Abstract:
A nasal delivery device for and method of delivering substance to a nasal cavity of a subject, the delivery device comprising: a container-receiving unit comprising a container chamber for receiving a substance-containing container which contains substance to be delivered to the nasal cavity of the subject, the container chamber including an inlet and an outlet; a nosepiece unit including a nosepiece for fitting to a nasal cavity of the subject and being in fluid communication with the outlet of the container chamber; a mouthpiece unit including a mouthpiece in fluid communication with the inlet of the container chamber and through which the subject in use exhales, such as to entrain substance from the container and deliver the same through the nosepiece; and moisture-mitigation means for mitigating an effect of moisture in an exhaled breath on the entrainment of substance from the container, which means are provided, for example, by providing the container in a replaceable container-containing member, by a pressure-sensitive valve which normally closes the fluid connection between the container chamber and the mouthpiece, and a temperature regulator upstream of the container chamber.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a continuation of U.S. patent application Ser. No. 13/471,146, filed May 14, 2012, which is a continuation of U.S. patent application Ser. No. 11/663,099, filed Aug. 22, 2007, which is a National Phase application of International Application No. PCT/GB2005/003549, filed on Sep. 15, 2005, which claims the benefit of and priority to UK patent application no. GB 0420513.4, filed on Sep. 15, 2004. The disclosures of the above applications are incorporated herein by reference in their entireties. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates to nasal delivery devices and methods for delivering substances, in particular particulate substances, such as powdered substances, to the nasal cavities of subjects, and in particular multi-dose devices adapted for use with a plurality of containers, such as capsules, blisters and vials, which each contain a single dose of substance. 
       BACKGROUND OF THE INVENTION 
       [0003]    Current nasal delivery systems can adequately treat topical diseases, but are not suited to the delivery of substances to the upper part of the nasal airway, and in particular for targeted delivery to the olfactory region and sinus ostia. 
         [0004]    The Turbohaler® as developed by AstraZeneca AB, where adapted for nasal delivery has not been a success. A large fraction of particles is deposited in the anterior region of the nasal cavity. Furthermore, the nasal cavity becomes narrower during nasal inhalation, thus further reducing the deposition efficiency in the posterior regions of the nasal airway, in particular in narrow and congested noses. There is also a considerable risk of inhalation of small particles to the lungs, as demonstrated in previous studies. 
       SUMMARY OF THE INVENTION 
       [0005]    It is thus an aim of the present invention to provide nasal delivery systems which are suited to deliver substances, in particular particulate substances, such as powdered substances, to the nasal cavities of subjects, and in particular nasal powder delivery systems for both topical delivery and nose-to-brain (N2B) delivery. 
         [0006]    In one embodiment it is an aim of the present invention to provide for bi-directional nasal delivery using a single-dose or multi-dose device, such as a duo-dose device, where utilizing capsules or blisters containing active drug substance having a suitable particle size, size distribution, surface properties and formulations, in order to achieve optimal delivery to the nasal mucosa in general and/or targeted delivery to specific regions of a nasal cavity. Bi-directional nasal delivery is disclosed in the applicant&#39;s earlier WO-A-00/51672, the content of which is incorporated herein by reference. 
         [0007]    In another embodiment it is an aim of the present invention to prevent delivery to selected regions of the nasal cavity, in particular to the anterior valve area, by utilizing two separate delivery channels, that is, a central channel for the drug substance and air, and an outer channel which acts to modify and optimize the deposition pattern of the particles in the nasal cavity. 
         [0008]    In one aspect the present invention provides a nasal delivery device for delivering substance to a nasal cavity of a subject, the delivery device comprising: a container-receiving unit comprising a container chamber for receiving a substance-containing container which contains substance to be delivered to the nasal cavity of the subject, the container chamber including an inlet and an outlet; a nosepiece unit including a nosepiece for fitting to a nasal cavity of the subject and being in fluid communication with the outlet of the container chamber; a mouthpiece unit including a mouthpiece in fluid communication with the inlet of the container chamber and through which the subject in use exhales, such as to entrain substance from the container and deliver the same through the nosepiece; and moisture mitigation means for mitigating an effect of moisture in an exhaled breath on the entrainment of substance from the container, which means are provided, for example, by providing the container in a replaceable container-containing member, by a pressure-sensitive valve which normally closes the fluid connection between the container chamber and the mouthpiece, and a temperature regulator upstream of the container chamber. 
         [0009]    In another aspect the present invention provides a nasal delivery device for delivering substance to a nasal cavity of a subject, the delivery device comprising: a container-receiving unit comprising a container chamber for receiving a substance-containing container which contains substance to be delivered to the nasal cavity of the subject, the container chamber including an inlet and an outlet; a nosepiece unit including a nosepiece for fitting to a nasal cavity of the subject and being in fluid communication with the outlet of the container chamber; a mouthpiece unit including a mouthpiece in fluid communication with the inlet of the container chamber and through which the subject in use exhales, such as to entrain substance from the container and deliver the same through the nosepiece; and a moisture-reducing element for reducing condensation at or downstream of the container chamber. 
