Abstract:
The present invention relates to a nasal delivery device for and a method of delivering a substance, in particular one of a liquid, as a suspension or solution, or a powder containing a medicament, especially systemic or topical pharmaceuticals, or a vaccine to the nasal airway of a subject.

Description:
RELATED APPLICATION DATA 
     This application is a national phase of International Application No. PCT/IB02/03034 filed Jun. 12, 2002 and published in the English language. 
     FIELD OF THE INVENTION 
     The present invention relates to a nasal delivery device for and a method of delivering a substance, in particular one of a liquid, as a suspension or solution, or a powder containing a medicament, especially systemic or topical pharmaceuticals, or a vaccine to the nasal airway of a subject. 
     BACKGROUND AND SUMMARY OF THE INVENTION 
     Referring to  FIG. 1 , the nasal airway  1  comprises the two nasal cavities separated by the nasal septum, which airway  1  includes numerous ostia, such as the paranasal sinus ostia  3  and the tubal ostia  5 , and olfactory cells, and is lined by the nasal mucosa. The nasal airway  1  can communicate with the nasopharynx  7 , the oral cavity  9  and the lower airway  11 , with the nasal airway  1  being in selective communication with the anterior region of the nasopharynx  7  and the oral cavity  9  by opening and closing of the oropharyngeal velum  13 . The velum  13 , which is often referred to as the soft palate, is illustrated in solid line in the closed position, as achieved by providing a certain positive pressure in the oral cavity  9 , such as achieved on exhalation through the oral cavity  9 , and in dashed line in the open position. 
     There are many nasal conditions which require treatment. One such condition is nasal inflammation, specifically rhinitis, which can be allergic or non-allergic and is often associated with infection and prevents normal nasal function. By way of example, allergic and non-allergic inflammation of the nasal airway can typically effect between 10 and 20% of the population, with nasal congestion of the erectile tissues of the nasal concha, lacrimation, secretion of watery mucus, sneezing and itching being the most common symptoms. As will be understood, nasal congestion impedes nasal breathing and promotes oral breathing, leading to snoring and sleep disturbance. Other nasal conditions include nasal polyps which arise from the paranasal sinuses, hypertrophic adenoids, secretory otitis media, sinus disease and reduced olfaction. 
     In the treatment of certain nasal conditions, the topical administration of medicaments is preferable, particularly where the nasal mucosa is the prime pathological pathway, such as in treating or relieving nasal congestion. Medicaments that are commonly topically delivered include decongestants, anti-histamines, cromoglycates, steroids and antibiotics. At present, among the known anti-inflammatory pharmaceuticals, topical steroids have been shown to have an effect on nasal congestion. Topical decongestants have also been suggested for use in relieving nasal congestion. The treatment of hypertrophic adenoids and chronic secretory otitis media using topical decongestants, steroids and anti-microbial agents, although somewhat controversial, has also been proposed. Further, the topical administration of pharmaceuticals has been used to treat or at least relieve symptoms of inflammation in the anterior region of the nasopharynx, the paranasal sinuses and the auditory tubes. 
     Medicaments can also be systemically delivered through the nasal pathway, the nasal pathway offering a good administration route for the systemic delivery of pharmaceuticals, such as hormones, for example, oxytocin and calcitionin, and analgetics, such as anti-migraine compositions, as the high blood flow and large surface area of the nasal mucosa advantageously provides for rapid systemic uptake. 
     Nasal delivery is also expected to be advantageous for the administration of medicaments requiring a rapid onset of action, for example, analgetics, anti-emetics, insulin, anti-epileptics, sedatives and hypnotica, and also other pharmaceuticals, for example, cardio-vascular drugs. It is envisaged that nasal administration will provide for a fast onset of action, at a rate similar to that of injection and at a rate much faster than that of oral administration. Indeed, for the treatment of many acute conditions, nasal administration is advantageous over oral administration, since gastric stasis can further slow the onset of action following oral administration. 
     It is also expected that nasal delivery could provide an effective delivery route for the administration of proteins and peptides as produced by modern biotechnological techniques. For such substances, the metabolism in the intestines and the first-pass-effect in the liver represent significant obstacles for reliable and cost-efficient delivery. 
     Furthermore, it is expected that nasal delivery using the nasal delivery technique of the present invention will prove effective in the treatment of many common neurological diseases, such as Alzheimer&#39;s, Parkinson&#39;s, psychiatric diseases and intracerebral infections, where not possible using existing techniques. The nasal delivery technique of the present invention allows for delivery to the olfactory region, which region is located in the superior region of the nasal cavities and represents the only region where it is possible to circumvent the blood-to-brain barrier (BBB) and enable communication with the cerebrospinal fluid (CSF) and the brain. 
     Also, it is expected that the nasal delivery technique of the present invention will allow for the effective delivery of vaccines. 
     Aside from the delivery of medicaments, the irrigation of the nasal mucosa with liquids, in particular saline solutions, is commonly practised to remove particles and secretions, as well as to improve the mucociliary activity of the nasal mucosa. These solutions can be used in combination with active pharmaceuticals. 
