Patent Publication Number: US-11642475-B2

Title: Dry powder inhaler

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation of U.S. patent application Ser. No. 15/101,689, filed Jun. 3, 2016, which is the U.S. National Stage of International Application No. PCT/EP2014/075043, filed Nov. 19, 2014, which claims the benefit of Great Britain application number 1321712.0, filed Dec. 9, 2013. The disclosures of each of the aforementioned applications is incorporated herein by reference in its entirety. 
    
    
     The present invention relates to a dry powder inhaler, and particularly to a dry powder inhaler containing a combination of budesonide and formoterol. 
     Budesonide is a corticosteroid indicated for the treatment of asthma and COPD. Formoterol is a long-acting β 2 -adrenergic receptor agonist that is also indicated for the treatment of asthma and COPD. Formoterol is typically administered as the fumarate salt. 
     Combination therapy with budesonide and formoterol fumarate (“BF”) is commonly used to treat asthma and COPD. The active ingredients may be administered separately or in a fixed dose combination. The usual approaches for formulating inhalable medicaments are using a dry powder inhaler (DPI), pressurised metered dose inhaler (pMDI) or nebuliser. 
     In the case of DPIs, it is important to balance the flow properties of the dry powder within the inhaler and the plume characteristics on inhalation. Coarse carrier particles, usually lactose, are used to aid the flow properties of the medicament, but it is important to ensure that the active ingredients separate from the coarse carrier on inhalation so that the fine particles of the active ingredients are entrained into the lungs. To provide an appropriate dose over the lifetime of the inhaler, it is important that this process occurs in a consistent manner. That is, inhalation devices must demonstrate a consistent delivered dose and fine particle mass from the first to the last dose. The EU Pharmacopeia compendial procedure specifies that 9 out of 10 DPI doses are within ±25% of the specified dose and that outliers should be within ±35% (Preparations for inhalation 01/2012:671 in the European Pharmacopoeia, 8th Edition. Council of Europe, 2013). 
     Thus, there is a requirement in the art for a BF DPI which provides a consistent delivered dose and fine particle mass over the lifetime of the inhaler. 
     Accordingly, the present invention provides a budesonide/formoterol dry powder inhaler comprising: 
     a reservoir containing a dry powder medicament and an arrangement for delivering a metered dose of the medicament from the reservoir; 
     a cyclone deagglomerator for breaking up agglomerates of the dry powder medicament; 
     a delivery passageway for directing an inhalation-induced air flow through a mouthpiece, the delivery passageway extending to the metered dose of medicament, 
     wherein the medicament comprises micronised formoterol fumarate, micronised budesonide and a lactose carrier, the lactose carrier having a particle size distribution of d10=20-65 μm, d50=80-120 μm, d90=130-180 μm and &lt;10 μm=&lt;10%. 
    
    
     
       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   ; 
         FIG.  23    shows the delivered dose (DD) of budesonide by low, middle and high strength BF Spiromax inhalers at BOL, MOL and EOL of each device (error bars represent standard deviation and data are presented as percentage of the labeled dose); 
         FIG.  24    shows the delivered dose (DD) of formoterol by low, middle and high strength BF Spiromax inhalers at BOL, MOL and EOL of each device (error bars represent standard deviation and data are presented as percentage of the labeled dose); and 
         FIG.  25    shows doses delivered by BF Spiromax: low strength inhaler (simulation schemes A &amp; B), high strength inhaler (simulation schemes C &amp; D and middle strength inhaler (simulation scheme E), with data presented as percentage of the labeled dose. 
     
