Patent Publication Number: US-2016243320-A1

Title: Dry powder inhaler

Description:
This application claims priority from U.S. Provisional Application No. 61/887,589, filed Oct. 7, 2013, and from U.S. Provisional Application No. 61/888,301, filed Oct. 8, 2013. The disclosures of each of these applications are incorporated herein by reference in their entirety for all purposes. 
    
    
     The present invention relates to a dry powder inhaler, and particularly to a dry powder inhaler containing a combination of fluticasone and salmeterol. 
     Fluticasone propionate is a corticosteroid indicated for the treatment of asthma and allergic rhinitis. It is also used to treat eosinophilic esophagitis. It is named as S-(fluoromethyl)-6α,9-difluoro-11β,17-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioate-17-propanoate and has the following structure: 
     
       
         
         
             
             
         
       
     
     Salmeterol is a long-acting β 2 -adrenergic receptor agonist that is indicated for the treatment of asthma and chronic obstructive pulmonary disease (COPD). It is named as (RS)-2-(hydroxymethyl)-4-{1-hydroxy-2-[6-(4-phenylbutoxy) hexylamino]ethyl}phenol and has the following structure: 
     
       
         
         
             
             
         
       
     
     Salmeterol is typically administered as the xinafoate salt, the structure of which is well-known in the art. 
     The combination of salmeterol (as the xinafoate salt) and fluticasone propionate is marketed in the EU by Allen &amp; Hanburys as Seretide®, using either the Evohaler® pressurised metered-dose inhaler (pMDI) or the Accuhaler® dry powder inhaler (DPI). The Accuhaler® uses blisters filled with a blend of the micronised active agents and lactose monohydrate. It is marketed in three dosage strengths, each providing 50 micrograms of salmeterol xinafoate and 100, 250 or 500 micrograms of fluticasone propionate. The delivered doses are lower. In the US, the product is called Advair® and the inhaler is called Diskus®. 
     Seretide is indicated in the regular treatment of asthma where use of a combination product (long-acting β 2 -agonist and inhaled corticosteroid) is appropriate. This is where either: patients are not adequately controlled with inhaled corticosteroids and as needed inhaled short acting β 2 -agonist; or patients are already adequately controlled on both inhaled corticosteroid and long-acting β 2 -agonist. 
     Seretide is also indicated for the symptomatic treatment of patients with COPD, with a FEV 1 &lt;60% predicted normal (pre-bronchodilator) and a history of repeated exacerbations, who have significant symptoms despite regular bronchodilator therapy. FEV 1  is a measurement used in spirometry which means the forced expiratory volume in one second. This is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. The measurement of FEV 1  is used by healthcare professionals to determine lung function. 
     Combination products are well established in the art and are known to improve patient convenience and compliance. A drawback of combination products are that control over the dose of the individual active ingredients is reduced. For the inhaled corticosteroid, this is not a serious concern because the therapeutic window of inhaled corticosteroids is wide. That is, it is difficult for a patient to exceed the recommended daily intake of inhaled corticosteroid. However, the β 2 -agonist is more of a concern since the therapeutic window is narrower and β 2 -agonists are associated with serious adverse effects, including cardiac side-effects. 
     Thus, there is a requirement in the art for an improved fluticasone/salmeterol combination product which retains the therapeutic effect of both products, but which reduces the adverse effects associated with the salmeterol. 
     Accordingly, the present invention provides a dry powder inhaler comprising: a dry powder medicament comprising fluticasone propionate, salmeterol xinafoate and a lactose carrier; wherein, the delivered dose of salmeterol per actuation is less than 50 μg; and wherein the dose provides a baseline-adjusted FEV 1  in a patient of more than 150 mL within 30 minutes of receiving the dose. 
     The present invention also provides a method for the treatment of asthma, allergic rhinitis, or COPD comprising administering to a patient a dry powder medicament according to any embodiment described herein. In one embodiment, the dry powder medicament comprises fluticasone propionate, salmeterol xinafoate and a lactose carrier; wherein, the delivered dose of salmeterol per actuation is less than 50 μg; and wherein the dose provides a baseline-adjusted FEV 1  in a patient of more than 150 mL within 30 minutes of receiving the dose. The method of treatment may use any inhaler, including any inhaler as described herein. In one embodiment, the method of treatment provides a dose of salmeterol that is less than 25 μg. In other embodiments, the method of treatment provides doses of fluticasone/salmeterol in μg that are 500/12.5, 400/12.5, 250/12.5, 200/12.5, 100/12.5, 50/12.5 or 25/12.5 per actuation. 
     The present invention also provides a method of measuring a delivered dose of active agent by an inhaler comprising:inserting the inhaler into a mouthpiece adapter; actuating the inhaler to provide a delivered dose through the mouthpiece adapter and into a dosage unit sampling apparatus; rinsing the mouthpiece adapter with a solvent and into the dosage unit sampling apparatus; dissolving the delivered dose in the dosage unit sampling apparatus; filtering the dissolved delivered dose to provide a filtered solution; and analyzing the filtered solution to determine the amount of the active agent in the delivered dose. The method of measuring may be carried out at the beginning, the middle and the end of the life of the inhaler. 
     Several types of dry powder inhaler are known in the art. In a preferred embodiment of the present invention, the dry powder inhaler comprises the following features. 
     The preferred inhaler includes a delivery passageway for directing an inhalation-induced air flow through a mouthpiece, a channel extending from the delivery passageway to the medicament, and more preferably a mouthpiece for patient inhalation, a delivery passageway for directing an inhalation-induced air flow through the mouthpiece, a channel extending from the delivery passageway, and a reservoir for containing medicament, with the reservoir having a dispenser port connected to the channel. In a preferred form, the dose metering system includes a cup received in the channel, which is movable between the dispenser port and the delivery passageway, a cup spring biasing the cup towards one of the dispenser port and the passageway, and a yoke movable between at least two positions. The yoke includes a ratchet engaging the cup and preventing movement of the cup when the yoke is in one of the positions, and allowing movement of the cup when the yoke is in another of the positions. 
     The inhaler preferably includes a cyclone deagglomerator for breaking up agglomerates of the active ingredients and carrier. This occurs prior to inhalation of the powder by a patient. The deagglomerator includes an inner wall defining a swirl chamber extending along an axis from a first end to a second end, a dry powder supply port, an inlet port, and an outlet port. 
     The supply port is in the first end of the swirl chamber for providing fluid communication between a dry powder delivery passageway of the inhaler and the first end of the swirl chamber. The inlet port is in the inner wall of the swirl chamber adjacent to the first end of the swirl chamber and provides fluid communication between a region exterior to the deagglomerator and the swirl chamber. The outlet port provides fluid communication between the second end of the swirl chamber and a region exterior to the deagglomerator. 
     A breath induced low pressure at the outlet port causes air flows into the swirl chamber through the dry powder supply port and the inlet port. The air flows collide with each other and with the wall of the swirl chamber prior to exiting through the outlet port, such that the active is detached from the carrier (lactose). The deagglomerator further includes vanes at the first end of the swirl chamber for creating additional collisions and impacts of entrained powder. 
     A first breath-actuated air flow is directed for entraining a dry powder from an inhaler into a first end of a chamber extending longitudinally between the first end and a second end, the first air flow directed in a longitudinal direction. 
     A second breath-actuated airflow is directed in a substantially transverse direction into the first end of the chamber such that the air flows collide and substantially combine. 
     Then, a portion of the combined air flows is deflected in a substantially longitudinal direction towards a second end of the chamber, and a remaining portion of the combined air flows is directed in a spiral path towards the second end of the chamber. All the combined air flows and any dry powder entrained therein are then delivered from the second end of the chamber to a patient&#39;s mouth. 
     The deagglomerator ensures that particles of the actives are small enough for adequate penetration of the powder into a bronchial region of a patient&#39;s lungs during inhalation by the patient. 
     Thus, in an embodiment of the present invention, the deagglomerator comprises: an inner wall defining a swirl chamber extending along an axis from a first end to a second end; a dry powder supply port in the first end of the swirl chamber for providing fluid communication between a dry powder delivery passageway of the inhaler and the first end of the swirl chamber; at least one inlet port in the inner wall of the swirl chamber adjacent to the first end of the swirl chamber providing fluid communication between a region exterior to the deagglomerator and the first end of the swirl chamber; an outlet port providing fluid communication between the second end of the swirl chamber and a region exterior to the deagglomerator; and vanes at the first end of the swirl chamber extending at least in part radially outwardly from the axis of the chamber, each of the vanes having an oblique surface facing at least in part in a direction transverse to the axis; whereby a breath induced low pressure at the outlet port causes air flows into the swirl chamber through the dry powder supply port and the inlet port. 
     The inhaler preferably has a reservoir for containing the medicament and an arrangement for delivering a metered dose of the medicament from the reservoir. The reservoir is typically a pressure system. The inhaler preferably includes: a sealed reservoir including a dispensing port; a channel communicating with the dispensing port and including a pressure relief port; a conduit providing fluid communication between an interior of the sealed reservoir and the pressure relief port of the channel; and a cup assembly movably received in the channel and including, a recess adapted to receive medicament when aligned with the dispensing port, a first sealing surface adapted to seal the dispensing port when the recess is unaligned with the dispensing port, and a second sealing surface adapted to sealing the pressure relief port when the recess is aligned with the dispensing port and unseal the pressure relief port when the recess is unaligned with the dispensing port. 
     The inhaler preferably has a dose counter. The inhaler includes a mouthpiece for patient inhalation, a dose-metering arrangement including a pawl movable along a predetermined path during the metering of a dose of medicament to the mouthpiece by the dose-metering arrangement, and a dose counter. 
     In a preferred form, the dose counter includes a bobbin, a rotatable spool, and a rolled ribbon received on the bobbin, rotatable about an axis of the bobbin. The ribbon has indicia thereon successively extending between a first end of the ribbon secured to the spool and a second end of the ribbon positioned on the bobbin. The dose counter also includes teeth extending radially outwardly from the spool into the predetermined path of the pawl so that the spool is rotated by the pawl and the ribbon advanced onto the spool during the metering of a dose to the mouthpiece. 
     The preferred inhaler includes a simple, accurate and consistent mechanical dose metering system that dispenses dry powdered medicament in discrete amounts or doses for patient inhalation, a reservoir pressure system that ensures consistently dispensed doses, and a dose counter indicating the number of doses remaining in the inhaler. 
    
    
     