         [0010]    In a further aspect the present invention provides a nasal delivery device for delivering substance to a nasal cavity of a subject, the delivery device comprising: a container-receiving unit comprising a container chamber for receiving a substance-containing container which contains substance to be delivered to the nasal cavity of the subject, the container chamber including an inlet and an outlet; a nosepiece unit including a nosepiece for fitting to a nasal cavity of the subject and being in fluid communication with the outlet of the container chamber; a mouthpiece unit including a mouthpiece in fluid communication with the inlet of the container chamber and through which the subject in use exhales, such as to entrain substance from the container and deliver the same through the nosepiece. 
         [0011]    In a yet further aspect the present invention provides a nasal delivery device for delivering substance to a nasal cavity of a subject, the delivery device comprising: a body member; a carrier which is supported by the body member and carries a plurality of substance-containing containers; a nosepiece unit including a nosepiece for fitting to a nasal cavity of the subject; a mouthpiece unit including a mouthpiece through which the subject in use exhales; and an actuating mechanism which is operative, in each operation, to open a plurality of the substance-containing containers, and including a valve unit for fluidly connecting the mouthpiece to a respective one of the opened substance-containing containers in successive exhalation cycles. 
         [0012]    In a still further aspect the present invention provides a method of delivering substance to a nasal cavity of a subject, the method comprising the steps of: disposing a substance-containing container which contains substance to be delivered to the nasal cavity of the subject in a container chamber, the container chamber including an inlet and an outlet; fitting a nosepiece in fluid communication with the outlet of the container chamber to a nasal cavity of the subject; the subject exhaling through a mouthpiece which is in fluid communication with the inlet of the container chamber, such as to deliver an air flow through the container chamber and entrain substance from the container and deliver the same through the nosepiece and into the nasal cavity of the subject; and drawing moisture from the exhaled air flow upstream of the container chamber, such as to reduce condensation at or downstream of the container chamber. 
         [0013]    In a yet still further aspect the present invention provides a method of delivering substance to a nasal cavity of a subject, the method comprising the steps of: disposing a substance-containing container which contains substance to be delivered to the nasal cavity of the subject in a container chamber, the container chamber including an inlet and an outlet; fitting a nosepiece in fluid communication with the outlet of the container chamber to a nasal cavity of the subject; and the subject exhaling through a mouthpiece which is in fluid communication with the inlet of the container chamber, such as to deliver an air flow through the container chamber and entrain substance from the container and deliver the same through the nosepiece and into the nasal cavity of the subject. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0014]    Preferred embodiments of the present invention will now be described hereinbelow by way of example only with reference to the accompanying drawings, in which: 
           [0015]      FIGS. 1(   a ) to ( f ) illustrate a nasal delivery device in accordance with a first embodiment of the present invention; 
           [0016]      FIGS. 2(   a ) to ( f ) illustrate a nasal delivery device in accordance with a second embodiment of the present invention; 
           [0017]      FIGS. 3(   a ) to ( f ) illustrate a nasal delivery device in accordance with a third embodiment of the present invention; and 
           [0018]      FIGS. 4(   a ) to ( f ) illustrate a nasal delivery device in accordance with a fourth embodiment of the present invention. 
           [0019]      FIGS. 1(   a ) to ( f ) illustrate a nasal delivery device in accordance with a first embodiment of the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0020]    The delivery device comprises a housing  15 , a capsule-receiving unit  16  for receiving a capsule C, a nosepiece unit  17  for fitting to a nasal cavity of a subject, a mouthpiece unit  19  through which the subject exhales, and a capsule-piercing mechanism  20 , which is operable to pierce a capsule C as contained by the capsule-receiving unit  16  and thereby prime the delivery device for operation, as will be described in more detail hereinbelow. 
         [0021]    The housing  15  includes a first, nosepiece aperture  21 , in this embodiment at the upper end of the housing  15 , which receives the nosepiece unit  17 , and a second, lateral aperture  22 , in this embodiment in the lateral wall of the housing  15 , through which extends an actuator button  81  of the capsule-piercing mechanism  20 , as will be described in more detail hereinbelow. 
         [0022]    The capsule-receiving unit  16  comprises a capsule-receiving member  23 , in this embodiment an elongate, upstanding chamber which is disposed opposite the nosepiece aperture  21  in the housing  15 , for receiving a capsule C, in this embodiment as contained within a capsule-containing member  49  of the nosepiece unit  17 , as will be described in more detail hereinbelow. 
         [0023]    In this embodiment the capsule-receiving member  23  includes an inlet  24  and an outlet  25  for providing for an air flow therethrough, with the outlet  25 , as defined by an upper, downstream end of the capsule-receiving member  23 , being adapted to receive the capsule-containing member  49  of the nosepiece unit  17 , such that the capsule-containing member  49  is a sealing fit within the capsule-receiving member  23 . 
         [0024]    The capsule-receiving unit  16  further comprises a pressure-sensitive valve  26  in fluid communication with the inlet  24  of the capsule-receiving member  23 , which is such as to prevent an air flow through the capsule-receiving member  23  until a predetermined pressure has been developed upstream thereof. In this embodiment the pressure-sensitive valve  26  is located at the inlet  24  to the capsule-receiving member  23 . 
