The present invention relates to an inhaler suitable for delivering medicament in dry powder form used in prophylaxis and treatment of respiratory diseases by the inhalation route.

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, some properties they hold and the physical form of the medicament to be delivered.

In the inhalers used to deliver medicament in dry powder form, the medicament is carried in reservoirs, capsules or blisters packages. It is highly significant to deliver sufficient amounts of the medicament to the patient since the amount of dry powder medicament that is to be delivered to the patient for each inhalation is very low. In the inhalers comprising a reservoir, one dose of dry powder medicament intake is enabled in each inhalation. In the inhalers comprising capsules, there is a metered dose of dry powder medicament in the capsule which is to be placed in the inhaler before each inhalation. In response to each actuation of the device, one capsule is pierced or opened by another method and the dry powder medicament contained in the capsule becomes ready for inhalation. In the inhalers comprising blister packs, at least one blister pocket is opened when the blister package is indexed and the dry powder medicament metered with high preciseness becomes ready for inhalation.

The inhalers in which the dry powder medicament is carried in blister packs or capsules can be multiple-dose or single-dose inhalers. The term "multiple-dose inhaler" refers to inhalers comprising more than one medicament dose. The term "single-dose inhaler", on the other hand, refers to inhalers comprising a single medicament dose.

The inhalers enabling the inhalation of dry powder medicament from capsules are commonly used. In general, one capsule is placed in the capsule chamber of the device before each inhalation in these devices; the capsule in the capsule chamber of the device is pierced, cut or opened by similar methods when the device is actuated, and the dry powder medicament contained in the capsule becomes ready for inhalation.

In the inhaler comprising a capsule, there exist piercing or cutting components which enable to pierce or cut the capsule placed in the capsule chamber before inhalation. Some pieces may be broken off the capsule when the capsule is pierced or cut by the piercing or cutting members in order to prepare the dry powder medicament for inhalation. Various sizes of pieces may be broken off the capsule depending on the shape and the size of the piercing or cutting members. In addition, there is a possibility that foreign objects enter the capsule chamber while the capsule is being placed. Inhalation of these pieces broken off the capsule and the foreign objects entering the capsule chamber together with dry powder medicament by the patient may result in dangerous consequences particularly in the respiratory tract of the patient.

Due to the moisture of the capsule and air, agglomerates occur in the dry powder formulation contained in the capsule during the storage and production. Besides preventing the problems mentioned above, it is necessary to break up the agglomerates occurred in the dry powder formulation during the inhalation of the dry powder formulation in the capsule that is pierced or cut by the piercing or cutting members of the inhaler. It is highly significant for sufficient amounts of the medicament with the uniform particle size distribution to be delivered to the patient and thus to provide an effective inhalation of the dry powder formulation in the capsule.

The inhaler marketed under the trade mark Spiriva® Handihaler® by Boehringer Ing. and Pfizer is among the inhalers on the market. Though this device is commonly used on the market, it remains incapable in eliminating the probability of the above mentioned problems.

In order to prevent the problems mentioned above, the inventor has designed a sieve which is suitable to be used in the inhaler comprising a capsule.

According to this, the inhaler comprising a capsule which is suitable for delivering medicament in dry powder form according to the present invention comprises a mouthpiece cover hiding the mouthpiece; a bottom casing where the device mechanism is situated; a movable mouthpiece which communicates with the bottom casing of the device; an air intake duct through which the air entraining the dry powder medicament passes and which is inserted into the mouthpiece; and a capsule chamber in which the capsule is placed. Said inhaler is characterized in that the number of pores per 1 mm ² of the sieve situated between the capsule chamber and the air intake duct is in the range of 0.1 to 8.

The fact that the number of pores per 1 mm ² of the sieve, namely per unit area, is in decimals means that the area of the pore is more than 1 mm ² . For instance, when the number of pores per 1 mm is 0.5, it means that one pore covers an area of two unit areas (2 mm ² ).