       The present invention will now be described with reference to the drawings, in which: 
         FIG. 1  is a first side isometric view of a dry powder inhaler according to a preferred embodiment; 
         FIG. 2  is an exploded, second side isometric view of the inhaler of  FIG. 1 ; 
         FIG. 3  is a second side isometric view of a main assembly of the inhaler of  FIG. 1 ; 
         FIG. 4  is a second side isometric view of the main assembly of the inhaler of  FIG. 1 , shown with a yoke removed; 
         FIG. 5  is an exploded first side isometric view of the main assembly of the inhaler of  FIG. 1 ; 
         FIG. 6  is an exploded enlarged isometric view of a medicament cup of the inhaler of  FIG. 1 ; 
         FIG. 7  is an exploded first side isometric view of a hopper and a deagglomerator of the inhaler of  FIG. 1 ; 
         FIG. 8  is an exploded second side isometric view of the hopper and a swirl chamber roof of the deagglomerator of the inhaler of  FIG. 1 ; 
         FIG. 9  is an exploded first side isometric view of a case, cams and a mouthpiece cover of the inhaler of  FIG. 1 ; 
         FIG. 10  is an enlarged side isometric view of one of the cams of the inhaler of  FIG. 1 ; 
         FIG. 11  is a second side isometric view of the yoke of the inhaler of  FIG. 1 ; 
         FIG. 12  is a first side isometric view of the yoke of the inhaler of  FIG. 1 , showing a ratchet and a push bar of the yoke; 
         FIG. 13  is a schematic illustration of lateral movement of a boss of the medicament cup in response to longitudinal movement of the ratchet and the push bar of the yoke of the inhaler of  FIG. 1 ; 
         FIG. 14  is an enlarged isometric view of a dose counter of the inhaler of  FIG. 1 ; 
         FIG. 15  is an exploded enlarged isometric view of the dose counter of the inhaler of  FIG. 1 ; and 
         FIG. 16  is an enlarged isometric view, partially in section, of a portion of the inhaler of  FIG. 1  illustrating medicament inhalation through the inhaler. 
         FIG. 17  is an exploded isometric view of a deagglomerator according to the present disclosure; 
         FIG. 18  is a side elevation view of the deagglomerator of  FIG. 17 ; 
         FIG. 19  is a top plan view of the deagglomerator of  FIG. 17 ; 
         FIG. 20  is a bottom plan view of the deagglomerator of  FIG. 17 ; 
         FIG. 21  is a sectional view of the deagglomerator of  FIG. 17  taken along line  5 ′- 5 ′ of  FIG. 18 ; 
         FIG. 22  is a sectional view of the deagglomerator of  FIG. 17  taken along line  6 ′- 6 ′ of  FIG. 19 ; and 
         FIG. 23  shows a comparison between FS Spiromax® (invention) and FS Advair® (comparison). 
     
    
    