    
    
     The inhaler of the present invention includes: a reservoir containing a dry powder medicament and an arrangement for delivering a metered dose of the medicament from the reservoir; a cyclone deagglomerator for breaking up agglomerates of the dry powder medicament; a delivery passageway for directing an inhalation-induced air flow through a mouthpiece, extending to the metered dose of medicament. 
     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 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 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. 
     With reference to the drawings, 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 substantial 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 assembled 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 radial 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 . 
     A suitable inhaler for working the present invention is the Spiromax® DPI available from Teva Pharmaceuticals. 
     The medicament used in the inhaler of the present invention comprises a mixture of micronised budesonide, micronised formoterol fumarate and a lactose carrier. Micronising may be performed by any suitable technique known in the art, e.g. jet milling. 
     The medicament contains budesonide. It is preferable that substantially all of the particles of budesonide 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 budesonide is d10&lt;1 μm, d50=&lt;5 μm, d90=&lt;10 μm and NLT 99%&lt;10 μm; more preferably, the particle size distribution of the budesonide is d10&lt;1 μm, d50=1-3 μm, d90=3-6 μm and NLT 99%&lt;10 μm. 
     The delivered dose of budesonide (the amount actually delivered to the patient) is preferably 50-500 μg per actuation, with specific examples being 80, 160 and 320 μg per actuation. The inhaler of the present invention provides a delivered dose uniformity for budesonide of ±15%. 
     The medicament also contains formoterol fumarate. It is preferable that substantially all of the particles of formoterol fumarate are less than 10 μm in size. This is also 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 formoterol fumarate is d10&lt;1 μm, d50=&lt;5 μm, d90=&lt;10 μm and NLT 99%&lt;10 μm; more preferably, the particle size distribution of the formoterol fumarate is d10&lt;1 μm, d50=1-3 μm, d90=3.5-6 μm and NLT 99%&lt;10 μm. 
     The delivered dose of formoterol fumarate (the “labeled” quantity), as base, is preferably 1-20 μg per actuation, with specific examples being 4.5 and 9 μg per actuation. The doses are based on the amount of formoterol present (i.e. the amount is calculated without including contribution to the mass of the counterion). The inhaler of the present invention provides a delivered dose uniformity for formoterol of ±15%. 
     Particularly preferred delivered doses of budesonide/formoterol in μg are 80/4.5, 160/4.5 and 320/9. 
     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 typically on three different days. 
     The lactose carrier has a particle size distribution of d10=20-65 μm, d50=80-120 μm, d90=130-180 μm and &lt;10 μm=&lt;10%. Preferably, the particle size distribution of the lactose is d10=20-65 μm, d50=80-120 μm, d90=130-180 μm and &lt;10 μm=&lt;6%. The lactose is preferably lactose monohydrate (for example, α-lactose monohydrate) and may be prepared by standard techniques, e.g. sieving. 
     The present inventors have shown that the combination of the device features, particularly the active metering from a reservoir and the cyclone chamber, and the particle size distribution of the lactose combine to provide a surprisingly uniform delivered dose. The present invention provides surprisingly improved uniform delivered dose over previously available inhaler and formulation combinations. This contributes to more consistent and reliable treatment of patients. Further surprisingly, the inhaler of the present invention has been shown to provide uniform delivered dose across a number of different flow rates. Thus, the uniform delivered dose may be obtained regardless of flow rate and thus regardless of disease severity in the patient using the device. 
     Indeed, a problem solved by the present invention is the need to provide consistent and reliable delivery of budesonide/formoterol to a patient in need thereof across a range of different flow rates. Generally, the more severe the patient&#39;s respiratory disease the lower the flow rate they are able to produce on inhalation. Poor delivered dose uniformity provided by prior art inhaler/formulation combination may lead to missed or inadequate dosage. This is a particular problem when the inhaler is used as a rescue or as needed medicament but is also a problem when used as a daily medicament. 
     Yet further, the inventors have shown that the present invention surprisingly provides uniform delivered dose independent of device orientation. Thus, the inhaler is effective at providing adequate dosing whether the patient is standing, sitting or lying down, for example. 
     The present invention also provides the inhaler of any aspect and embodiment of the invention for use in treating a respiratory disease. In particular, the respiratory disease may be asthma or chronic obstructive pulmonary disease (COPD). 
     In any aspect of the invention, it is envisaged that the asthma may be any severity of asthma, for example the asthma may be mild, mild to moderate, moderate, moderate to severe, or severe asthma. Such asthma may be classified as GINA stage 1, 2, 3 or 4 according to the Global Initiative for Asthma (GINA) guidelines, as would be understood by a person of skill in the art. 
     The particle size distributions of the active ingredients and lactose provided herein may be measured by laser diffraction as a dry dispersion, e.g. in air, such as with a Sympatec HELOS/BF equipped with a RODOS disperser. 
     The present invention also provides a pharmaceutical composition for inhalation, wherein the composition comprises micronised formoterol fumarate, micronised budesonide and a lactose carrier, the lactose carrier having a particle size distribution of d10=20-65 μm, d50=80-120 μm, d90=130-180 μm and &lt;10 μm=&lt;10%. The particle size distribution of the lactose may be d10=20-65 μm, d50=80-120 μm, d90=130-180 μm and &lt;10 μm=&lt;6%. The particle size of the budesonide may be d10&lt;1 μm, d50=&lt;5 μm, d90=&lt;10 μm and NLT 99%&lt;10 μm. The particle size of the formoterol fumarate may be d10&lt;1 μm, d50=&lt;5 μm, d90=&lt;10 μm and NLT 99%&lt;10 μm. 
     The invention also includes the pharmaceutical composition according to the preceding aspect for use in treating a respiratory disease, such as asthma or COPD. 
     The present invention will now be described with reference to the examples, which are not intended to be limiting. 
     EXAMPLES 
     Example 1 
     Three formulations of Budesonide/Formoterol (BF) Spiromax (Teva Pharmaceuticals) were prepared: low strength (120 inhalations, each delivering 80 μg budesonide and 4.5 μg formoterol), middle strength (120 inhalations, 160 μg budesonide and 4.5 μg formoterol per inhalation), and high strength (60 inhalations, 320 μg budesonide and 9 μg formoterol per inhalation). Two studies were performed: the first was a laboratory study designed to measure the uniformity of delivered dose (UDD) throughout the lifetime of the BF Spiromax inhaler (as an indication of dose consistency) from the first dose until the last labeled dose. The second study investigated the dose consistency (as UDD) of BF Spiromax under conditions simulating real-world inhaler handling and dosing regimens. 
     The compositions of the three strengths of BF Spiromax per container are set out in Tables 1-3. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Composition per container of BF Spiromax 80/4.5 μg 120 inhalation product 
               