         [0025]    In this embodiment the pressure-sensitive valve  26  comprises a flap member  27  which is hingeable about a pivot  28  and normally biased to a closed, sealing position by a resilient element  29 , here a spring, such that a predetermined pressure is required to overcome the biasing force of the resilient element  29 . 
         [0026]    The nosepiece unit  17  comprises a main body member  45  which is configured to fit in the nosepiece aperture  21  of the housing  15 , a nosepiece  47  which extends outwardly of the main body member  45  for fitting to the nostril of the subject, and a capsule-containing member  49  which extends inwardly of the main body member  45  and contains a capsule C, the contents of which are to be delivered to the nasal cavity of the subject. In this embodiment the capsule C is a conventional gelatine capsule which contains a particulate substance, such as a powdered substance, and typically a pharmaceutical substance. 
         [0027]    In this embodiment the nosepiece  47  has a substantially frusto-conical outer section  53  for insertion into a nostril of the subject such as to provide a fluid-tight seal therewith, and includes an inner channel  55 , here of substantially cylindrical section, through which substance is delivered to the nasal cavity of the subject. In this embodiment the nosepiece  47 , in providing a fluid-tight seal with the nostril of the subject, provides for bi-directional delivery through the nasal airway of the subject, as disclosed in the applicant&#39;s earlier WO-A-00/51672. In another embodiment, however, the nosepiece  47  need not provide a sealing fit, thus encompassing delivery to the nasal cavity, but not necessarily bi-directional delivery. 
         [0028]    In this embodiment the nosepiece  47  includes a trap element  57 , typically a perforated or mesh element, for preventing any foreign matter, such as a part of the capsule C, which is above a predetermined size from passing through the nosepiece  47  and into the nasal cavity of the subject. 
         [0029]    The capsule-containing member  49  includes an elongate flow passage  63 , in this embodiment cylindrical in shape, in which the capsule C is oriented axially therealong such as to be rotatable therewithin when an air flow is delivered therethrough, and an inlet aperture  65  in fluid communication with one, the downstream, end of the flow passage  63 , which inlet aperture  65  provides a flow restriction to an air flow as delivered therethrough and acts as a seat for one, the lower, end of the capsule C prior to the delivery of an air flow through the flow passage  63 . 
         [0030]    The capsule-containing member  49  further includes a plurality of, in this embodiment first and second piercing apertures  71 ,  73  in a lateral wall thereof for enabling the capsule C to be pierced at locations spaced along the axial length thereof. In this embodiment the first, lower aperture  71  is located such that the capsule C is pierced at a location above the height of the dose of substance as contained thereby when the lower end of the capsule C is seated in the inlet aperture  65  of the flow passage  63 . In this way, the dose of substance as contained by the capsule C is not released into the flow passage  63  until an air flow is delivered through the flow passage  63 . 
         [0031]    In this embodiment the nosepiece unit  17  is provided as a replaceable unit which is replaced following each operation of the delivery device. In this embodiment the nosepiece unit  17  can be packaged in air-tight packaging, for example, an aluminum foil package. 
         [0032]    In an alternative embodiment only the capsule-containing member  49  could be replaceable, such as to be replaceable following each operation, with the nosepiece  47  being a sealing fit to the other, downstream end of the capsule-containing member  49 . In this embodiment the capsule-containing member  49  can be packaged in air-tight packaging, for example, an aluminum foil package. 
         [0033]    In still another alternative embodiment the nosepiece unit  17  could be a re-useable unit, with the capsule-containing member  49  being separable from the nosepiece  47  to allow for replacement of the capsule C following operation of the delivery device. In this embodiment the capsule C can be packaged in air-tight packaging, for example, an aluminum foil package. 
         [0034]    The mouthpiece unit  19  comprises a mouthpiece  77 , in this embodiment as gripped in the lips of the subject, through which the subject exhales to deliver an entraining air flow through the capsule-receiving unit  16 , and an air chamber  78 , in this embodiment an elongate tubular section, which fluidly connects the mouthpiece  77  and the pressure-sensitive valve  26  of the capsule-receiving unit  16 . 
         [0035]    In this embodiment the air chamber  78  has a greater volume than the capsule-receiving member  23  of the capsule-receiving unit  16 , and preferably has a volume at least twice that of the capsule-receiving member  23 . 
         [0036]    In this embodiment the air chamber  78  incorporates a temperature regulator  79 , here formed as a condenser for cooling the exhaled air flow, at least at the upstream end thereof. With this configuration, the exhaled air flow is cooled during exhalation, and also a predetermined volume of cooler air, as contained by the air chamber  78 , is available prior to release of the pressure-sensitive valve  26 . 
         [0037]    In this embodiment the temperature regulator  79  comprises a labyrinthine structure. In another embodiment the temperature regulator  79  could be provided by a filter element, which could also act as a microbiological filter. 
         [0038]    In one embodiment the temperature regulator  79  could include means for drying the condensate as collected therein when the delivery device is not in use. 