     For any kind of drug delivery, accurate and reliable dosing is essential, but it is of particular importance in relation to the administration of potent drugs which have a narrow therapeutic window, drugs with potentially serious adverse effects and drugs for the treatment of serious and life-threatening conditions. For some conditions, it is essential to individualize the dosage to the particular situation, for example, in the case of diabetes mellitus. For diabetes, and, indeed, for many other conditions, the dosage of the pharmaceutical is preferably based on actual real-time measurements. Currently, blood samples are most frequently used, but the analysis of molecules in the exhalation breath of subjects has been proposed as an alternative to blood analysis for several conditions. Breath analysis is currently used for the diagnosis of conditions such as helicobacter pylori infections which cause gastric ulcers. 
     WO-A-00/51672 discloses a delivery device for delivering a substance, in particular a medicament, in a bi-directional flow through the nasal cavities, that is, an air flow which passes into one nostril, around the posterior margin of the nasal septum and in the opposite direction out of the other nostril. This bi-directional air flow advantageously acts to stimulate the sensory nerves in the nasal mucosa, thereby conditioning the subject for the delivery and providing a more comfortable delivery situation. 
     It is an aim of the present invention to provide improved nasal delivery devices and nasal delivery methods for providing for the improved delivery of a substance to a nasal cavity of subject. 
     In one aspect the present invention provides a nasal delivery device for delivering substance to a nasal airway of a subject, comprising: a nosepiece for fitting to a nostril of a subject, the nosepiece including a nozzle through which substance is in use delivered to the nasal airway, and at least one inflatable cuff member which is configured to be inflated subsequent to exhalation by the subject; and a delivery unit for delivering substance through the nozzle of the nosepiece. 
     In another aspect the present invention provides a nasal delivery device for delivering substance to a nasal cavity of a subject, comprising: a nosepiece including a nozzle through which substance is in use delivered to the nasal cavity, and at least one inflatable cuff member which is configured such as, when inflated, to provide a fluid-tight seal between the nosepiece and an inner wall of the nasal cavity of the subject; and a delivery unit for delivering substance through the nozzle of the nosepiece. 
     In a further aspect the present invention provides a nasal delivery device for delivering substance to a nasal airway of a subject, comprising: a nosepiece for fitting to a nostril of a subject, the nosepiece including a nozzle through which substance is in use delivered to the nasal airway, and at least one cuff member which is configured such as, when fitted in a nasal cavity of the subject, to engage an inner wall of the nasal cavity of the subject and direct at least a distal end of the nozzle towards a site in the nasal airway of the subject; and a delivery unit for delivering substance through the nozzle of the nosepiece. 
     In yet another aspect the present invention provides a nasal delivery device for delivering substance to a nasal airway of a subject, comprising: a nosepiece for fitting to a nostril of a subject, the nosepiece including a nozzle through which substance is in use delivered to the nasal airway, and at least one cuff member, at least one of the at least one cuff member including at least one lobe which, when the at least one of the at least one cuff member is fitted in the nasal cavity of the subject, extends into a region of the nasal cavity of the subject such as to at least partially obstruct the same and prevent flow thereinto; and a delivery unit for delivering substance through the nozzle of the nosepiece. 
     In a yet further aspect the present invention provides a nasal delivery device for delivering substance to a nasal airway of a subject, comprising: a nosepiece for fitting to a nasal cavity of a subject, the nosepiece including a first delivery outlet through which substance is in use delivered to the nasal airway of the subject, and at least one second delivery outlet through which at least one gas flow, separate to an exhalation breath of the subject, is in use delivered to the nasal airway of the subject; a delivery unit for delivering substance through the first delivery outlet of the nosepiece; and a gas supply unit for supplying a flow of gas through the at least one second delivery outlet of the nosepiece. 
     In yet another further aspect the present invention provides a method of delivering substance to a nasal airway of a subject, comprising: fitting a nosepiece to a nasal cavity of a subject, the nosepiece including a nozzle through which substance is delivered to the nasal airway, and at least one inflatable cuff member; inflating the at least one cuff member subsequent to exhalation by the subject; and delivering substance through the nozzle of the nosepiece. 
     In a still further aspect the present invention provides a method of delivering substance to a nasal cavity of a subject, comprising the steps of: fitting a nosepiece to a nasal cavity of a subject, the nosepiece including a nozzle through which substance is delivered to the nasal cavity, and at least one inflatable cuff member which is configured such as, when inflated, to provide a fluid-tight seal between the nosepiece and an inner wall of the nasal cavity of the subject; and delivering substance through the nozzle of the nosepiece. 
     In still yet another further aspect the present invention provides a method of delivering substance to a nasal airway of a subject, comprising the steps of: fitting a nosepiece to a nasal cavity of a subject, the nosepiece including a nozzle through which substance is delivered to the nasal airway, and at least one cuff member which is configured such as, when fitted in the nasal cavity of the subject, to engage an inner wall of the nasal cavity of the subject and direct at least a distal end of the nozzle towards a site in the nasal airway of the subject; and delivering substance through the nozzle of the nosepiece. 