            
           
           
               
               
               
               
            
               
                 Material 
                 Weight 
                 Function 
                 Quality Standard 
               
               
                   
               
               
                 Budesonide (micronised) 
                  12.0 mg 
                 Drug 
                 Ph. Eur. 
               
               
                   
                   
                 substance 
                   
               
               
                 Formoterol fumarate dihydrate 
                 0.645 mg 
                 Drug 
                 Ph. Eur. 
               
               
                 (micronised) 
                   
                 substance 
                   
               
               
                 Lactose monohydrate 
                 1.487 g 
                 Excipient 
                 Ph. Eur. 
               
               
                 Target fill weight per device 
                 1.500 g 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Composition per Container of BF Spiromax 160/4.5 μg 120 inhalation product 
               
            
           
           
               
               
               
               
            
               
                 Material 
                 Weight 
                 Function 
                 Quality Standard 
               
               
                   
               
               
                 Budesonide (micronised) 
                  31.6 mg 
                 Drug 
                 Ph. Eur. 
               
               
                   
                   
                 substance 
                   
               
               
                 Formoterol fumarate dihydrate 
                 0.914 mg 
                 Drug 
                 Ph. Eur. 
               
               
                 (micronised) 
                   
                 substance 
                   
               
               
                 Lactose monohydrate 
                 0.838 g 
                 Excipient 
                 Ph. Eur. 
               
               
                 Target fill weight per device 
                 0.870 g 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Composition per Container of BF Spiromax 320/9 μg 60 inhalation product 
               
            
           
           
               
               
               
               
            
               
                 Material 
                 Weight 
                 Function 
                 Quality Standard 
               
               
                   
               
               
                 Budesonide (micronised) 
                  28.7 mg 
                 Drug 
                 Ph. Eur. 
               