         [0039]    In one embodiment the air chamber  78  is removable, such as to allow for cleaning or replacement. 
         [0040]    This arrangement has been found to provide for reliable operation of the delivery device, in delivering substance from the capsule C. The present inventors have established that the provision of moist exhaled air directly to the capsule C can sometimes prevent the required rotation of the capsule C, and thereby prevent proper release of the substance as contained thereby. By providing a volume of cooler air, and arranging for that volume of cooler air to be delivered initially in a burst, the required rotation of the capsule C is seen repeatedly. 
         [0041]    The capsule-piercing mechanism  20  comprises an actuator button  81  which extends through the lateral aperture  22  in the housing  15  such as to allow for operation by the subject, a plurality of, in this embodiment first and second piercing elements  83 ,  85  which are supported by the actuator button  81  and extend forwardly thereof, such that, on depression of the actuator button  81  from a retracted position, as illustrated in  FIG. 1(   a ), to an extended position, as illustrated in  FIG. 1(   b ), the piercing elements  83 ,  85  are driven through respective ones of the piercing apertures  71 ,  73  in the lateral wall of the capsule-containing member  49  to pierce the capsule C. 
         [0042]    In this embodiment the capsule-piercing mechanism  20  includes a resilient element  87  which acts to bias the actuator button  81  outwardly towards the retracted position, such that, following depression of the actuator button  81  to pierce the capsule C, the actuator button  81  is returned to the retracted position. In this embodiment the resilient element  87  is formed as an integral part of the actuator button  81 , but in other embodiments could be provided by a separate element, such as a compression spring. 
         [0043]    Operation of the delivery device will now be described hereinbelow. 
         [0044]    Firstly, taking the delivery device in hand, and with a nosepiece unit  17  inserted in the housing  15 , as illustrated in  FIG. 1(   a ), the subject depresses the actuator button  81  of the capsule-piercing mechanism  20  such as to pierce the capsule C as contained in the capsule-containing member  49 , as illustrated in  FIG. 1(   b ). 
         [0045]    By depressing the actuator button  81 , the capsule C is pierced by the piercing elements  83 ,  85  at two locations spaced along the axial length thereof. In this embodiment the first, lower piercing element  83  acts to pierce the capsule C at a location just above the height of the substance as contained by the capsule C, the capsule C only being part filled, and the second, upper piercing element  85  acts to pierce the upper, distal end of the capsule C. 
         [0046]    The actuator button  81  is then released, which causes the actuator button  81  to be returned to the retracted under the bias of the biasing element  87 , as illustrated in  FIG. 1(   c ). In this way, the delivery device is primed and ready for use. 
         [0047]    The subject then inserts the nosepiece  53  into one of his nostrils, grips the mouthpiece  77  in his or her lips and begins to exhale through the mouthpiece  77 , as illustrated in  FIG. 1(   d ). Initially, this exhalation is resisted by the pressure-sensitive valve  26 , thereby preventing the delivery of an air flow through the capsule-containing member  49  and over the capsule C. 
         [0048]    When the subject exhales with sufficient force to develop a pressure upstream of the pressure-sensitive valve  26  which is greater than a predetermined pressure, the pressure-sensitive valve  26  is opened, causing a sudden flow of air, as a burst of air, through the capsule-containing member  49 , as illustrated in  FIG. 1(   e ). 
         [0049]    This burst of air acts to lift the capsule C from the seat as defined by the inlet aperture  65  of the capsule-containing member  49  and initiate the rotation of the capsule C, which rotation acts to release the substance from within the capsule C. With continued exhalation, the capsule C continues to rotate. 
         [0050]    Following exhalation, as illustrated in  FIG. 1(   f ), the pressure-sensitive valve  26  is returned to the closed, sealing position and the, now empty, capsule C is returned to a rest position. 
         [0051]    This operation of the delivery device can be repeated with a new capsule C. As described hereinabove, in this embodiment the entire nosepiece unit  17  is replaced, but in other embodiments either the capsule-containing member  49  or just the capsule C could be replaced. 
         [0052]      FIGS. 2(   a ) to ( f ) illustrate a nasal delivery device in accordance with a second embodiment of the present invention. 
         [0053]    The delivery device of this embodiment is very similar to the delivery device of the above-described first embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail. 
         [0054]    The delivery device of this embodiment differs from that of the above-described embodiment in that the nosepiece  53  includes first and second channels  55   a ,  55   b , in this embodiment concentric annular channels, which are centred about the longitudinal axis of the capsule-containing member  49 , where the first, inner channel  55   a  is fluidly connected to the downstream end of the capsule-containing member  49  such that the substance as contained by the capsule C is delivered therethrough and the second, outer channel  55   b  is fluidly connected by a ducting channel  91  to the mouthpiece  77 , in this embodiment upstream of the air chamber  78 . 
         [0055]    With this arrangement, a focussed powder aerosol is delivered from the outlet end of the inner channel  55   a , and entrained by the co-axial air flow as delivered from the mouthpiece  77 . This arrangement is particularly advantageous in targeting specific regions of the nasal airway, in particular posterior regions, such as the olfactory region. As this entraining air flow does not pass over the capsule C, the humidity of the entraining air flow is not significant. 