Furthermore, reduction in the number of the pores per area of 1 mm ² of the sieve means either increase in the size of the pores per 1 mm ² of the sieve or increase in the size of the area without pores per 1 mm of the sieve. Increase in the number of the pores per area of 1 mm of the sieve, on the other hand, means either decrease in the size of the pores in per 1 mm of the sieve or decrease in the size of the area without pores in per 1 mm of the sieve. In other words, as the number of the pores per 1 mm ² of the sieve is changed, the size of the pores per area of 1 mm of the sieve can change or remain the same.

It has been found that the other pieces inhaled together with the dry powder medicament by the patient do not lead to dangerous consequences in the patient in the case that the number of pores per 1 mm , namely per unit area, of the sieve used in the inhaler of the present invention is in the range of 0.1 to 8, for example in the range of 0.1, 0.2, 0.3, 0.4, 0.5, 0.7, 0.9, 1, 1.2, 1.4, 1.5 or 1.7 to 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8, preferably in the range of 0.5 to 5, for example, in the range of 0.5, 0.7, 0.9, 1, 1.2, 1.4, 1.5 or 2 to 3, 3.5, 4, 4.5 5, more preferably in the range of 1 to 3, for example in the range of 1, 1.2, 1.4, 1.5, 1.6 or 1.8 to 1.9, 2, 2.2, 2.3, 2.5, 2.7, 2.9 or 3. In addition, since the sieve between the capsule chamber and the air intake duct of the inhaler comprising a capsule according to the present invention is concave towards the capsule chamber, the movement distance, in which the capsule moves upwards and backwards during the inhalation, and the space of the chamber, through which the external air entering into the chamber circulates during the inhalation, causes a controlled and thus effective turbulence in the capsule chamber of the inhaler in order to break up the agglomerates occurred in the dry powder formulation; and also the pieces which are avoided to be inhaled with the dry powder medicament cannot block the pores of the sieve. Since the sieve is concave towards the capsule chamber, a bow is formed towards the capsule chamber. To this respect, the radius of the bow of the sieve towards the capsule chamber is in the range of 0.5 mm to 5 mm, for example 0.5 mm, 0.7 mm, 0.9 mm or 1 mm to 1.2 mm, 1.5 mm, 1.7 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm, preferably in the range of 0.5 mm to 3 mm, for example 0.5 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm or 1.2 mm to 1.4 mm, 1.5 mm, 1.7 mm, 1.9 mm, 2 mm, 2.2 mm, 2.4 mm, 2.6 mm, 2.8 mm or 3 mm, more preferable 0.5 mm to 2 mm, for example, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm or 1 mm to 1.2 mm, 1.4 mm, 1.6 mm, 1.8 mm, 2 mm. The bow of the sieve can be considered as an arc of a hypothetical circle. The term "radius of the bow of the sieve" means the radius of said hypothetical circle and thus the length of arc of this hypothetical circle is equal to the length of the bow of the sieve. The arc of this circle that represents the bow of sieve is preferably in the range of 30° to 150°, preferably in the range of 30° to 135°, most preferably in the range of 45° to 120°. Furthermore, since the wire constituting the porous structure of the sieve is preferably plastics and/or stainless steel, most preferably stainless steel, the wire remains durable against delaceration and disintegration which may result from the turbulence occurring in the capsule chamber, and this provides to realize reliable inhalation for long periods of time. In addition, diameter of the wire is in the range of 0.1 mm to 1 mm, preferably in the range of 0.1 mm to 0.5 mm, more preferably in the range of 0.1 mm to 0.25 mm.

Moreover, the wire constituting the porous structure of the sieve can be made of a material comprising antistatic substance or a material coated with antistatic substance in order to prevent adhesion of the medicament in dry powder form caused by the electrostatic forces.

Additionally, the pores of the sieve can be in any shape such as circular, square, rectangular, hexagonal, pentagon. The shapes of the pores of the sieve can be identical or different from each other. The shape of the pores of the sieve is preferably square. Also, said sieve can consist of at least one part.

The present invention relates to an inhaler which preferably comprises a pierceable capsule and provides inhalation of the dry powder medicament in the capsule opened upon the actuation of the device safely owing to said sieve it possesses. Said sieve in accordance with the present invention can be used in any inhalation device that is used for inhalation of the medicament from the capsule.