     In a still yet further aspect the present invention provides a method of delivering substance to a nasal airway of a subject, comprising the steps of: fitting a nosepiece to a nasal cavity of a subject, the nosepiece including a nozzle through which substance is delivered to the nasal airway, and at least one cuff member, at least one of the at least one cuff member including at least one lobe which, when the at least one of the at least one cuff member is fitted in the nasal cavity of the subject, extends into a region of the nasal cavity of the subject such as to at least partially obstruct the same and prevent flow thereinto; and delivering substance through the nozzle of the nosepiece. 
     In a still yet another further aspect the present invention provides a method of delivering substance to a nasal airway of a subject, comprising the step of: delivering substance through a first delivery outlet and at least one gas flow, separate to an exhalation breath of a subject, through at least one second delivery outlet into the nasal airway of the subject. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Preferred embodiments of the present invention will now be described hereinbelow by way of example only with reference to the accompanying drawings, in which: 
         FIG. 1  schematically illustrates the anatomy of the upper respiratory tract of a human subject; 
         FIG. 2  schematically illustrates a nasal delivery device in accordance with a first embodiment of the present invention; 
         FIG. 3  schematically illustrates the delivery device of  FIG. 2  inserted in a nasal cavity of a subject for operation; 
         FIG. 4  schematically illustrates the delivery device of  FIG. 2  during actuation; 
         FIG. 5  schematically illustrates the delivery device of  FIG. 2  following actuation; 
         FIG. 6  schematically illustrates a nasal delivery device in accordance with a second embodiment of the present invention; 
         FIG. 7  schematically illustrates the delivery device of  FIG. 6  inserted in a nasal cavity of a subject for operation; 
         FIG. 8  schematically illustrates the delivery device of  FIG. 6  during actuation; 
         FIG. 9  schematically illustrates the delivery device of  FIG. 6  following actuation; 
         FIG. 10  schematically illustrates a nasal delivery device in accordance with a third embodiment of the present invention; 
         FIG. 11  schematically illustrates the delivery device of  FIG. 10  inserted in a nasal cavity of a subject for operation; 
         FIG. 12  schematically illustrates the delivery device of  FIG. 10  during actuation; 
         FIG. 13  schematically illustrates the delivery device of  FIG. 2  following actuation; 
         FIG. 14  schematically illustrates a nasal delivery device in accordance with a fourth embodiment of the present invention; 
         FIG. 15  schematically illustrates the delivery device of  FIG. 14  inserted in a nasal cavity of a subject for operation; 
         FIG. 16  schematically illustrates the delivery device of  FIG. 14  during actuation; 
         FIG. 17  schematically illustrates a nasal delivery device in accordance with a fifth embodiment of the present invention; 
         FIG. 18  schematically illustrates the delivery device of  FIG. 17  inserted in a nasal cavity of a subject for operation; 
         FIG. 19  schematically illustrates the delivery device of  FIG. 17  during actuation; 
         FIG. 20  schematically illustrates a nasal delivery device in accordance with a sixth embodiment of the present invention; 
         FIG. 21  schematically illustrates the delivery device of  FIG. 20  inserted in a nasal cavity of a subject for operation; 
         FIG. 22  schematically illustrates the delivery device of  FIG. 20  during actuation; 
         FIG. 23  schematically illustrates a nasal delivery device in accordance with a seventh embodiment of the present invention; 
         FIG. 24  schematically illustrates the delivery device of  FIG. 23  inserted in a nasal cavity of a subject for operation; 
         FIG. 25  schematically illustrates the delivery device of  FIG. 23  during actuation; 
         FIG. 26  schematically illustrates the delivery device of  FIG. 23  following actuation; 
         FIG. 27  schematically illustrates a nasal delivery device in accordance with an eighth embodiment of the present invention; 
         FIG. 28  schematically illustrates the delivery device of  FIG. 27  inserted in a nasal cavity of a subject for operation; 
         FIG. 29  schematically illustrates the delivery device of  FIG. 27  during actuation; 
         FIG. 30  schematically illustrates the delivery device of  FIG. 27  following actuation; 
         FIG. 31  schematically illustrates a nasal delivery device in accordance with a ninth embodiment of the present invention; 
         FIG. 32  schematically illustrates the delivery device of  FIG. 31  inserted in a nasal cavity of a subject for operation; 
         FIG. 33  schematically illustrates the delivery device of  FIG. 31  during actuation; 
         FIG. 34  schematically illustrates the delivery device of  FIG. 31  following actuation; 
         FIG. 35  schematically illustrates a nasal delivery device in accordance with a tenth embodiment of the present invention, illustrated in the inoperative configuration; 
         FIG. 36  schematically illustrates the delivery device of  FIG. 35  where the driving unit is primed for actuation; 
         FIG. 37  schematically illustrates the delivery device of  FIG. 35  inserted in a nasal cavity of a subject for operation; 