         [0056]      FIGS. 3(   a ) to ( f ) illustrate a nasal delivery device in accordance with a third embodiment of the present invention. 
         [0057]    The delivery device comprises a housing  101  which includes a central support spindle  105 , a carrier  109  which carries a plurality of substance-containing capsules C, the contents of which are to be delivered to a nasal cavity of the subject, and is movably disposed to the housing  101 , in this embodiment rotatably mounted to the housing  101  about the support spindle  105 , a nosepiece unit  119  for fitting to a nasal cavity of a subject, a mouthpiece unit  121  through which the subject exhales, and a capsule-piercing mechanism  123 , which is operable, in this embodiment simultaneously, to pierce a pair of capsules C and thereby prime the delivery device for operation, as will be described in more detail hereinbelow. 
         [0058]    In this embodiment the capsules C are conventional gelatine capsules which contain a particulate substance, such as a powdered substance, and typically a pharmaceutical substance. 
         [0059]    The carrier  109  comprises a body member  131 , in this embodiment an annular element, and a plurality of capsule-containing members  133 , each containing a capsule C, which are disposed symmetrically in adjacent pairs about the support spindle  105 , such that, as the carrier  109  is indexed successively to new positions, new pairs of capsule-containing members  133  are indexed to the capsule-piercing mechanism  123 . 
         [0060]    In this embodiment the capsule-containing members  133  each comprise a tubular element  137  which defines an elongate flow passage  139 , in this embodiment cylindrical in shape, in which the capsule C is oriented axially therealong such as to be rotatable therewithin when an air flow is delivered therethrough, and first and second sealing members  141 ,  142  which seal the opposite, lower and upper ends of the tubular element  137 . 
         [0061]    In this embodiment the capsule-containing members  133  each include a plurality of, in this embodiment first and second piercing apertures  143 ,  144  in a lateral wall thereof for enabling the capsule C to be pierced at locations spaced along the axial length thereof. In this embodiment the first, lower aperture  143  is located such that the capsule C is pierced at a location above the height of the dose of substance as contained thereby. In this way, the dose of substance as contained by the capsule C is not released into the flow passage  139  until an air flow is delivered through the flow passage  139 . 
         [0062]    The nosepiece unit  119  comprises a body member  145  which is movably, in this embodiment pivotally, coupled to the housing  101  such as to be movable between a first, inoperative position, as illustrated in  FIG. 3(   a ), in which the nosepiece unit  119  is stowed away and a second, operative position, as illustrated in  FIG. 3(   c ), and a nosepiece  147  which extends outwardly of the body member  145  for fitting to a nostril of the subject. 
         [0063]    In this embodiment the body member  145  includes a flow channel  149  which fluidly connects the flow passages  139  of an adjacent pair of the capsule-containing members  133  to the nosepiece  147  when the nosepiece unit  119  is in the operative position. 
         [0064]    In this embodiment the body member  145  includes first and second cutters  151  which are adapted to cut the upper sealing members  142  of the adjacent pair of capsule-containing members  133  when the nosepiece unit  119  is in the operative position. 
         [0065]    In this embodiment the body member  145  includes a catch member  155 , here having a diamond-shaped cross section which presents forwardly-directed, tapering surfaces when the nosepiece unit  119  is pivoted in either sense from or to the operative position, which acts to operate in part the capsule-piercing mechanism  123  and also latch the nosepiece unit  119  in the operative position, as will be described in more detail hereinbelow. 
         [0066]    In this embodiment the nosepiece  147  has a substantially frusto-conical outer section  157  for insertion into a nostril of the subject such as to provide a fluid-tight seal therewith, and includes an inner channel  159  through which substance is delivered to the nasal cavity of the subject. In this embodiment the nosepiece  147 , in providing a fluid-tight seal with the nostril of the subject, provides for bi-directional delivery through the nasal airway of the subject, as disclosed in the applicant&#39;s earlier WO-A-00/51672. In another embodiment, however, the nosepiece  147  need not provide a sealing fit, thus encompassing delivery to the nasal cavity, but not necessarily bi-directional delivery. 
         [0067]    The mouthpiece unit  121  comprises a body member  165  which is movably, in this embodiment pivotally, coupled to the housing  101  such as to be movable between a first, inoperative position, as illustrated in  FIG. 3(   a ), in which the mouthpiece unit  121  is stowed away and a second, operative position, as illustrated in  FIG. 3(   c ), a mouthpiece  167  which extends outwardly of the body member  165 , in this embodiment as gripped in the lips of the subject, through which the subject exhales to deliver an entraining air flow, and a valve unit  169  which is operative fluidly to connect the mouthpiece  167  to a respective one of the adjacent pair of opened capsule-containing members  133  in successive exhalation cycles. 
         [0068]    In this embodiment the valve unit  169  comprises a pressure sensor which is operative to detect the pressure as developed in the mouthpiece  167  and an electro-mechanical valve, which includes two flow channels and is switchable such as fluidly to connect the mouthpiece  167  first to one of the pair of capsule-containing members  133  and, following the first exhalation cycle, which is represented by a return to ambient pressure, then to the other of the pair of capsule-containing members  133 . 