               
                   
                   
                 substance 
                   
               
               
                 Formoterol fumarate dihydrate 
                 0.870 mg 
                 Drug 
                 Ph. Eur. 
               
               
                 (micronised) 
                   
                 substance 
                   
               
               
                 Lactose monohydrate 
                 0.840 g 
                 Excipient 
                 Ph. Eur. 
               
               
                 Target fill weight per device 
                 0.870 g 
               
               
                   
               
            
           
         
       
     
     Study 1, UDD Over Product Lifetime 
     BF Spiromax devices were used according to the information for patients with respect to storage, orientation, and minimum dosing interval. Three different BF Spiromax inhalers were investigated: low strength; middle strength; and high strength. The devices were not cleaned throughout their lifetime (from beginning of life (“BOL”) to end of life (“EOL”)). Inhalers were selected from three batches of low strength BF Spiromax (n=42), three batches of the middle strength product (n=42) and three batches of high strength BF Spiromax (n=42). 
     To assess UDD over the device lifetime a fixed flow rate of 62.5 L/min, representing a 4 KPa pressure drop over the device (Q) was applied to achieve an inhalation volume of 4 L. Ten doses from different stages of the BF Spiromax lifetime were collected separately using a dose uniformity sampling apparatus (DUSA). Three doses were collected from the first discharges of the device (BOL), four doses were taken midway through the inhaler lifetime (middle of life (“MOL”)) and three doses from the end of the inhaler&#39;s lifetime including the last labeled dose (EOL). After 4 L of air had been drawn through the device, the collected doses of budesonide and formoterol were recovered and analysed using validated high performance liquid chromatography (HPLC). 
     Study 2, Real-World Simulations 
     Real-world conditions were simulated by analysts carrying inhalers with them during working day hours, dispensing doses according to specified schemes and cleaning the inhaler mouthpiece weekly with a dry cloth in accordance with the patient leaflet. Five different simulation schemes were designed to test inhalers up to their last labeled doses, as summarised in Table 4. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Study simulation schemes 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Inhaler 
                   
                   
                 Number of 
                 UDD 
               
               
                 Scheme 
                 Strength 
                 Dosing Regimen 
                 Duration 
                 Inhalers 
                 Assessments 
               
               
                   
               
               
                 A 
                 Low 
                 One inhalation 
                 72 days 
                 6 (3 from  
                 Day 1-2  
               
               
                   
                   
                 twice daily 
                   
                 each of 
                 (3 doses) 
               
               
                   
                   
                   
                   
                 2 batches) 
                 Day 36-37  
               
               
                   
                   
                   
                   
                   
                 (4 doses) 
               
               
                   
                   
                   
                   
                   
                 Day 71-72  
               
               
                   
                   
                   
                   
                   
                 (3 doses) 
               
               
                 B 
                 Low 
                 Four inhalations 
                 21 days 
                 6 (3 from  
                 Day 1  
               
               
                   
                   
                 twice daily 
                   
                 each of 
                 (3 doses) 
               
               
                   
                   
                   
                   
                 2 batches) 
                 Day 10  
               
               
                   
                   
                   
                   
                   
                 (4 doses) 
               
               
                   
                   
                   
                   
                   
                 Day 21  
               
               
                   
                   
                   
                   
                   
                 (3 doses) 
               
               
                 C 
                 High 
                 One inhalation 
                 32 days 
                 6 (3 from  
                 Day 1-4  
               
               
                   
                   
                 twice daily 
                   
                 each of 
                 (3 doses) 
               
               
                   
                   
                   
                   
                 2 batches) 
                 Day 15-18  
               
               
                   
                   
                   
                   
                   
                 (4 doses) 
               
               
                   
                   
                   
                   
                   
                 Day 29-32  
               
               
                   
                   
                   
                   
                   
                 (3 doses) 
               
               
                 D 
                 High 
                 Two inhalations 
                 16 days 
                 6 (3 from  
                 Day 1  
               
               
                   