     The inhaler  10  generally includes a housing  18 , and an assembly  12  received in the housing (see  FIG. 2 ). The housing  18  includes a case  20  having an open end  22  and a mouthpiece  24  for patient inhalation, a cap  26  secured to and closing the open end  22  of the case  20 , and a cover  28  pivotally mounted to the case  20  for covering the mouthpiece  24  (see  FIGS. 1, 2 and 9 ). The housing  18  is preferably manufactured from a plastic such as polypropylene, acetal or moulded polystyrene, but may be manufactured from metal or another suitable material. 
     The internal assembly  12  includes a reservoir  14  for containing dry powered medicament in bulk form, a deagglomerator  10 ′ that breaks down the medicament between a delivery passageway  34  and the mouthpiece  24 , and a spacer  38  connecting the reservoir to the deagglomerator. 
     The reservoir  14  is generally made up of a collapsible bellows  40  and a hopper  42  having an dispenser port  44  (see  FIGS. 2-5 and 7-8 ) for dispensing medicament upon the bellows  40  being at least partially collapsed to reduce the internal volume of the reservoir. 
     The hopper  42  is for holding the dry powder medicament in bulk form and has an open end  46  closed by the flexible accordion-like bellows  40  in a substantially air-tight manner. 
     An air filter  48  covers the open end  46  of the hopper  42  and prevents dry powder medicament from leaking from the hopper  42  (see  FIG. 7 ). 
     A base  50  of the hopper  42  is secured to a spacer  38 , which is in turn secured to the deagglomerator  10 ′ (see  FIGS. 3-5 and 7-8 ). The hopper  42 , the spacer  38 , and the deagglomerator  10 ′ are preferably manufactured from a plastic such as polypropylene, acetal or moulded polystyrene, but may be manufactured from metal or another suitable material. 
     The hopper  42 , the spacer  38  and the deagglomerator  10 ′ are connected in a manner that provides an air tight seal between the parts. For this purpose heat or cold sealing, laser welding or ultrasonic welding could be used, for example. 
     The spacer  38  and the hopper  42  together define the medicament delivery passageway  34 , which preferably includes a venturi  36  (see  FIG. 16 ) for creating an entraining air flow. The spacer  38  defines a slide channel  52  communicating with the dispenser port  44  of the hopper  42 , and a chimney.  54  providing fluid communication between the medicament delivery passageway  34  and a supply port  22 ′ of the deagglomerator  10 ′ (see  FIGS. 7  and  8 ). The slide channel  52  extends generally normal with respect to the axis “A” of the inhaler  10 . 
     The deagglomerator  10 ′ breaks down agglomerates of dry powder medicament before the dry powder leaves the inhaler  10  through the mouthpiece  24 . 
     Referring to  FIGS. 17 to 22 , the deagglomerator  10 ′ breaks down agglomerates of medicament, or medicament and carrier, before inhalation of the medicament by a patient. In general, the deagglomerator  10 ′ includes an inner wall  12 ′ defining a swirl chamber  14 ′ extending along an axis A′ from a first end  18 ′ to a second end  20 ′. The swirl chamber  14 ′ includes circular cross-sectional areas arranged transverse to the axis A′, that decrease from the first end  18 ′ to the second end  20 ′ of the swirl chamber  14 ′, such that any air flow traveling from the first end of the swirl chamber to the second end will be constricted and at least in part collide with the inner wall  12 ′ of the chamber. 
     Preferably, the cross-sectional areas of the swirl chamber  14 ′ decrease monotonically. In addition, the inner wall  12 ′ is preferably convex, i.e., arches inwardly towards the axis A′, as shown best in  FIG. 22 . 
     As shown in  FIGS. 17, 19 and 22 , the deagglomerator  10 ′ also includes a dry powder supply port  22 ′ in the first end  18 ′ of the swirl chamber  14 ′ for providing fluid communication between a dry powder delivery passageway of an inhaler and the first end  18 ′ of the swirl chamber  14 ′. Preferably, the dry powder supply port  22 ′ faces in a direction substantially parallel with the axis A′ such that an air flow, illustrated by arrow  1 ′ in  FIG. 22 , entering the chamber  14 ′ through the supply port  22 ′ is at least initially directed parallel with respect to the axis A′ of the chamber. 
     Referring to  FIGS. 17 to 22 , the deagglomerator  10 ′ additionally includes at least one inlet port  24 ′ in the inner wall  12 ′ of the swirl chamber  14 ′ adjacent to or near the first end  18 ′ of the chamber providing fluid communication between a region exterior to the deagglomerator and the first end  18 ′ of the swirl chamber  14 ′. Preferably, the at least one inlet port comprises two diametrically opposed inlet ports  24 ′,  25 ′ that extend in a direction substantially transverse to the axis A′ and substantially tangential to the circular cross-section of the swirl chamber  14 ′. As a result, air flows, illustrated by arrows  2 ′ and  3 ′ in  FIGS. 17 and 21 , entering the chamber  14 ′ through the inlet ports are at least initially directed transverse with respect to the axis A′ of the chamber and collide with the air flow  1 ′ entering through the supply port  22 ′ to create turbulence. The combined air flows, illustrated by arrow  4 ′ in  FIGS. 21 and 22 , then collide with the inner wall  12 ′ of the chamber  14 ′, form a vortex, and create additional turbulence as they move towards the second end  20 ′ of the chamber. 
     Referring to  FIGS. 17-19 and 22 , the deagglomerator  10 ′ includes vanes  26 ′ at the first end  18 ′ of the swirl chamber  14 ′ extending at least in part radially outwardly from the axis A′ of the chamber. Each of the vanes  26 ′ has an oblique surface  28 ′ facing at least in part in a direction transverse to the axis A′ of the chamber. The vanes  26 ′ are sized such that at least a portion  4 A′ of the combined air flows  4 ′ collide with the oblique surfaces  28 ′, as shown in  FIG. 22 . Preferably, the vanes comprise four vanes  26 ′, each extending between a hub  30 ′ aligned with the axis A′ and the wall  12 ′ of the swirl chamber  14 ′. 