         [0069]    In this embodiment the body member  165  includes first and second cutters  171  which are adapted to cut the lower sealing members  141  of the adjacent pair of capsule-containing members  133  when the mouthpiece unit  121  is in the operative position. 
         [0070]    In this embodiment the body member  165  includes a catch member  175 , here having a diamond-shaped cross section which presents forwardly-directed, tapering surfaces when the mouthpiece unit  121  is pivoted in either sense from or to the operative position, which acts to operate in part the capsule-piercing mechanism  123  and also latch the mouthpiece unit  121  in the operative position, as will be described in more detail hereinbelow. 
         [0071]    The capsule-piercing mechanism  123  comprises first and second piercing units  181 , which are disposed in opposed, back-to-back relation and are actuated by movement of the nosepiece unit  119  and the mouthpiece unit  121  from the inoperative, stowed positions to the operative positions. 
         [0072]    Each of the piercing units  181  includes an actuator button  182  and a plurality of, in this embodiment first and second piercing elements  183 ,  185  which are supported by the actuator button  182  and extend forwardly thereof, such that, on depression of the actuator button  182  from a retracted position, as illustrated in  FIG. 3(   a ), to an extended position, as illustrated in  FIG. 3(   b ), the piercing elements  183 ,  185  are driven through respective ones of the piercing apertures  143 ,  144  in the lateral wall of the respective capsule-containing member  133  to pierce the capsule C. 
         [0073]    In this embodiment the capsule-piercing units  181  each include a resilient element  187  which acts to bias the respective actuator button  182  inwardly towards the retracted position, such that, following depression of the actuator button  182  to pierce the capsule C, the actuator button  182  is returned to the retracted position. 
         [0074]    In this embodiment the actuator buttons  182  each include first and second recesses  189 ,  191  in a rear surface thereof, here V-shaped in cross section, which are configured such as to engage respective ones of the catches  155 ,  175  on the body members  145 ,  165  of the nosepiece and mouthpiece units  119 ,  121 , such as to latch the same in the operative positions. 
         [0075]    Operation of the delivery device will now be described hereinbelow. 
         [0076]    Firstly, the subject indexes the carrier  109  such as to present the next pair of capsule-containing members  133  at the capsule-piercing mechanism  123 , as illustrated in  FIG. 3(   a ). 
         [0077]    The subject then moves the nosepiece unit  119  and the mouthpiece unit  121  to the respective operative positions, in this embodiment by pivoting the same relative to the housing  101 , as illustrated in  FIGS. 3(   b ) and ( c ). 
         [0078]    In moving the nosepiece unit  119  and the mouthpiece unit  121  to the respective operative positions, the catch member  155  on the body member  145  of the nosepiece unit  119  and the catch member  175  on the body member  165  of the mouthpiece unit  121  engage between the respective ends of the opposing actuator buttons  182  of the piercing units  181 , such as to bias the actuator buttons  182  outwardly and pierce the capsules C as contained in the capsule-containing members  133 , as illustrated in  FIG. 3(   b ). 
         [0079]    By depressing the actuator buttons  182 , the capsules C are pierced by the piercing elements  183 ,  185  at two locations spaced along the axial length thereof, with the piercing elements  183 ,  185  extending through the piercing apertures  143 ,  144  in the lateral walls of the tubular elements  137  of the capsule-containing members  133 . In this embodiment the first, lower piercing elements  183  act to pierce the capsules C at locations just above the height of the substance as contained by the capsules C, the capsules C only being part filled, and the second, upper piercing elements  185  act to pierce the upper, distal ends of the capsules C. 
         [0080]    On further moving the nosepiece unit  119  and the mouthpiece unit  121  to the respective operative positions, the catch member  155  on the body member  145  of the nosepiece unit  119  and the catch member  175  on the body member  165  of the mouthpiece unit  121  engage in the respective recesses  189 ,  191  in the rear surfaces of the opposing actuator buttons  182  of the piercing units  181 , as illustrated in  FIG. 3(   c ), with the actuator buttons  182  being returned to the retracted positions under the bias of the biasing elements  187 , whereby the nosepiece unit  119  and the mouthpiece unit  121  are latched in the operative positions. 
         [0081]    Also, with movement of the nosepiece unit  119  and the mouthpiece unit  121  to the operative positions, the cutters  151  on the body member  145  of the nosepiece unit  119  act to rupture the upper sealing members  142  of the capsule-containing members  133  and the cutters  171  on the body member  165  of the mouthpiece unit  121  act to rupture the lower sealing members  141  of the capsule-containing members  133 . 
         [0082]    The subject then inserts the nosepiece  147  into one of his or her nostrils, grips the mouthpiece  167  in his or her lips and exhales through the mouthpiece  167 , as illustrated in  FIG. 3(   d ). 