         FIG. 38  schematically illustrates the delivery device of  FIG. 35  during actuation where the subject has commenced exhaling and the delivery device is at the point of actuation; 
         FIG. 39  schematically illustrates the delivery device of  FIG. 35  during actuation; 
         FIG. 40  schematically illustrates a nasal delivery device in accordance with an eleventh embodiment of the present invention, illustrated in the inoperative configuration; 
         FIG. 41  schematically illustrates the delivery device of  FIG. 40  where the driving unit is primed for actuation; 
         FIG. 42  schematically illustrates the delivery device of  FIG. 40  inserted in a nasal cavity of a subject for operation; 
         FIG. 43  schematically illustrates the delivery device of  FIG. 40  where the subject has commenced exhaling and the delivery device is at the point of actuation; 
         FIG. 44  schematically illustrates the delivery device of  FIG. 40  where the driving unit has been actuated, the driving unit having initiated actuation of the gas delivery unit and being at the point of initiating actuation of the substance supply unit; 
         FIG. 45  schematically illustrates the delivery device of  FIG. 40  during full actuation; 
         FIG. 46  schematically illustrates a nasal delivery device in accordance with a twelfth embodiment of the present invention, illustrated in the inoperative configuration; 
         FIG. 47  schematically illustrates the delivery device of  FIG. 46  where the driving unit is primed for actuation; 
         FIG. 48  schematically illustrates the delivery device of  FIG. 46  inserted in a nasal cavity of a subject for operation; 
         FIG. 49  schematically illustrates the delivery device of  FIG. 46  where the subject has commenced exhaling and the delivery device is at the point of actuation; 
         FIG. 50  schematically illustrates the delivery device of  FIG. 46  where the driving unit has been actuated, the driving unit having initiated actuation of the gas delivery unit and being at the point of initiating actuation of the substance supply unit; and 
         FIG. 51  schematically illustrates the delivery device of  FIG. 46  during full actuation. 
     
    
    
       FIGS. 2 to 5  illustrate an exhalation breath-actuated nasal delivery device in accordance with a first embodiment of the present invention. 
     DETAILED DESCRIPTION 
     The delivery device comprises a housing  15 , a nosepiece  17  for fitting in a nasal cavity of a subject, and a mouthpiece  19  through which the subject exhales to actuate the delivery device. 
     The nosepiece  17  comprises a guide member  20 , in this embodiment a frusto-conical element, for guiding the nosepiece  17  into a nasal cavity of the subject, and an outlet unit  21  for delivering substance into the nasal airway of the subject. In this embodiment the nosepiece  17  is a replaceable unit. 
     In this embodiment the outlet unit  21  comprises a delivery channel  23  which is in fluid communication with the mouthpiece  19  such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through the mouthpiece  19 , and a nozzle  25  for delivering substance to the nasal airway of the subject. In this embodiment the nozzle  25  is disposed in the delivery channel  23  co-axially with the same. In this embodiment the nozzle  25  is configured to provide an aerosol spray. In an alternative embodiment, for the delivery of a liquid, the nozzle  25  could be configured to deliver a liquid jet as a column of liquid. 
     In this embodiment the outlet unit  21  is movably coupled to the housing  15 , here as provided by a flexible coupling, such as to allow for the positioning of the outlet unit  21  in the nasal cavity of the subject, as will be described in more detail hereinbelow. 
     In an alternative embodiment the outlet unit  21  could be fixed to the housing  15 , and the mouthpiece  19  instead movably coupled to the housing  15 , here as provided by a flexible coupling, such as to allow for the positioning of the outlet unit  21  in the nasal cavity of the subject. 
     In this embodiment at least the tip of the delivery channel  23  comprises a tubular section of a flexible, preferably resilient, material. In a preferred embodiment the material is a semi-soft plastics material, such as silicone rubber. 
     In this embodiment at least the tip of the delivery channel  23  has a tapering section which narrows to the distal end thereof. The delivery channel  23 , in having a narrowing taper, acts, on insertion, to expand the narrow nasal valve of the nasal cavity of the subject. In a preferred embodiment the delivery channel  23  has an elliptical section, preferably an oval section. 
     In a preferred embodiment the distal end of the outlet unit  21  is configured to extend at least about 2 cm, preferably at least about 3 cm, and more preferably from about 2 cm to about 3 cm, into the nasal cavity of the subject. 
     The nosepiece  17  further comprises at least one expandable cuff member  27  for expansion in the nasal cavity of the subject. In this embodiment the at least one cuff member  27  comprises an inflatable member. 
     In this embodiment the at least one cuff member  27  is in fluid communication with the delivery channel  23 , whereby the air flow generated by the subject on exhalation through the mouthpiece  19  acts to inflate the at least one cuff member  27 . In an alternative embodiment the delivery device could include a separate pump unit for inflating the at least one cuff member  27  subsequent to fitting of the nosepiece  17 , and in a preferred embodiment subsequent to, preferably in response to, exhalation through the mouthpiece  19 . 