     As shown in  FIGS. 17 to 22 , the deagglomerator  10 ′ further includes an outlet port  32 ′ providing fluid communication between the second end  20 ′ of the swirl chamber  14 ′ and a region exterior to the deagglomerator. A breath induced low pressure at the outlet port  32 ′ causes the air flow  1 ′ through the supply port  22 ′ and the air flows  2 ′, 3 ′ through the inlet ports and draws the combined air flow  4 ′ through the swirl chamber  14 ′. The combined air flow  4 ′ then exits the deagglomerator through the outlet port  32 ′. Preferably the outlet port  32 ′ extends substantially transverse to the axis A′, such that the air flow  4 ′ will collide with an inner wall of the outlet port  32 ′ and create further turbulence. 
     During use of the deagglomerator  10 ′ in combination with the inhaler, patient inhalation at the outlet port  32 ′ causes air flows  1 ′, 2 ′, 3 ′ to enter through, respectively, the dry powder supply port  22 ′ and the inlet ports. Although not shown, the air flow  1 ′ through the supply port  22 ′ entrains the dry powder into the swirl chamber  14 ′. The air flow  1 ′ and entrained dry powder are directed by the supply port  22 ′ into the chamber in a longitudinal direction, while the air flows  2 ′, 3 ′ from the inlet ports are directed in a transverse direction, such that the air flows collide and substantially combine. 
     A portion of the combined air flow  4 ′ and the entrained dry powder then collide with the oblique surfaces  28 ′ of the vanes  26 ′ causing particles and any agglomerates of the dry powder to impact against the oblique surfaces and collide with each other. The geometry of the swirl chamber  14 ′ causes the combined air flow  4 ′ and the entrained dry powder to follow a turbulent, spiral path, or vortex, through the chamber. As will be appreciated, the decreasing cross-sections of the swirl chamber  14 ′ continuously changes the direction and increases the velocity of the spiralling combined air flow  4 ′ and entrained dry powder. Thus, particles and any agglomerates of the dry powder constantly impact against the wall  12 ′ of the swirl chamber  14 ′ and collide with each other, resulting in a mutual grinding or shattering action between the particles and agglomerates. In addition, particles and agglomerates deflected off the oblique surfaces  28 ′ of the vanes  26 ′ cause further impacts and collisions. 
     Upon exiting the swirl chamber  14 ′, the direction of the combined air flow  4  and the entrained dry powder is again changed to a transverse direction with respect to the axis A′, through the outlet port  32 ′. The combined air flow  4 ′ and the entrained dry powder retain a swirl component of the flow, such that the air flow  4 ′ and the entrained dry powder spirally swirls through the outlet port  32 ′. The swirling flow causes additional impacts in the outlet port  32 ′ so as to result in further breaking up of any remaining agglomerates prior to being inhaled by a patient. 
     As shown in  FIGS. 17 to 22 , the deagglomerator is preferably assembly from two pieces: a cup-like base  40 ′ and a cover  42 ′. The base  40 ′ and the cover  42 ′ are connected to form the swirl chamber  14 ′. The cup-like base  40 ′ includes the wall  12 ′ and the second end  20 ′ of the chamber and defines the outlet port  32 ′. The base  40 ′ also includes the inlet ports of the swirl chamber  14 ′. The cover  42 ′ forms the vanes  26 ′ and defines the supply port  22 ′. 
     The base  40 ′ and the cover  42 ′ of the deagglomerator are preferably manufactured from a plastic such as polypropylene, acetal or moulded polystyrene, but may be manufactured from metal or another suitable material. Preferably, the cover  42 ′ includes an anti-static additive, so that dry powder will not cling to the vanes  26 ′. The base  40 ′ and the cover  42 ′ are then connected in a manner that provides an air tight seal between the parts. For this purpose heat or cold sealing, laser welding or ultra-sonic welding could be used, for example. 
     Although the inhaler  10  is shown with a particular deagglomerator  10 ′, the inhaler  10  is not limited to use with the deagglomerator shown and can be used with other types of deagglomerators or a simple swirl chamber. 
     The dose metering system includes a first yoke  66  and a second yoke  68  mounted on the internal assembly  12  within the housing  18 , and movable in a linear direction parallel with an axis “A” of the inhaler  10  (see  FIG. 2 ). An actuation spring  69  is positioned between the cap  26  of the housing  18  and the first yoke  66  for biasing the yokes in a first direction towards the mouthpiece  24 . In particular, the actuation spring  69  biases the first yoke  66  against the bellows  40  and the second yoke  68  against cams  70  mounted on the mouthpiece cover  28  (see  FIG. 9 ). 
     The first yoke  66  includes an opening  72  that receives and retains a crown  74  of the bellows  40  such that the first yoke  66  pulls and expands the bellows  40  when moved towards the cap  26 , i.e., against the actuation spring  69  (see  FIG. 2 ). The second yoke  68  includes a belt  76 , which receives the first yoke  66 , and two cam followers  78  extending from the belt in a direction opposite the first yoke  66  (see  FIGS. 3, 11 and 12 ), towards the cams  70  of the mouthpiece cover  28  ( FIGS. 9,10 ). 
     The dose metering system also includes the two cams  70  mounted on the mouthpiece cover  28  (see  FIGS. 9 and 10 ), and movable with the cover  28  between open and closed positions. The cams  70  each include an opening  80  for allowing outwardly extending hinges  82  of the case  20  to pass therethrough and be received in first recesses  84  of the cover  28 . The cams  70  also include bosses  86  extending outwardly and received in second recesses  88  of the cover  28 , such that the cover  28  pivots about the hinges  82  and the cams  70  move with the cover  28  about the hinges. 
     Each cam  70  also includes first, second and third cam surfaces  90 , 92 , 94 , and the cam followers  78  of the second yoke  68  are biased against the cam surfaces by the actuation spring  69 . The cam surfaces  90 , 92 , 94  are arranged such the cam followers  78  successively engage the first cam surfaces  90  when the cover  28  is closed, the second cam surfaces  92  when the cover  28  is partially opened, and the third cam surfaces  94  when the cover  28  is fully opened. The first cam surfaces  90  are spaced further from the hinges  82  than the second and the third cam surfaces, while the second cam surfaces  92  are spaced further from the hinges  82  than the third cam surfaces  94 . The cams  70 , therefore, allow the yokes  66 , 68  to be moved by the actuation spring  69  parallel with the axis “A” of the inhaler  10  in the first direction (towards the mouthpiece  24 ) through first, second and third positions as the cover  28  is opened. The cams  70  also push the yokes  66 ,  68  in a second direction parallel with the axis “A” (against the actuation spring  69  and towards the cap  26  of the housing  18 ) through the third, the second and the first positions as the cover  28  is closed. 