                   
                 twice daily 
                   
                 each of 
                 (3 doses) 
               
               
                   
                   
                   
                   
                 2 batches) 
                 Day 8  
               
               
                   
                   
                   
                   
                   
                 (4 doses) 
               
               
                   
                   
                   
                   
                   
                 Day 15-16  
               
               
                   
                   
                   
                   
                   
                 (3 doses) 
               
               
                 E 
                 Middle 
                 One inhalation 
                 90 days 
                 9 (3 from  
                 Day 1-2  
               
               
                   
                   
                 twice daily 
                   
                 each of 
                 (3 doses) 
               
               
                   
                   
                   
                   
                 3 batches) 
                 Day 45-48  
               
               
                   
                   
                   
                   
                   
                 (4 doses) 
               
               
                   
                   
                   
                   
                   
                 Day 87-90  
               
               
                   
                   
                   
                   
                   
                 (3 doses) 
               
               
                   
               
            
           
         
       
     
     Within each scheme, inhaler doses were collected for UDD analysis. For UDD assessments, doses were collected into a DUSA at a pressure drop of 4 KPa over the device. After 4 L of air were drawn through the device, collected drug substances were recovered and analysed using a validated HPLC. Results obtained from the same inhaler batches under laboratory conditions (25° C., 60% relative humidity) over a single day were used for comparison. 
     Results for Study 1, UDD Over Product Lifetime 
     The BF Spiromax devices delivered consistent doses of budesonide and formoterol throughout their lifetime ( FIGS.  23  and  24   ). Importantly, mean doses for the lifetime of each formulation were similar to the labeled doses (Table 5). Although there was a trend for BOL doses to be slightly lower than MOL and EOL, all doses were within ±15% of the labeled quantity (low strength doses ranged between 90.7 and 108.0% of the labeled dose for budesonide and 87.6-101.1% for formoterol. Middle strength ranges were 92.4-108.5% and 94.8-109.9%. High strength ranges were 92.7-104.8% and 96.8-110.2%). 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Delivered doses of budesonide and formoterol: device lifetime mean, calculated for each 
               
               
                 formulation (three doses at beginning of life, four doses at middle of life and three doses at end of 
               
               
                 life). Standard deviations are shown in parentheses. 
               
            
           
           
               
               
               
               
            
               
                   
                 Low Strength 
                 Middle Strength 
                 High Strength 
               
               
                   
               
               
                 Budesonide, μg 
                  82 (5) 
                  163 (9) 
                  317 (12) 
               
               
                 Formoterol, μg 
                 4.3 (0.3) 
                  4.7 (0.3) 
                  9.4 (0.4) 
               
               
                   
               
            
           
         
       
     
     Results for Study 2, Real-World Simulations 
     UDD data for budesonide and formoterol under ‘real-world’ conditions (expressed as delivered dose [% of labeled dose]) across simulation schemes A-E are shown in  FIG.  25   . For all three inhaler strengths, delivered doses were consistent throughout the lifetime. There was no difference in UDD data between single-inhalation/day and multiple-inhalation/day regimens ( FIG.  25   ). 
     Example 2 
     Certain patients, such as children, adolescents and adults with COPD, tend to have lower peak inspiratory flow rates. It is therefore important for a device/formulation to provide a UDD over a range of flow rates. In this example, the flow rates of 40, 60 and 90 L/min were employed to represent the minimum, median and maximum flow rates achievable by all patients through the Spiromax device. Delivered dose uniformity and fine particle mass of BF Spiromax were investigated over this clinically relevant flow rate range. 
     The study was conducted on three batches of the low and middle strength products, containing 120 doses and of the high strength product, containing 60 doses. Three inhalers were tested for each batch at each flow rate. Ten delivered doses, three at the beginning, for in the middle and three at end of the inhaler life were collected from each inhaler separately into a dose unit sampling apparatus using 4 L air volume at the selected flow rate per the standard UDD procedure. Two APSD determinations were conducted on the inhaler used for UDD test, one at the beginning and another at the end of the inhaler life. Therefore, the mean delivered dose was calculated from a total of 30 delivered dose results and the mean FPD was calculated from a total of six sets of data (i.e. two NGIs per inhaler) for each batch tested at each flow rate. 
     The mean delivered dose and relative standard deviation (RSD) per batch and flow rate are presented in Tables 6-8 for low, middle and high strength BF Spiromax products, respectively. Typically, lower delivered doses are obtained at the test flow rate of 40 L/min and higher delivered doses at the test flow rate of 90 L/min. On all occasions the mean delivered dose (n=30 doses) per batch per test is well within 85-115% of the label claim for low, middle and high strength BF Spiromax products, respectively. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Mean delivered dose (DD) and RSD results obtained at different flow  
               