     In this embodiment the at least one cuff member  27  is an inflatable member which is inflated on exhalation by the subject. In an alternative embodiment the at least one cuff member  27  could be inflated on the nosepiece  17  being located in the correct position. 
     In this embodiment the at least one cuff member  27  comprises a flexible balloon element which is inflated by the generation of a pressure in the delivery channel  23 , with the at least one cuff member  27  deflating on the release of pressure from the delivery channel  23 . In the alternative embodiment, where the at least one cuff member  27  is inflated by a separate pump unit, the at least one cuff member  27  could equally be deflated by the evacuation of gas therefrom using the same pump unit. 
     In one embodiment the at least one cuff member  27  could comprise a resilient balloon element which is inflated by the generation of a pressure in the delivery channel  23 , with the at least one cuff member  27  returning to the original, deflated configuration on the release of pressure from the delivery channel  23 . 
     In another embodiment the at least one cuff member  27  could comprise an inflatable sponge element, in one embodiment a foam element having an encapsulating sealing layer, which can be compressed, in this embodiment by evacuation, to adopt a compact configuration to allow for insertion into a nasal cavity of the subject and inflated, in this embodiment by breaking the vacuum, to allow for the introduction of a gas into the porous structure of the sponge element. In one embodiment such a cuff member  27  could be in selective fluid communication with the atmosphere. In another embodiment such a cuff member  27  could be in selective fluid communication with the delivery channel  23 , whereby the pressure developed in the delivery channel  23  would assist in the inflation of the cuff member  27 . In the alternative embodiment which includes a separate pump unit, the pump unit could be employed to assist in inflating such a cuff member  27  and in deflating the cuff member  27  by the evacuation of gas therefrom. In one embodiment the inflation could be triggered on exhalation by the subject. In another embodiment the inflation could be triggered on the nosepiece  17  being located in the correct position in the nasal cavity of the subject. 
     The at least one cuff member  27  is disposed to an outer surface of the outlet unit  21  such as, on expansion, to engage the inner wall of the nasal cavity of the subject. The at least one cuff member  27 , in being expandable, provides for the expansion of the narrow nasal valve of the nasal cavity of the subject, the sealing of the nosepiece  17  in the nasal cavity of the subject, and the positioning, in particular the direction, of the outlet unit  21  in the nasal cavity of the subject. 
     In this embodiment the at least one cuff member  27  comprises a single annular cuff member  27  which is located about the outlet unit  21  such as to provide a seal between the delivery channel  23  and the inner wall of the nasal cavity of the subject when inflated. 
     In an alternative embodiment the at least one cuff member  27  could comprise a plurality of cuff members  27  which together provide a seal between the delivery channel  23  and the inner wall of the nasal cavity of the subject when inflated. 
     The delivery device further comprises a substance supply unit  29  for delivering metered doses of a substance, in this embodiment an aerosol canister for delivering metered volumes of a propellant, preferably a hydrofluoroalkane (HFA) propellant or the like, containing medicament, either as a suspension or solution, which is fluidly connected to the nozzle  25  to deliver substance from the nosepiece  17 , in this embodiment as an aerosol spray. 
     In this embodiment the substance supply unit  29  is a multi-dose unit for delivering a plurality of metered doses of substance. In another embodiment the substance supply unit  29  could be a single-dose unit for delivering a single metered dose of substance. 
     The substance supply unit  29  is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism  31  which, when triggered, releases the resilient element and actuates the substance supply unit  29  to deliver a metered dose of a substance through the nozzle  25 . 
     In this embodiment the trigger mechanism  31  is configured to cause actuation of the substance supply unit  29  on generation of a predetermined flow rate through the delivery channel  23 . 
     In another embodiment the trigger mechanism  31  could be configured to cause actuation of the substance supply unit  29  on generation of a predetermined pressure within the delivery channel  23 . 
     In a further embodiment the trigger mechanism  31  could be configured to cause actuation of the substance supply unit  29  on generation of either one of a predetermined flow rate through the delivery channel  23  or a predetermined pressure within the delivery channel  23 . 
     In an alternative embodiment the substance supply unit  29  could comprise a mechanical delivery pump, in particular a liquid delivery pump or a powder delivery pump, which delivers metered doses of a substance on actuation thereof. 
     In another alternative embodiment the substance supply unit  29  could comprise a dry powder delivery unit which delivers metered doses of a substance, as a dry powder, on actuation thereof. 
     In yet another alternative embodiment the substance supply unit  29  could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof. 
     Operation of the delivery device will now be described hereinbelow with reference to  FIGS. 3 to 5  of the accompanying drawings. 
     Referring to  FIG. 3 , the nosepiece  17  is first inserted into one of the nasal cavities of a subject until the guide member  20  abuts the nares of the nostril, at which point the distal end of the outlet unit  21  extends about 2 cm into the nasal cavity of the subject, and the mouthpiece  19  is gripped in the lips of the subject. 