         [0083]    In this first exhalation cycle, the valve unit  169  is configured such as to direct the exhaled air flow through one of the pair of capsule-containing members  133 , which air flow acts to lift the capsule C and cause rotation of the capsule C, and which rotation acts to release the substance from within the capsule C. With continued exhalation, the capsule C continues to rotate. 
         [0084]    Following exhalation, the, now empty, capsule C returns to a rest position, and, as detected by the absence of any pressure in the mouthpiece  167 , the valve unit  169  is re-configured such that the mouthpiece  167  is fluidly connected to the other of the pair of capsule-containing members  133 , whereby the air flow as developed by a subsequent exhalation breath is directed through the other of the pair of capsule-containing members  133 . 
         [0085]    In one mode of operation the nosepiece  147  is inserted in the other of the nostrils of the subject, and the subject grips the mouthpiece  167  in his or her lips and exhales through the mouthpiece  167 , as illustrated in  FIG. 3(   e ). 
         [0086]    In this second, subsequent exhalation cycle, the valve unit  169  is configured such as to direct the exhaled air flow through the other of the pair of capsule-containing members  133 , which air flow acts to lift the capsule C and cause rotation of the capsule C, and which rotation acts to release the substance from within the capsule C. With continued exhalation, the capsule C continues to rotate. 
         [0087]    In this mode of operation the same, or indeed different, substances can be delivered to each of the nasal cavities of the subject. 
         [0088]    Following exhalation, the, now empty, capsule C returns to a rest position. 
         [0089]    In another mode of operation, where the capsules C in the pair of capsule-containing members  133  contain different substances, and these substances are both to be delivered to one nasal cavity, the nosepiece  147  is not moved to the other nostril of the subject. 
         [0090]    Following use of the delivery device, the nosepiece unit  119  and the mouthpiece unit  121  are returned to the respective stowed, inoperative positions, in this embodiment by pivoting the same relative to the housing  101 , as illustrated in  FIG. 3(   f ). 
         [0091]    In moving the nosepiece unit  119  and the mouthpiece unit  121  to the respective inoperative positions, the catch member  155  on the body member  145  of the nosepiece unit  119  and the catch member  175  on the body member  165  of the mouthpiece unit  121  are released from engagement with the recesses  189 ,  191  in the rear surfaces of the opposing actuator buttons  182  of the piercing units  181 . 
         [0092]    This operation of the delivery device can then subsequently be repeated for the next pair of capsules C. 
         [0093]      FIGS. 4(   a ) to ( f ) illustrate a nasal delivery device in accordance with a fourth embodiment of the present invention. 
         [0094]    The delivery device comprises a housing  201  which includes a central support spindle  205 , a carrier  209  which carries a plurality of substance-containing blisters B, the contents of which are to be delivered to a nasal cavity of the subject, and is movably disposed to the housing  201 , in this embodiment rotatably mounted to the housing  201  about the support spindle  205 , an interface assembly  211  which provides the interface to the subject, and a latch mechanism  223  which acts to latch the interface assembly  211  in the operative position, as will be described in more detail hereinbelow. 
         [0095]    In this embodiment the blisters B are conventional blisters which contain a particulate substance, such as a powdered substance, and typically a pharmaceutical substance. 
         [0096]    The carrier  209  comprises a body member  231 , in this embodiment an annular element, and a plurality of blisters B which are disposed symmetrically in adjacent pairs about the support spindle  205 , such that, as the carrier  209  is indexed successively to new positions, new pairs of blisters B are indexed to the operative position of the interface assembly  211 . 
         [0097]    The interface assembly  211  comprises a body member  235  which is movably, in this embodiment pivotally, coupled to the housing  201  such as to be movable between a first, inoperative position, as illustrated in  FIG. 4(   a ), in which the interface assembly  211  is stowed away and a second, operative position, as illustrated in  FIG. 4(   c ), a nosepiece unit  219  which includes a nosepiece  247  which extends outwardly of the body member  235  for fitting to a nostril of the subject, a mouthpiece unit  221  which includes a mouthpiece  249  which extends outwardly of the body member  235 , in this embodiment as gripped in the lips of the subject, through which the subject exhales to deliver an entraining air flow, and a valve unit  251  which is operative fluidly to connect the mouthpiece  249  to a respective one of the adjacent pair of opened blisters B in successive exhalation cycles. 
         [0098]    In this embodiment the body member  235  includes a flow channel  259  which fluidly connects the adjacent pair of blisters B to the nosepiece  249  when the interface assembly  211  is in the operative position. 
         [0099]    In this embodiment the body member  235  includes first and second cutters  261  which are adapted to cut the sealing members of the adjacent pair of blisters B when the interface assembly  211  is in the operative position. 
         [0100]    In this embodiment the body member  235  includes a catch member  265 , here having a diamond-shaped cross section which presents forwardly-directed, tapering surfaces when the interface assembly  211  is pivoted in either sense from or to the operative position, which acts to latch the interface assembly  211  in the operative position, as will be described in more detail hereinbelow. 