     The dose metering system further includes a cup assembly  96  movable between the dispenser port  44  of the reservoir  14  and the delivery passageway  34 . The cup assembly  96  includes a medicament cup  98  mounted in a sled  100  slidably received in the slide channel  52  of the spacer  38  below the hopper  42  (see  FIGS. 5 and 6 ). The medicament cup  98  includes a recess  102  adapted to receive medicament from the dispenser port  44  of the reservoir  14  and sized to hold a predetermined dose of dry powdered medicament when filled. The cup sled  100  is biased along the slide channel  52  from the dispenser port  44  of the hopper  42  towards the delivery passageway  34  by a cup spring  104 , which is secured on the hopper  42  (see  FIGS. 4 and 5 ). 
     The dose metering system also includes a ratchet  106  and a push bar  108  on one of the cam followers  78  of the second yoke  68  that engage a boss  110  of the cup sled  100  (see  FIGS. 5,11 and 12 ). The ratchet  106  is mounted on a flexible flap  112  and is shaped to allow the boss  110  of the sled  100  to depress and pass over the ratchet  106 , when the boss  110  is engaged by the push bar  108 . Operation of the dose metering system is discussed below. 
     The reservoir pressure system includes a pressure relief conduit  114  in fluid communication with the interior of the reservoir  14  (see  FIGS. 7 and 8 ), and a pressure relief port  116  in a wall of the slide channel  52  (see  FIGS. 5 and 8 ) providing fluid communication with the pressure relief conduit  114  of the hopper  42 . 
     The medicament cup assembly  96  includes a first sealing surface  118  adapted to seal the dispenser port  44  upon the cup assembly being moved to the delivery passageway  34  (see  FIGS. 5 and 6 ). A sealing spring  120  is provided between the sled  100  and the cup  98  for biasing the medicament cup  98  against a bottom surface of the hopper  42  to seal the dispenser port  44  of the reservoir  14 . The cup  98  includes clips  122  that allow the cup to be biased against the reservoir, yet retain the cup in the sled  100 . 
     The sled  100  includes a second sealing surface  124  adapted to seal the pressure relief port  116  when the recess  102  of the cup  98  is aligned with the dispenser port  44 , and an indentation  126  (see  FIG. 6 ) adapted to unseal the pressure relief port  116  when the first sealing surface  118  is aligned with the dispenser port  44 . Operation of the pressure system is discussed below. 
     The dose counting system  16  is mounted to the hopper  42  and includes a ribbon  128 , having successive numbers or other suitable indicia printed thereon, in alignment with a transparent window  130  provided in the housing  18  (see  FIG. 2 ). The dose counting system  16  includes a rotatable bobbin  132 , an indexing spool  134  rotatable in a single direction, and the ribbon  128  rolled and received on the bobbin  132  and having a first end  127  secured to the spool  134 , wherein the ribbon  128  unrolls from the bobbin  132  so that the indicia is successively displayed as the spool  134  is rotated or advanced. 
     The spool  134  is arranged to rotate upon movement of the yokes  66 , 68  to effect delivery of a dose of medicament from the reservoir  14  into the delivery passageway  34 , such that the number on the ribbon  128  is advanced to indicate that another dose has been dispensed by the inhaler  10 . The ribbon  128  can be arranged such that the numbers, or other suitable indicia, increase or decrease upon rotation of the spool  134 . For example, the ribbon  128  can be arranged such that the numbers, or other suitable indicia, decrease upon rotation of the spool  134  to indicate the number of doses remaining in the inhaler  10 . 
     Alternatively, the ribbon  128  can be arranged such that the numbers, or other suitable indicia, increase upon rotation of the spool  134  to indicate the number of doses dispensed by the inhaler  10 . 
     The indexing spool  134  preferably includes radially extending teeth  136 , which are engaged by a pawl  138  extending from one of the cam followers  78  (see  FIGS. 3 and 11 ) of the second yoke  68  upon movement of the yoke to rotate, or advance, the indexing spool  134 . More particularly, the pawl  138  is shaped and arranged such that it engages the teeth  136  and advances the indexing spool  134  only upon the mouthpiece  24  cover  28  being closed and the yokes  66 , 68  moved back towards the cap  26  of the housing  18 . 
     The dose counting system  16  also includes a chassis  140  that secures the dose counting system to the hopper  42  and includes shafts  142 , 144  for receiving the bobbin  132  and the indexing spool  134 . The bobbin shaft  142  is preferably forked and includes radially nubs  146  for creating a resilient resistance to rotation of the bobbin  132  on the shaft  142 . A clutch spring  148  is received on the end of the indexing spool  134  and locked to the chassis  140  to allow rotation of the spool  134  in only a single direction (anticlockwise as shown in  FIG. 14 ). Operation of the dose counting system  16  is discussed below. 
       FIG. 13  illustrates the relative movements of the boss  110  of the cup sled  100 , and the ratchet  106  and the push bar  108  of the second yoke  68  as the mouthpiece cover  28  is opened and closed. In the first position of the yokes  66 , 68  (wherein the cover  28  is closed and the cam followers  78  are in contact with the first cam surfaces  90  of the cams  70 ), the ratchet  106  prevents the cup spring  104  from moving the cup sled  100  to the delivery passageway  34 . The dose metering system is arranged such that when the yokes are in the first position, the recess  102  of the medicament cup  98  is directly aligned with the dispenser port  44  of the reservoir  14  and the pressure relief port  116  of the spacer  38  is sealed by the second sealing surface  124  of the cup sled  100 . 