     The subject then begins to exhale through the mouthpiece  19 , which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through the delivery channel  23  of the outlet unit  21 , with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject. Exhalation through the mouthpiece  19  acts to develop a pressure in the delivery channel  23 , which pressure acts to inflate the at least one cuff member  27 . As illustrated in  FIG. 4 , the expansion of the at least one cuff member  27  acts to expand the nasal valve in the nasal cavity, seal the delivery channel  23  to the inner wall of the nasal cavity, and position the outlet unit  21  in relation to the nasal cavity of the subject. As will be noted from  FIG. 4 , the outlet unit  21  is forced to adopt the required position by the at least one cuff member  27 , in this embodiment as accommodated by flexing of the outlet unit  21 . 
     In this embodiment, when the flow rate developed through the delivery channel  23  reaches a predetermined value, the release mechanism  31  is triggered to actuate the substance supply unit  29  to deliver a metered dose of a substance to the nozzle  25  and into the nasal cavity of the subject. In the alternative embodiment the release mechanism  31  could be triggered on the generation of a predetermined pressure in the delivery channel  23 . 
     Following exhalation, the pressure in the delivery channel  23  decreases and the at least one cuff member  27  deflates, as illustrated in  FIG. 5 , at which point the mouthpiece  19  is released and the nosepiece  17  withdrawn from the nasal cavity of the subject. 
     In one embodiment, where the delivery device is a single-dose device, the device can be discarded. 
     In another embodiment, where the delivery device is a multi-dose device, the device is ready for further use following priming of the substance supply unit  29 . In a preferred embodiment, where the nosepiece  17  is replaceable, the nosepiece  17  can be replaced with a new nosepiece  17 . 
       FIGS. 6 to 9  illustrate an exhalation breath-actuated nasal delivery device in accordance with a second embodiment of the present invention. 
     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, with like reference signs designating like parts 
     The delivery device of this embodiment differs from that of the above-described first embodiment in further comprising an oral exhalation breath-actuatable gas supply unit  33  for delivering a gas flow through the delivery channel  23  of the outlet unit  21  in response to exhalation by a subject, and in that the mouthpiece  19  is in fluid communication with the gas supply unit  33  and not the delivery channel  23  of the outlet unit  21 , whereby a gas flow is delivered to the delivery channel  23  of the outlet unit  21 , and hence the nasal airway of the subject, in response to exhalation through the mouthpiece  19 . 
     Operation of the delivery device is the same as for the above-described first embodiment, with a gas flow being delivered to the delivery channel  23  of the outlet unit  21  in response to exhalation through the mouthpiece  19 . 
       FIGS. 10 to 13  illustrate an exhalation breath-actuated nasal delivery device in accordance with a third embodiment of the present invention. 
     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, with like reference signs designating like parts. 
     The delivery device of this embodiment differs from that of the above-described first embodiment only in that the nosepiece  17  comprises a plurality of, in this embodiment two, inflatable cuff members  27   a ,  27   b . This arrangement of cuff members  27   a ,  27   b  enables the distalmost cuff member  27   b  to have a reduced size, and thereby facilitates insertion of the outlet unit  21  through the narrow nasal valve in the nasal cavity of the subject. 
     Operation of the delivery device is the same as for the above-described first embodiment. 
       FIGS. 14 to 16  illustrate an exhalation breath-actuated nasal delivery device in accordance with a fourth embodiment of the present invention. 
     The delivery device comprises a housing  35 , a nosepiece  37  for fitting in a nasal cavity of a subject, and a mouthpiece  39  through which the subject exhales to actuate the delivery device. 
     The nosepiece  37  comprises a guide member  40 , in this embodiment a frusto-conical element, for guiding the nosepiece  37  into the nasal cavity of the subject, and an outlet unit  41  for delivering substance into the nasal airway of the subject. In this embodiment the nosepiece  37  is a replaceable unit. 
     In this embodiment the outlet unit  41  comprises a delivery channel  43  which is in fluid communication with the mouthpiece  39  such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through the mouthpiece  39 , and a nozzle  45  for delivering substance into the nasal cavity of the subject. In this embodiment the nozzle  45  is disposed in the delivery channel  43  co-axially with the same. In this embodiment the nozzle  45  is configured to provide an aerosol spray. In an alternative embodiment, for the delivery of a liquid, the nozzle  45  could be configured to deliver a liquid jet as a column of liquid. 
     In this embodiment at least the tip of the delivery channel  43  comprises a tubular section of a flexible, preferably resilient, material. In a preferred embodiment the material is a semi-soft plastics material, such as silicone rubber. 
     In this embodiment at least the tip of the delivery channel  43  has a tapering section which narrows to the distal end thereof. The delivery channel  43 , in having a narrowing taper, acts, on insertion, to expand the narrow nasal valve of the nasal cavity of the subject. In a preferred embodiment the delivery channel  43  has an elliptical section, preferably an oval section. 