The inhaler of the present invention is composed of various constituents in order to provide inhalation of the dry powder medicament in preferably a pierceable capsule.

According to this, the basic constituents of the inhaler of the present invention are the mouthpiece cover, the bottom casing, the mouthpiece and the center cover. These four constituents are connected to each other by a pin and move around the same axis. The mouthpiece cover covers the mouthpiece and provides to keep it clean. Furthermore, the capsule cannot be placed in the device or the device cannot be actuated unless the mouthpiece cover is pulled upwards. Thus, it is necessary to open the mouthpiece cover, expose and move the mouthpiece so as to use the device.

The mouthpiece and the central cover are attached to each other and they synchronize. Thus, moving the mouthpiece, which is exposed when the mouthpiece cover is pulled upwards, outwardly around an axis enables the capsule chamber to get to an available position for placing the capsule. One capsule is placed in the capsule chamber and the mouthpiece is closed on the capsule chamber again. While the mouthpiece is closed on the capsule chamber again, the double-cogged rail under the mouthpiece triggers the piercing mechanism which consists of the cogged rod, the piercing member (needles), the spring and piercing member holder; and then the piercing member moves with the spring and the piercing member holder towards the capsule chamber to pierce the capsule to provide inhalation of the dry powder formulation in it. The piercing member can be moved towards the capsule chamber by the cogged rod owing to the spring it possesses. Therefore, the piercing member which synchronizes with the spring and piercing holder also moves towards the capsule chamber and pierce the capsule in the chamber. The dry powder medicament contained in the capsule becomes ready for inhalation after the capsule is pierced.

When the patient breathes in so as to inhale the dry powder medicament in the pierced capsule, the dry powder medicament reaches the patient by passing through the sieve placed between the air intake duct and the capsule chamber, and then the air intake duct respectively. The sieve between the capsule chamber and the air intake duct can be a separate component or attached to any other component of the device. The sieve between the capsule chamber and the air intake duct is preferably situated in the midpoint of the center cover, right on the capsule chamber, when the mouthpiece is closed. The sieve is fixed at the end of the air intake duct that is near to the capsule chamber. The air intake duct which is inserted into the mouthpiece, the sieve between the air intake duct and the capsule chamber where the capsule is situated are about the same axis with the midpoint of the center cover which is under the mouthpiece as attached to it. The mouthpiece is moved outwardly away from the capsule chamber after the dry powder medicament in the pierced capsule is inhaled by the patient. The discharged capsule in the capsule chamber which is exposed after the mouthpiece is moved away is taken off the chamber. The capsule chamber is suitably cleaned if necessary and the mouthpiece is closed on the capsule chamber again.

In order to remain stable, the mouthpiece is interlocked with the locking member in the bottom casing where the spring and the piercing member holder, the capsule chamber, the cogged rod, the spring, the cogged member are situated.

The inhalation device can be made of the same or different materials. According to this, each component of the inhaler can be made of a suitable material though it is preferably selected from a group comprising styrene-acrylonitrile, polyoxymethylene, acrylic polymethyl metacrylate, cellulose acetate, polyetheretherketone, polyvinyl chloride, polyethylene, polypropylene, acrylonitrile butadiene styrene, silicon, polycarbonate, polyamide, polystyrene, polyurethane or fluoropolymer types. Furthermore, each component of the device can be in any suitable color.

The capsule used in the inhaler comprising a capsule pertaining to the present invention can be made of any suitable substance though it is preferably made of a substance selected from the group comprising gelatin, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers and it is composed of intertwining top and bottom compartments. The top and the bottom compartments of the capsule can be made oT ^* identical or different materials.

According to this, in the case that the capsule used in the present invention is made of cellulose or its derivatives, the capsule material can be selected from, but not limited to, a group comprising hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose.

In the case that the capsule used in the present invention is synthetic polymer, the capsule material can be selected from, but not limited to, a group comprising polyethylene, polyetheleneteraphtalate, polycarbonate or polypropylene.

In the case that the capsule material used in the present invention is gelatine, additional agents such as polyethylene glycol, sorbitol, glycerol, propylene glycol, polyethylene oxide - polypropylene oxide block copolymers and/or other polyalcohols and poly ethers at different molecular weights can be added into it.