     Upon the cover  28  being partially opened such that the second cam surfaces  92  of the cams  70  engage the cam followers  78 , the actuator spring  69  is allowed to move the yokes  66 , 68  linearly towards the mouthpiece  24  to the second position and partially collapse the bellows  40  of the medicament reservoir  14 . The partially collapsed bellows  40  pressurizes the interior of the reservoir  14  and ensures medicament dispensed from the dispenser port  44  of the reservoir fills the recess  102  of the medicament cup  98  such that a predetermined dose is provided. In the second position, however, the ratchet  106  prevents the cup sled  100  from being moved to the delivery passageway  34 , such that the recess  102  of the medicament cup  98  remains aligned with the dispenser port  44  of the reservoir  14  and the pressure relief port  116  of the spacer  38  remains sealed by the second sealing surface  124  of the cup assembly  96 . 
     Upon the cover  28  being fully opened such that the third cam surfaces  94  engage the cam followers  78 , the actuator spring  69  is allowed to move the yokes  66 , 68  further towards the mouthpiece  24  to the third position. When moved to the third position, the ratchet  106  disengages, or falls below the boss  110  of the cup sled  100  and allows the cup sled  100  to be moved by the cup spring  104 , such that the filled recess  102  of the cup  98  is position in the venturi  36  of the delivery passageway  34  and the dispenser port  44  of the reservoir  14  is sealed by the first sealing surface  118  of the cup assembly  96 . In addition, the pressure relief port  116  is uncovered by the indentation  126  in the side surface of the sled  100  to release pressure from the reservoir  14  and allow the bellows  40  to further collapse and accommodate the movement of the yokes  66 , 68  to the third position. The inhaler  10  is then ready for inhalation by a patient of the dose of medicament placed in the delivery passageway  34 . 
     As shown in  FIG. 16 , a breath-induced air stream  4 ′ diverted through the delivery passageway  34  passes through the venturi  36 , entrains the medicament and carries the medicament into the deagglomerator  10 ′ of the inhaler  10 . Two other breath-induced air streams  2 ′,  3 ′ (only one shown) enter the deagglomerator  10 ′ through the diametrically opposed inlet ports  24 ′,  25 ′ and combine with the medicament entrained air stream  150  from the delivery passageway  34 . The combined flows  4 ′ and entrained dry powder medicament then travel to the outlet port  32 ′ of the deagglomerator and pass through the mouthpiece  24  for patient inhalation. 
     Once inhalation is completed, the mouthpiece cover  28  can be closed. When the cover  28  is closed, the trigger cams  70  force the yokes  66 , 68  upwardly such that the first yoke  66  expands the bellows  40 , and the pawl  138  of the second yoke  68  advances the indexing spool  134  of the dose counting system  16  to provide a visual indication of a dose having been dispensed. In addition, the cup assembly  96  is forced back to the first position by the pusher bar  108  of the upwardly moving second yoke  68  (see  FIG. 13 ) such that the boss  110  of the cup sled  100  is engaged and retained by the ratchet  106  of the second yoke  68 . 
     The medicament used in the inhaler of the present invention comprises a mixture of micronised fluticasone propionate, micronised salmeterol xinafoate and a lactose carrier. Micronising may be performed by any suitable technique known in the art, e.g., jet milling. 
     The medicament contains fluticasone propionate. It is preferable that substantially all of the particles of fluticasone propionate are less than 10 μm in size. This is to ensure that the particles are effectively entrained in the air stream and deposited in the lower lung, which is the site of action. Preferably, the particle size distribution of the fluticasone propionate is: d10=0.4-1.1 μm, d50=1.1-3.0 μm, d90=2.6-7.5 μm and NLT95%&lt;10 μm; more preferably d10=0.5-1.0 μm, d50=1.8-2.6 μm, d90=3.0-6.5 μm and NLT99%&lt;10 μm; and most preferably d10=0.5-1.0 μm, d50=1.90-2.50 μm, d90=3.5-6.5 μm and NLT99%&lt;10 μm. 
     The particle size of the fluticasone propionate may be measured by laser diffraction as an aqueous dispersion, e.g., using a Malvern Mastersizer 2000 instrument. In particular, the technique is wet dispersion. The equipment is set with the following optical parameters: Refractive index for fluticasone propionate=1.530, Refractive index for dispersant water=1.330, Absorption=3.0 and Obscuration=10-30%. The sample suspension is prepared by mixing approximately 50 mg sample with 10 ml of de-ionized water containing 1% Tween® 80 in a 25 ml glass vessel. The suspension is stirred with a magnetic stirrer for 2 mins at moderate speed. The Hydro 2000S dispersion unit tank is filled with about 150 ml de-ionized water. The de-ionized water is sonicated by setting the ultrasonics at the level of 100% for 30 seconds and then the ultrasonic is turned back down to 0%. The pump/stirrer in the dispersion unit tank is turned to 3500 rpm and then down to zero to clear any bubbles. About 0.3 ml of 1% TA-10X FG defoamer is added into the dispersion media and the pump/stirrer is turned to 2000 rpm and then the background is measured. Slowly the prepared suspension samples are dropped into the dispersion unit until a stabilized initial obscuration at 10-20% is reached. The sample is continued to be stirred in the dispersion unit for about 1 min at 2000 rpm, then the ultrasound is turned on and the level is set to 100%. After sonicating for 5 min with both the pump and ultrasound on, the sample is measured three times. The procedure is repeated two more times. 
     The delivered dose of fluticasone propionate is preferably 25-500 μg per actuation. 
     The medicament contains salmeterol xinafoate. It is preferable that substantially all of the particles of salmeterol xinafoate are less than 10 μm in size. This is to ensure that the particles are effectively entrained in the air stream and deposited in the lower lung, which is the site of action. Preferably, the particle size distribution of the salmeterol xinafoate is: d10=0.4-1.3 μm, d50=1.4-3.0 μm, d90=2.4-6.5 μm and NLT95%&lt;10 μm; more preferably d10=0.6-1.1 μm, d50=1.75-2.65 μm, d90=2.7-5.5 μm and NLT99%&lt;10 μm; most preferably d10=0.7-1.0 μm, d50=2.0-2.4 μm, d90=3.9-5.0 μm and NLT99%&lt;10 μm. 