         [0101]    In this embodiment the nosepiece  247  has a substantially frusto-conical outer section  267  for insertion into a nostril of the subject such as to provide a fluid-tight seal therewith, and includes an inner channel  269  through which substance is delivered to the nasal cavity of the subject. In this embodiment the nosepiece  247 , in providing a fluid-tight seal with the nostril of the subject, provides for bi-directional delivery through the nasal airway of the subject, as disclosed in the applicant&#39;s earlier WO-A-00/51672. In another embodiment, however, the nosepiece  247  need not provide a sealing fit, thus encompassing delivery to the nasal cavity, but not necessarily bi-directional delivery. 
         [0102]    In this embodiment the valve unit  251  comprises a pressure sensor which is operative to detect the pressure as developed in the mouthpiece  249  and an electro-mechanical valve, which includes two flow channels and is switchable such as fluidly to connect the mouthpiece  249  first to one of the pair of blisters B and, following the first exhalation cycle, which is represented by a return to ambient pressure, then to the other of the pair of blisters B. 
         [0103]    The latch mechanism  223  comprises first and second latch elements  281 , which are disposed in opposed, back-to-back relation, and each comprise a latch body  282  and a resilient element  287  which acts to bias the latch body  282  forwardly to a latching position. 
         [0104]    In this embodiment the latch bodies  282  each include a recess  289  in a rear surface thereof, here V-shaped in cross section, which acts to engage the catch  265  on the body member  235  of the interface assembly  211  when the interface assembly  211  is in the operative position. 
         [0105]    Operation of the delivery device will now be described hereinbelow. 
         [0106]    Firstly, the subject indexes the carrier  209  such as to present the next pair of blisters B at the operative position of the interface assembly  211 , as illustrated in  FIG. 4(   a ). 
         [0107]    The subject then moves the interface assembly  211  to the operative position, in this embodiment by pivoting the same relative to the housing  201 , as illustrated in  FIGS. 4(   b ) and ( c ). 
         [0108]    In moving the interface assembly  211  to the operative position, the catch member  265  on the body member  235  of the interface assembly  211  engages between the respective ends of the latch bodies  282  of the latch units  281 , such as to bias the latch bodies  282  outwardly, as illustrated in  FIG. 4(   b ). 
         [0109]    On further moving the interface assembly  211  to the operative position, the catch member  265  on the body member  235  of the interface assembly  211  engages in the respective recesses  289  in the rear surfaces of the opposing latch bodies  282  of the latch units  281 , as illustrated in  FIG. 4(   c ), with the latch bodies  282  being returned to the retracted positions under the bias of the biasing elements  287 , whereby the interface assembly  211  is latched in the operative position. 
         [0110]    Also, with movement of the interface assembly  211  to the operative position, the cutters  261  on the body member  235  of the interface assembly  211  act to rupture the sealing members of the adjacent pair of blisters B. 
         [0111]    The subject then inserts the nosepiece  247  into one of his or her nostrils, grips the mouthpiece  249  in his or her lips and exhales through the mouthpiece  249 , as illustrated in  FIG. 4(   d ). 
         [0112]    In this first exhalation cycle, the valve unit  251  is configured such as to direct the exhaled air flow through one of the pair of blisters B, which air flow acts to entrain the substance from the blister B. 
         [0113]    Following exhalation, the blister B is emptied, and, as detected by the absence of any pressure in the mouthpiece  249 , the valve unit  251  is re-configured such that the mouthpiece  249  is fluidly connected to the other of the pair of blisters B, whereby the air flow as developed by a subsequent exhalation breath is directed through the other of the pair of blisters B. 
         [0114]    In one mode of operation the nosepiece  247  is inserted in the other of the nostrils of the subject, and the subject grips the mouthpiece  249  in his or her lips and exhales through the mouthpiece  249 , as illustrated in  FIG. 4(   e ). 
         [0115]    In this second, subsequent exhalation cycle, the valve unit  251  is configured such as to direct the exhaled air flow through the other of the pair of blisters B, which acts to entrain the substance from the blister B. 
         [0116]    In this mode of operation the same, or indeed different, substances can be delivered to each of the nasal cavities of the subject. 
         [0117]    Following exhalation, the blister B is emptied. 
         [0118]    In another mode of operation, where the blisters B contain different substances, and these substances are both to be delivered to one nasal cavity, the nosepiece  247  is not moved to the other nostril of the subject. 
         [0119]    Following use of the delivery device, the interface assembly  211  is returned to the stowed, inoperative position, in this embodiment by pivoting the same relative to the housing  201 , as illustrated in  FIG. 4(   f ). 
         [0120]    In moving the interface assembly  211  to the stowed position, the catch member  265  on the body member  235  of the interface assembly  211  is released from engagement with the recesses  289  in the rear surfaces of the opposing latch bodies  282  of the latch units  281 . 
         [0121]    This operation of the delivery device can then subsequently be repeated for the next pair of blisters B. 
         [0122]    Finally, it will be understood that the present invention has been described in its preferred embodiments and can be modified in many different ways without departing from the scope of the invention as defined by the appended claims. 
         [0123]    In one modification the delivery device could be modified to include a rotatable cartridge which includes a plurality of capsule-containing members  49 , which are each successively indexed into the capsule-receiving chamber  23  of the capsule-receiving unit  16 . fd