The volume of the capsule containing the dry powder medicament in the inhaler of the present invention is the range of 0.10 ml to 0.70 ml, preferably in the range of 0.10 ml to 0.52 ml and it is filled up to 0.01-30 %, preferably 0.01-25 % of said volume.

Moreover, the capsule pack containing the dry powder medicament and used in the inhaler of the present invention can be in any suitable shape and color on condition that it holds the specifications mentioned above.

The drawings given in the appendix in order to exemplify the present invention are explained with reference numbers below. The drawings aims to exemplify the invention, yet the invention cannot be limited to these drawings and descriptions.

Figure 1 is a front view of the inhaler of the present invention.

Figure 2 is an exploded view of the inhaler of the present invention.

Figure 3 is a perspective view of the sieve used in the inhaler of the present invention.

The preferred embodiment of the inhaler of the present invention is as in Figure 1 and Figure 2 in the appendix. The preferred embodiment of the sieve in the inhaler of the present invention is as in Figure 3 in the appendix.

The inhaler of the present invention illustrated in Figure 1 is in pre-use position. In pre-use position, only the mouthpiece cover (1) hiding the mouthpiece (3) and the bottom casing (2) where the mouthpiece (3) and the mechanism of the device are situated are visible. The mouthpiece cover (1) and the bottom casing (2) of the inhaler are connected to each other by a pin (12). The mouthpiece cover (1) covers the movable mouthpiece (3) component which is connected with the bottom casing (2) of the inhaler in pre-use position. Therefore, it enables to keep the mouthpiece (3) clean in pre-use position and carry it everywhere comfortably.

The communication of each component of the inhaler with each other can be clearly seen in the exploded view of the inhaler of the present invention in Figure 2. The mechanism of the inhaler is situated in the bottom casing (2) of the device. The constituents composing this mechanism are all the components that contribute to prepare the inhaler for inhalation and use it effectively in course of inhalation which are situated in the bottom casing (2) except for the mouthpiece (3).

The mouthpiece cover (1), the bottom casing (2), the mouthpiece (3) and the center cover (7) of the inhaler are connected to each other by a pin (12) and they all move around the same axis. The pin (12) enabling the mouthpiece cover (1), the bottom casing (2), the mouthpiece (3) and the center cover (7) to move together also provides the components to move around the same axis by passing through the pin hole (la, 2a, 3a, 7a) of each component. The center cover (7) is under the mouthpiece (3) of the device as attached to it. Thus, the center cover (7) synchronizes with the mouthpiece (3) of the device.

Before each inhalation, a capsule containing dry powder medicament has to be placed in the capsule chamber (13) of the inhaler illustrated in figure 2. To this end, the mouthpiece (3) which is exposed after the mouthpiece cover (1) is lifted is moved such that a capsule can be placed in the capsule chamber (13). Owing to this movement of the mouthpiece (3), the mouthpiece (3) is away from the bottom casing (2) and the capsule chamber (13) becomes available for placing a capsule.

After a capsule is placed in the capsule chamber (13), the mouthpiece (3) is moved back towards the bottom casing. Thus, both the bottom casing (2) and the capsule chamber (13) are covered. The dry powder medicament in the pierced capsule can comfortably and securely be inhaled in this position.

The double-cogged rail (4) which lies under the mouthpiece (3) while the mouthpiece (3) is moved towards the bottom casing after the capsule is placed in the capsule chamber (13) moves together with the mouthpiece and it enters into the bottom casing when the mouthpiece is completely closed. The cogged rod (11) that is in contact with the center cover (7) of the inhaler pushes the needle and spring holder (8) towards the capsule chamber when the piercing mechanism of the inhaler is triggered by the double-cogged rail (4). The needle and spring holder (8) comprises the needles (9) which provide to pierce the capsule in the capsule chamber (13) and a spring (10) which provides the needles to move towards or away from the capsule chamber (13). The needles pierce the capsule as the cogged rod (11) pushes the needle and spring holder (8) towards the capsule chamber (13). The dry powder medicament becomes ready for inhalation after the capsule is pierced.