     The particle size of the salmeterol xinafoate may be measured using the same methodology as described for fluticasone propionate. In particular, the technique is wet dispersion. The equipment is set with the following optical parameters: Refractive index for salmeterol xinafoate=1.500, Refractive index for dispersant water=1.330, Absorption=0.1 and Obscuration=10-30%. The sample suspension is prepared by mixing approximately 50 mg sample with 10 ml of de-ionized water containing 1% Tween® 80 in a 25 ml glass vessel. The suspension is stirred with a magnetic stirrer for 2 mins at moderate speed. The Hydro 2000S dispersion unit tank is filled with about 150 ml de-ionized water. The de-ionized water is sonicated by setting the ultrasonics at the level of 100% for 30 seconds and then the ultrasonic is turned back down to 0%. The pump/stirrer in the dispersion unit tank is turned to to 3500 rpm and then down to zero to clear any bubbles. About 0.3 ml of 1% TA-10X FG defoamer is added into the dispersion media and the pump/stirrer is turned to 2250 rpm and then the background is measured. The prepared suspension samples are slowly dropped into the dispersion unit until a stabilized initial obscuration at 15-20% is reached. The sample is continued to be stirred in the dispersion unit for about 1 min at 2250 rpm, then the ultrasound is turned on and the level is set to 100%. After sonicating for 3 min with both the pump and ultrasound on, the sample is measured three times. The procedure is repeated two more times. 
     The delivered dose of salmeterol xinafoate (as base) is less than 50 μg per actuation, more preferably less than 40 μg per actuation, more preferably less than 30 μg per actuation, more preferably less than 25 μg per actuation and most preferably less than 15 μg per actuation, based on the amount salmeterol present (i.e. the amount is calculated without including contribution to the mass of the counterion). 
     Particularly preferred delivered doses of fluticasone/salmeterol in μg are 500/12.5, 400/12.5, 250/12.5, 200/12.5, 100/12.5, 50/12.5 or 25/12.5. 
     The inhaler of the present invention administers a delivered dose of fluticasone/salmeterol which provides a baseline-adjusted FEV 1  in a patient of more than 150 mL within 30 minutes of receiving the dose. The baseline-adjusted FEV 1  preferably remains above 150 mL for at least 6 hours after receiving the dose. 
     The delivered dose of the active agent is measured as per the USP &lt;601&gt;, using the following method. A vacuum pump (MSP HCP-5) is connected to a regulator (Copley TPK 2000), which is used for adjusting the required drop pressure P 1  in a DUSA sampling tube (Dosage Unit Sampling Apparatus, Copley). The inhaler is inserted into a mouthpiece adaptor, ensuring an airtight seal. P 1  is adjusted to a pressure drop of 4.0 KPa (3.95 -4.04 KPa) for the purposes of sample testing. After actuation of the inhaler, the DUSA is removed and the filter paper pushed inside with the help of a transfer pipette. Using a known amount of solvent (acetonitrile:methanol:water (40:40:20)), the mouthpiece adaptor is rinsed into the DUSA. The DUSA is shaken to dissolve fully the sample. A portion of the sample solution is transferred into a 5 mL syringe fitted with Acrodisc PSF 0.45 μm filter. The first few drops from the filter are discarded and the filtered solution is transferred into a UPLC vial. A standard UPLC technique is then used to determine the amount of active agent delivered into the DUSA. The delivered doses of the inhaler are collected at the beginning, middle and end of inhaler life on three different days. 
     It is preferable that substantially all of the particles of lactose are less than 300 μm in size. It is preferable that the lactose carrier includes a portion of fine material, that is, lactose particles of less than 10 μm in size. The fine lactose fraction may be present in an amount of 1-10 wt %, more preferably 2.5-7.5 wt %, based on the total amount of lactose. Preferably, the particle size distribution of the lactose fraction is d10=15-50 μm, d50=80-120 μm, d90=120-200 μm, NLT99%&lt;300 μm and 1.5-8.5%&lt;10 μm. Most preferably, the particle size distribution of the lactose fraction is d10=25-40 μm, d50=87-107 μm, d90=140-180 μm, NLT99%&lt;300 μm and 2.5-7.5%&lt;10 μm. The lactose is preferably α-lactose monohydrate (e.g., from DMV Fronterra Excipients). 
     The particle size distribution of the lactose provided herein is measured by laser diffraction in air, e.g., with a Sympatec HELOS/BF equipped with a RODOS dispenser and VIBRI feeder unit. In particular, lens type R5: 05/4.5 . . . 875 μm is used; The following information is set on the equipment: density=1.5500 g/cm 3 , shape factor=1.00, calculation mode=HRLD, forced stability=0; The following trigger conditions are set: Name=CH12, 0.2%, reference duration=10 s (single), time base=100 ms, focus prior to first measurement=Yes, normal measurement=standard mode, start=0.000 s, channel 12 0.2%, valid=always, stop after=5.000 s, channel 12≦0.2%, or after=60.000 s, real time, repeat measurement=0, repeat focus=No; The following disperser conditions are set: Name 1.5 bar; 85%; 2.5 mm, dispersing type=RODOS/M, injector=4 mm, with=0 cascade elements, primary pressure=1.5 bar, always auto adjust before ref. meas.=No, feeder type=VIBRI, feed rate=85%, gap width=2.5 mm, funnel rotation=0%, cleaning time=10 s, use VIBRI Control=No, vacuum extraction type=Nilfisk, delay=5 s. An adequate amount of approximate 5 g of the sample is transferred into a weighing paper using a clean dry stainless steel spatula, and then poured into the funnel on the VIBRI chute. The sample is measured. The pressure is maintained at about 1.4-1.6 bar, measurement time=1.0-10.0 seconds, C opt =5-15% and vaccum≦7 mbar. The procedure is repeated two more times. 
     The inhaler described herein is provided for the treatment of asthma or COPD. 
     EXAMPLES 
     Example 1 
     Dry powder formulations were prepared by combining the following ingredients:
         fluticasone propionate having a particle size of d10=0.5-0.9 μm, d50=1.5-2.4 μm, d90=3.3-6.0 μm, and NLT99%&lt;10 μm.   salmeterol xinafoate having a particle size of d10=0.6-1.1 μm, d50=1.75-2.65 μm, d90=2.7-5.5 μm, and NLT99%&lt;10 μm.   α-lactose monohydrate (DMV Fronterra Excipients) having a particle size of d10=25-40 μm, d50=87-107 μm, d90=140-180 μm, NLT99%&lt;300 μm and 3-9%&lt;10 μm,       

