drug in dry powder form contains lactose as an excipient. The drug in dry powder form includes fine or coarse excipients, preferably having various particle size ranges, in order to deliver the required amount to the lungs.

  One or more active agents contained in the dry powder drug stored in the blister package used in the device according to the present invention are cromolyn, anti-infective drug, antihistamine, steroid, anti-inflammatory drug, bronchial It can be selected from the group comprising dilators, leukotriene inhibitors, PDE IV inhibitors, antitussives, diuretics, anticholinergics, hormones, xanthines, and pharmaceutically acceptable combinations thereof.

  The active agent contained in the drug in dry powder form delivered via the inhaler according to the present invention is tiotropium, oxitropium, flurtropium, ipratropium, glycopyrronium, flunisolide, beclomethasone, budesonide, fluticasone, mometasone, ciclesonide , Rofleponide, dexamethasone, montelukast, methylcyclopropane acetate, sodium cromoglycate, nedocromil sodium, N propylene, theophylline, roflumilast, Ariflo (siromilast), salmeterol, salbutamol, formoterol, terbutaline, carmoterol, indacaterol, cetirizine, Levocetirizine, efletirizine, fexofenadine and their racemates, free bases, enantiomers or diastereomers, Beauty their pharmaceutically acceptable salts, is preferably selected from the group comprising a combination of solvates and / or hydrates or the effective agent.

  The device according to the invention is used for the administration of a medicament in the form of a dry powder used for the treatment of many respiratory diseases, in particular asthma, chronic obstructive pulmonary disease (COPD) and allergic rhinitis. Therefore, respiratory diseases include any phase of allergic or non-allergic asthma, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), exacerbation of airway motility, bronchiectasis, emphysema and chronic bronchitis Chronic obstructive pulmonary disease, respiratory tract or pulmonary disease (COPD, COAD or COLD), pneumoconiosis, aluminosis, anthracnose, asbestosis, asbestosis, loss of eyelash, iron deposition, silicosis, tobacco addiction And cotton pneumonia, but not limited to. The device according to the invention can be used for preventive treatment or symptomatic therapy. In addition, a drug in dry powder form, preferably used for symptomatic treatment of allergic asthma and COPD, is administered to the patient via the device according to the present invention.

Claims (28)