               
                 rates for the low strength product (n = 30) 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Budesonide 
                 Formoterol 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 Mean 
                   
                 Mean 
                   
               
               
                 Batch 
                 Flow rate 
                 DD (μg) 
                 RSD (%) 
                 DD (μg) 
                 RSD (%) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 MD0001 
                 40 L/min 
                 76.2 
                 7.0 
                 4.0 
                 6.9 
               
               
                   
                 60 L/min 
                 81.3 
                 6.5 
                 4.2 
                 6.7 
               
               
                   
                 90 L/min 
                 86.4 
                 3.5 
                 4.6 
                 5.1 
               
               
                 MD0002 
                 40 L/min 
                 78.4 
                 9.5 
                 4.0 
                 8.1 
               
               
                   
                 60 L/min 
                 83.6 
                 7.1 
                 4.3 
                 7.1 
               
               
                   
                 90 L/min 
                 87.2 
                 5.6 
                 4.7 
                 7.1 
               
               
                 MD0003 
                 40 L/min 
                 75.0 
                 7.1 
                 3.8 
                 6.5 
               
               
                   
                 60 L/min 
                 80.3 
                 6.3 
                 4.2 
                 5.5 
               
               
                   
                 90 L/min 
                 83.6 
                 3.8 
                 4.5 
                 4.7 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Mean DD and RSD results obtained at different flow rates for the middle strength product  
               
               
                 (n = 30) 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Budesonide 
                 Formoterol 
               
            
           
           
               
               
               
               
               
               
            
               
                 Batch 
                 Flow rate 
                 Mean DD (μg) 
                 RSD (%) 
                 Mean DD (μg) 
                 RSD (%) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 MD8001 
                 40 L/min 
                 147.4 
                 11.0 
                 4.1 
                 13.8 
               
               
                   
                 60 L/min 
                 155.7 
                 6.9 
                 4.4 
                 7.5 
               
               
                   
                 90 L/min 
                 175.2 
                 6.0 
                 5.1 
                 7.7 
               
               
                 MD8002 
                 40 L/min 
                 157.8 
                 8.0 
                 4.3 
                 7.9 
               
               
                   
                 60 L/min 
                 157.7 
                 8.2 
                 4.4 
                 7.8 
               
               
                   
                 90 L/min 
                 171.3 
                 3.9 
                 4.9 
                 5.5 
               
               
                 MD8003 
                 40 L/min 
                 148.2 
                 10.1 
                 4.1 
                 12.3 
               
               
                   
                 60 L/min 
                 164.7 
                 7.1 
                 4.6 
                 10.4 
               
               
                   
                 90 L/min 
                 172.9 
                 4.8 
                 5.1 
                 6.7 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Mean DD and RSD results obtained at different flow rates for the high  
               
               
                 strength product (n = 30) 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Budesonide 
                 Formoterol 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 Mean DD  
                   
                 Mean DD  
                   
               
               
                 Batch 
                 Flow rate 
                 (μg) 
                 RSD (%) 
                 (μg) 
                 RSD (%) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 MD9001 
                 40 L/min 
                 288.4 
                 7.7 
                 8.2 
                 8.2 
               
               
                   
                 60 L/min 
                 313.6 
                 5.8 
                 9.0 
                 7.7 
               
               
                   