     Formulations were provided having delivered doses of fluticasone propionate/salmeterol xinafoate of 100/6.25, 100/12.5, 100/25 and 100/50 mcg. 
     Example 2 
     A six-period crossover, dose-ranging study was performed to evaluate the efficacy and safety of four doses of FS Spiromax® (fluticasone propionate/salmeterol xinafoate inhalation powder) administered as single doses compared with single doses of fluticasone propionate Spiromax® and open label Advair® Diskus® in adult and adolescent subjects with persistent asthma. 
     Fluticasone propionate/salmeterol xinafoate Spiromax® was manufactured by Teva Pharmaceuticals. The specifications were as set out in Example 1. Doses tested were fluticasone propionate/salmeterol xinafoate 100/6.25, 100/12.5, 100/25, and 100/50 mcg. Advair® Diskus® was manufactured by GlaxoSmithKline and is a commercially available product. The label claim emitted dose of fluticasone propionate/salmeterol xinafoate of Advair® Diskus® was 100/50 mcg which is equivalent to delivered dose of 93/45 mcg. 
     Assessments were performed using forced expiratory volume in 1 second (FEV 1 ) measurements. The study included a run-in period is to complete baseline safety evaluations and to obtain baseline measures of asthma status, including baseline FEV 1  measurements. 
     It was found that the product of the present invention provided comparable efficacy (as determined by FEV 1  measurements) despite having an approximately four-fold lower dose of salmeterol xinafoate than that of the commercially available product. This substantial reduction in dose was surprising and suggests a synergistic relationship between the components tested which could not have been predicted in advance. These results were also not found during in vitro testing. The results are shown graphically in  FIG. 23 . 
       FIG. 23  compares FS Spiromax® at a delivered dose of 100/12.5 mcg (curve labelled “100/12.5”) and Advair® at a dose of 100/50 mcg (curve labelled “100/50”). The two curves are surprisingly close given the approximately four-fold lower dose of salmeterol in the product of the present invention.