There is one protrusion (11a; l ib) on both sides of the cogged rod (11) which enables the cogged rod (11) to connect with the center cover (7). These two protrusions (11a, 1 lb) fix into the holes (7c, 7d) on the ends of the extensions under the center cover (7) and establish a connection between the cogged rod (11) and the center cover (7). In addition, the bar (11c) which lies between the two sides of the cogged rod (11) fixes into the recess (8a) on the needle and spring holder. Thus, when the mouthpiece moves towards the bottom casing, the cogged rod (11) pushes the needle and spring holder (8) towards the capsule chamber (13). As the capsule and the spring holder (8) move towards the capsule chamber (13) owing to the spring it possesses, each needle (9) is ensured to pierce the capsule placed in the capsule chamber (13). The dry powder medicament contained in the capsule becomes ready for inhalation after the capsule is pierced.

When the mouthpiece (4) is moved towards the bottom casing (2) in order to provide the needles (9) to pierce the capsule after the capsule is placed in the capsule chamber (13), the piercing mechanism of the inhalation device is triggered and the needle and spring holder (8) is pushed towards the capsule chamber (13) to enable the needles to pierce the capsule

The sieve (6) used in the inhaler of the present invention is displayed in figure 3. The external air entering the capsule chamber (13) of the device upon the inhalation of the patient entrains the dry powder medicament contained in the capsule which is pierced by the needles of the spring holder (8) to the patient via the air intake duct (5) by passing the medicament through the sieve (6) between the capsule chamber (13) and the air intake duct (3) traversing the mouthpiece (3). As clearly displayed in figure 2, the air intake duct (5), the sieve (6) and the capsule chamber (13) are on the same axis with the center (7b) of the center cover.

Number of pores per 1 mm of the sieve (6), a preferred embodiment of which is illustrated in figure 3, is in the range of 0.1 to 8, preferably in the range of 0.5 to 5, more preferably in the range of 1 to 3. In addition, the number of pores per unit area (1 mm ² ) of the sieve shown in figure 3 is 2. The sieve (6) between the capsule chamber and the air intake duct can be separate or as attached to any other component of the device. The capsule chamber (13) and the air intake duct (5) are preferably situated in the midpoint (7b) of the center cover.

The fact that the number of pores per 1 mm of the sieve, namely per unit area, is in decimals means that the area of the pore is more than 1 mm . For instance, when the number of pores per 1 mm (6a) is 0.5, it means that one pore (6a) covers an area of two unit areas (2 mm ² ).

Furthermore, the sieve (6) used in the inhaler is preferably concave towards the capsule chamber (13). As the sieve (6) is concave, the pieces which are avoided to be inhaled with the dry powder medicament cannot block the pores of the sieve (6), therefore it cannot prevent the inhalation of the dry powder medicament. To this respect, the radius of the bow of the sieve towards the capsule chamber is in the range of 0.5 mm to 5 mm, preferably in the range of 0.5 mm to 3 mm. Furthermore, the wire (6b) constituting the porous structure of said sieve (6) can be made of any material though it is preferably plastics and/or stainless steel. Since the wire (6b) constituting the porous structure of said sieve (6) is plastics and/or stainless steel, the wire (6b) remains durable against delaceration and disintegration which may result from the turbulence occurring in the capsule chamber (13), and this provides to realize reliable inhalation for long periods of time. In addition, diameter of the wire (6b) is in the range of 0.1 mm to 1 mm, preferably in the range of 0.1 mm to 0.5 mm, more preferably in the range of 0.1 to 0.25 mm.

The capsule containing the dry powder medicament in the inhaler of the present invention illustrated in figure 1 and figure 2 is produced according to the prior art. According to the present invention, the particle size of the active agents contained in the capsule is less than 20 μπι, preferably less than 10 μπι.

The inhaler of 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 used.

The dry powder medicament delivered via the device of 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 capsules 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, rofiumilast, 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 of the present invention is used in the administration of the medicament in dry powder form which is utilized in the treatment of many respiratory diseases, particularly in asthma, chronic obstructive pulmonary disease (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.