                 90 L/min 
                 321.9 
                 6.2 
                 9.4 
                 8.9 
               
               
                 MD9002 
                 40 L/min 
                 302.7 
                 6.5 
                 8.8 
                 6.7 
               
               
                   
                 60 L/min 
                 318.9 
                 8.4 
                 9.3 
                 10.3 
               
               
                   
                 90 L/min 
                 321.7 
                 5.7 
                 9.6 
                 6.8 
               
               
                 MD9003 
                 40 L/min 
                 304.6 
                 8.3 
                 9.0 
                 9.1 
               
               
                   
                 60 L/min 
                 320.2 
                 5.6 
                 9.4 
                 6.0 
               
               
                   
                 90 L/min 
                 330.3 
                 4.8 
                 9.9 
                 6.0 
               
               
                   
               
            
           
         
       
     
     This example demonstrates the consistency of the minimum delivered dose and the fine particle mass over the range of flow rates achievable by the intended patient populations, at constant volume of 4 L. It can therefore be concluded based on this study outcome that the present BF Spiromax product is capable of delivering safe and efficacious doses at clinically relevant flow rates. 
     Example 3 
     Routine laboratory testing is conducted on inhalers when they are actuated and metered doses extracted with the inhalers being held in the upright orientation. A patient may actuate the device and inhale the dose while holding the inhaler in other orientations. A device orientation study was conducted to evaluate how the orientation during actuation or inhalation affects dose delivery from the present BF Spiromax product. Product performance was assessed in terms of UDD with the inhaler angled forwards (plus) or backwards (minus) 45° of the default upright orientation, during actuation or discharge and compared with routine test results (Control). 
     Three batches of the low strength and three batches of the high strength products were tested in accordance with the routine test scheme for UDD. Per batch three inhalers were tested. Waste doses were actuated and collected when the inhalers are held in the upright orientation. Tilted actuation: Actuation with device held at +45° or −45° followed by discharge into a sample collection tube in the normal upright orientation. Tilted discharge: Actuation in the normal upright orientation followed by discharge into a sample collection tube in an angled orientation of +45° or −45°. The results are shown in Table 9. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Overall mean delivered doses per strength obtained in different orientations of  
               
               
                 actuation or inhalation (n = 9 inhalers) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                 Mean dose (μg) 
                 RSD (%) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Component 
                 Strength 
                 Test 
                 +45° 
                 −45° 
                 Control 
                 +45° 
                 −45° 
                 Control 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Budesonide 
                 Low 
                 Inhalation 
                 81.9 
                 81.2 
                 81.9 
                 5.5 
                 5.7 
                 5.1 
               
               
                 Budesonide 
                 Low 
                 Actuation 
                 81.5 
                 82.9 
                 81.9 
                 6.8 
                 6.2 
                 5.1 
               
               
                 Budesonide 
                 High 
                 Inhalation 
                 332.1 
                 323.4 
                 326.0 
                 4.9 
                 8.1 
                 5.3 
               
               
                 Budesonide 
                 High 
                 Actuation 
                 328.0 
                 328.0 
                 326.0 
                 5.1 
                 5.9 
                 5.3 
               
               
                 Formoterol 
                 Low 
                 Inhalation 
                 4.33 
                 4.35 
                 4.35 
                 6.2 
                 5.7 
                 6.8 
               
               
                 Formoterol 
                 Low 
                 Actuation 
                 4.33 
                 4.43 
                 4.35 
                 7.4 
                 6.2 
                 6.8 
               
               
                 Formoterol 
                 High 
                 Inhalation 
                 9.52 
                 9.50 
                 9.53 
                 8.0 
                 11.2 
                 8.0 
               
               
                 Formoterol 
                 High 
                 Actuation 
                 9.52 
                 9.54 
                 9.53 
                 9.1 
                 7.8 
                 8.0 
               
               
                   
               
            
           
         
       
     
     The results show that actuating the present device/formulation or inhaling the metered dose at angled orientations within 45° from upright orientation does not change the dose delivery profile compared to the inhalers actuated and metered dose inhaled in the upright orientation.