     In a preferred embodiment the outlet unit  41  is configured to extend at least about 2 cm, preferably at least about 3 cm, and more preferably from about 2 cm to about 3 cm, into the nasal cavity of the subject. 
     The nosepiece  37  further comprises at least one cuff member  47  for fitting in the nasal cavity of the subject. In this embodiment the at least one cuff member  47  is a resilient member which is deformable to allow for insertion into the nasal cavity of the subject and, on insertion, expansion to adopt the required position in the nasal cavity, in which position the outlet unit  41  is correctly positioned. When so positioned, the at least one cuff member  47  provides for the expansion of the narrow nasal valve in the nasal cavity, the sealing of the outlet unit  41  in the nasal cavity, and the positioning, in particular the direction, of the outlet unit  41  in the nasal cavity of the subject. In this embodiment the at least one cuff member  47  comprises a sponge member, here a foam member. In an alternative embodiment the at least one cuff member  47  could comprise a gel-filled member, such as a silicone-filled member. 
     In this embodiment the at least one cuff member  47  is configured such that, when inserted in the nasal cavity, the outlet unit  41  is directed at a lower region of the nasal cavity of the subject. In preferred embodiments the at least one cuff member  47  can be configured to direct the outlet unit  41  at any region of the inferior meatus and the inferior region of the middle meatus, whereby substance can be targeted in particular at the inferior nasal concha, and the adenoids and tubal ostia in the superior region of the epipharynx. 
     Regions in the nasal airway adjacent the inferior meatus and the inferior region of the middle meatus represent the regions in the nasal airway which provide the path of least flow resistance therethrough. With existing nasal spray systems, the delivery is such that the delivered substance flows along the floor of the nasal cavity, with the result that the substance does not reach the adenoids or the tubal ostia. 
     In this embodiment the at least one cuff member  47  includes at least one lobe  54 , here a single lobe  54 , which is configured such as to extend into, and thereby obstruct, an upper region of the nasal cavity of the subject, the at least one lobe  54  acting to force the delivered flow to follow a flow path defined by the inferior meatus and the inferior region of the middle meatus. The achievement of such a flow path, allied with an optimization of the particle size distribution, provides that a much larger fraction of substance can be delivered to sites in the inferior meatus and the inferior region of the middle meatus. 
     In this embodiment the at least one cuff member  47  comprises a single annular cuff member  47  which is disposed about the outlet unit  41 . 
     In an alternative embodiment the at least one cuff member  47  could comprise a plurality of cuff members  47  which are disposed about the outlet unit  41 . 
     The delivery device further comprises a substance supply unit  49  for delivering metered doses of a substance, in this embodiment an aerosol canister for delivering metered volumes of a propellant, preferably a hydrofluoroalkane (HFA) propellant or the like, containing medicament, either as a suspension or solution, which is fluidly connected to the nozzle  45  to deliver substance from the nosepiece  37 , in this embodiment as an aerosol spray. 
     In this embodiment the substance supply unit  49  is a multi-dose unit for delivering a plurality of metered doses of substance. In another embodiment the substance supply unit  49  could be a single-dose unit for delivering a single metered dose of substance. 
     The substance supply unit  49  is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism  51  which, when triggered, releases the resilient element and actuates the substance supply unit  49  to deliver a metered dose of a substance through the nozzle  45 . 
     In this embodiment the trigger mechanism  51  is configured to cause actuation of the substance supply unit  49  on generation of a predetermined flow rate through the delivery channel  43 . 
     In another embodiment the trigger mechanism  51  could be configured to cause actuation of the substance supply unit  49  on generation of a predetermined pressure within the delivery channel  43 . 
     In a further embodiment the trigger mechanism  51  could be configured to cause actuation of the substance supply unit  49  on generation of either one of a predetermined flow rate through the delivery channel  43  or a predetermined pressure within the delivery channel  43 . 
     In an alternative embodiment the substance supply unit  49  could comprise a mechanical delivery pump, in particular a liquid delivery pump or a powder delivery pump, which delivers metered doses of a substance on actuation thereof. 
     In another alternative embodiment the substance supply unit  49  could comprise a dry powder delivery unit which delivers metered doses of a substance, as a dry powder, on actuation thereof. 
     In yet another alternative embodiment the substance supply unit  49  could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof. 
     Operation of the delivery device will now be described hereinbelow with reference to  FIGS. 15 and 16  of the accompanying drawings. 
     Referring to  FIG. 15 , the nosepiece  37  is first inserted into a nasal cavity of a subject until the guide member  40  abuts the nares of the nostril, at which point the distal end of the outlet unit  41  extends about 2 cm into the nasal cavity of the subject, and the mouthpiece  39  is gripped in the lips of the subject. 
     The subject then begins to exhale through the mouthpiece  39 , which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through the delivery channel  43  of the outlet unit  41 , with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject. 