An inhaler suitable for delivering a drug in dry powder form from a blister pack (15) comprising a plurality of equally spaced blister pockets (15a) each containing a drug in dry powder form And
A mouthpiece (14) that allows a patient to inhale the drug in the form of the dry powder from an opened blister pocket (15a);
A rotating mouthpiece cover (2) covering the mouthpiece (14);
A gear mechanism that enables the blister package (15) to be indexed and ready for inhalation of the drug in the form of the dry powder;
A housing (10) positioned between the upper housing member (4a) and the lower housing member (4b) and enclosing the blister package and the gear mechanism;
A manifold (20) through which air entering from the air inlet (22) passes;
Channels (25a and 25b) interconnecting the manifold outlet (20c) and the mouthpiece outlet (14a);
With
An inhaler wherein the ratio of the cross section of the manifold outlet (20c) to the cross section of the mouthpiece outlet (14a) is in the range of 1:10 to 1:50.   Inhaler (1) according to claim 1, wherein the ratio of the cross section of the manifold outlet (20c) to the cross section of the mouthpiece outlet (14a) is preferably in the range of 1:20 to 1:30.   The inhaler (1) according to claim 1, wherein the pressure drop caused by the ventilation resistance in the device is at least 4 kPa.   The inhaler (1) according to claim 1, wherein the flow path interconnecting the manifold outlet (20c) and the mouthpiece outlet (14a) in the device is preferably tapered.   The inhaler (1) according to claim 4, wherein the angle of the peak point of the tapered channel interconnecting the manifold outlet (20c) and the mouthpiece outlet (14a) is in the range of 30 ° to 150 °. .   The inhaler (1) according to claim 1, wherein the distance between the manifold outlet (20c) and the mouthpiece outlet (14c) is at least 2 mm.   Inhaler (1) according to claim 1, wherein the housing (10) preferably encloses a beak (16) and a manifold (20).   The inhaler (1) according to claim 1, wherein the mouthpiece cover (2) rotates by sliding on the upper housing member (4a) and the lower housing member (4b). The mouthpiece cover (2) is only in two positions, i.e.
A position in which the mouthpiece cover (2) is in the first position, the mouthpiece (14) is completely covered and the device (1) is in standby mode;
The mouthpiece cover (2) is in the second position and when the device (1) is activated, it can be placed in a position where a single dose of the dry powder form of the drug is ready for inhalation; Inhaler (1) according to any one of the preceding claims.   Inhaler (1) according to claim 1, wherein there is a curved portion (2a) at one end of the mouthpiece cover so that the mouthpiece cover rotates easily.   The inhaler (1) according to claim 1, wherein all the components of the gear mechanism engage each other directly or indirectly. The gear mechanism is
A drive gear (12) for operating the device (1) by transmitting the movement of the mouthpiece cover (2) to the index ratchet wheel (3);
An indexing wheel (8) which is synchronized with the indexing ratchet wheel (3) and which allows indexing of the blister pack (15);
A winding wheel gear (6) that, when the indexing wheel (8) rotates, operates the winding wheel (13) via the mechanism wheel (5);
A pinion gear (11) and a base gear (7) for transmitting the operation of the indexing wheel (8) to the counter wheel (9);
Inhaler according to any one of the preceding claims, comprising a counter wheel (9) indicating the number of unused blister pockets (15a) remaining in the device (1) 1).   The inhaler (1) according to claim 1, wherein there is at least one air inlet (22) that provides a flow of air over the upper housing member (4b).   14. An inhaler (13) according to claim 13, wherein the air inlet (22) into which the external air enters the device is designed not to be close to where the patient holds the device (1) in order not to disturb the air flow. 1).   15. The blister package (15) according to any one of the preceding claims, further comprising a blister pack (15) comprising a plurality of blister pockets (15a) each containing a drug in dry powder form and equally spaced. Inhaler (1).   Inhaler (1) according to claim 1, wherein the blister package (15) with which it is provided is preferably a blister strip.   Inhaler (1) according to any one of the preceding claims, wherein the blister pack (15) with which it is provided is preferably peelable.   The inhaler according to claim 17, wherein the blister package comprises a lid sheet (15b) and a base sheet (15c).   Inhaler (1) according to claim 18, wherein the lid sheet (15b) and the base sheet (15c) constituting the blister pack (15) preferably have a plurality of layers.   The layers constituting the lid sheet (15b) and the base sheet (15b) of the blister package are each selected from the group comprising polymer layers, aluminum foils and fluoropolymer films, preferably made of various polymer materials. Inhaler (1) according to claim 19.   At least one of the layers constituting the lid sheet (15b) and the base sheet (15b) of the blister package is preferably silica gel, zeolite, alumina, bauxite, anhydrous calcium sulfate, activated carbon, and water-absorbing viscosity, Inhaler (1) according to claim 20, comprising at least one of a desiccant comprising   The inhaler according to claim 19, wherein the thickness of the aluminum foil contained in the lid sheet or the base sheet of the blister package is preferably in the range of 5 µm to 80 µm, more preferably in the range of 15 µm to 65 µm. (1).   The thickness of the polymer layer contained in the lid sheet (15b) or the base sheet (15c) of the blister package is preferably in the range of 5 μm to 100 μm, more preferably in the range of 15 μm to 60 μm. 21. The inhaler according to 20.   Drugs in the dry powder form include cromolyn, anti-infectives, antihistamines, steroids, anti-inflammatory drugs, bronchodilators, leukotriene inhibitors, PDE IV inhibitors, antitussives, diuretics, anticholinergics, hormones, 24. Suitable for delivery of a medicament in the form of the dry powder according to any one of claims 1 to 23, comprising at least one active agent selected from the group comprising xanthine and pharmaceutically acceptable combinations thereof. Inhaler (1).   25. An inhaler (1) suitable for delivery of a medicament in the form of a dry powder according to any one of the preceding claims, wherein the medicament in the form of a dry powder is used for monotherapy or combination therapy.   26. Suitable for delivery of a medicament in the form of the dry powder according to any one of claims 1-25, wherein the medicament comprises at least one excipient with one or more of the active agents contained therein. Inhaler (1).   The excipients contained in the dry powder drug include monosaccharides (glucose, arabinose, etc.), disaccharides (lactose, sucrose, maltose, etc.), oligosaccharides and polysaccharides (dextran, etc.), polyhydric alcohols (sorbite, man 27. An inhaler (1) suitable for delivery of a medicament in the dry powder form according to claim 26, which can be selected from the group comprising knit, xylitol), salt (sodium chloride, calcium carbonate, etc.), or combinations thereof.   Inhaler (1) suitable for delivery of a medicament in the form of the dry powder according to claim 26 or 27, wherein the excipient contained in the dry powder medicament is preferably lactose.

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