     In this embodiment, when the flow rate developed through the delivery channel  43  reaches a predetermined value, the release mechanism  51  is triggered to actuate the substance supply unit  49  to deliver a metered dose of a substance to the nozzle  45  and into the nasal cavity of the subject. In the alternative embodiment the release mechanism  51  could be triggered on the generation of a predetermined pressure in the delivery channel  43 . 
     Following exhalation, the mouthpiece  39  is released and the nosepiece  37  withdrawn from the nasal cavity of the subject. 
     In one embodiment, where the delivery device is a single-dose device, the device can be discarded. 
     In another embodiment, where the delivery device is a multi-dose device, the device is ready for further use following priming of the substance supply unit  49 . In a preferred embodiment, where the nosepiece  37  is replaceable, the nosepiece  37  can be replaced with a new nosepiece  37 . 
       FIGS. 17 to 19  illustrate an exhalation breath-actuated nasal delivery device in accordance with a fifth embodiment of the present invention. 
     The delivery device of this embodiment is very similar to the delivery device of the above-described fourth embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts. 
     The delivery device of this embodiment differs from that of the above-described fourth embodiment only in the configuration of the outlet unit  41  and the at least one cuff member  47 . 
     In this embodiment the at least one cuff member  47  is configured such that, when inserted in the nasal cavity of the subject, the outlet unit  41  is directed at a middle region of the nasal cavity of the subject. In a preferred embodiment the at least one cuff member  47  can be configured to direct the outlet unit  41  at any region of the middle meatus and the inferior region of the superior meatus, whereby substance can be targeted in particular at the middle nasal concha, the sinus infundibulum and the sinus ostia. 
     The middle meatus is the region of the nasal cavity located under and lateral to the middle nasal concha, with the sinus infundibulum and the sinus ostia representing the sites of the main pathologies in many very common diseases, such as chronic sinusitis, which affects about 10 to 15% of the population and has no FDA approved treatment, and nasal polyposis. The only known treatment of these conditions is the application of drops during a rigorous and complex procedure involving severe neck extension and the so-called “Mecca” position. As will be appreciated, however, owing to the complicated and often painful procedure, compliance is very poor. Existing nasal spray systems are ineffective in delivering substance to this region of the nasal cavity. 
     In this embodiment the at least one cuff member  47  includes upper and lower lobes  54   a ,  54   b  which are configured such as to extend into, and thereby obstruct, respective ones of the upper and lower regions of the nasal cavity of the subject, the lobes  54   a ,  54   b  acting to force a delivered flow to follow a flow path defined by the middle meatus and the inferior region of the superior meatus. The achievement of such a flow path, allied with an optimization of the particle size distribution, provides that a much larger fraction of substance can be delivered to sites in the middle meatus and the inferior region of the middle meatus. 
     Operation of the delivery device is the same as for the above-described fourth embodiment. 
       FIGS. 20 to 22  illustrate an exhalation breath-actuated nasal delivery device in accordance with a sixth embodiment of the present invention. 
     The delivery device of this embodiment is very similar to the delivery device of the above-described fourth embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts. 
     The delivery device of this embodiment differs from that of the above-described fourth embodiment only in the configuration of the outlet unit  41  and the at least one cuff member  47 . 
     In this embodiment the at least one cuff member  47  is configured such that, when inserted in the nasal cavity of the subject, the outlet unit  41  is directed at a superior region of the nasal cavity of the subject. In a preferred embodiment the at least one cuff member  47  can be configured to direct the outlet unit  41  at any region of the superior meatus, and in particular provide for the targeting of the superior nasal concha and the olfactory region. 
     The olfactory region is located in the superior region of the nasal cavity and typically has a surface area of from about 4 to 6 cm 2 . The olfactory region represents the only region where it is possible to circumvent the blood-to-brain barrier (BBB) and enable communication with the cerebrospinal fluid (CSF) and the brain. Such delivery is necessary to enable effective treatment of neurological diseases, such as Alzheimer&#39;s and Parkinson&#39;s disease, psychiatric diseases and intracerebral infections. 
     The olfactory region is reached through narrow slit-like passages and the delivery of substance to this region is not possible using existing nasal delivery systems. 
     In existing nasal spray systems, substantially all of the particles are far too large to pass through the passages in communication with the olfactory region. Indeed, such spray systems are specifically designed to deliver particles having an average diameter of greater than 10 μm in order to comply with the FDA requirements which require that the maximum fraction of particles having a diameter of less than 10 μm be 5% of the total fraction. The reason for this requirement is that, where the velum is not closed, as would be the case where a subject inhales through the nose as prescribed for delivery, particles having a diameter of less than 10 μm could escape from the nasal cavity and be inhaled into the lungs. 
     In addition, in existing nasal spray systems, the flow characteristics of particles delivered into the nasal cavity are not suited to enable delivery through the passages communicating with the olfactory region. 
     Furthermore, the sniffing action by a subject during delivery causes the particles to be drawn into the inferior and middle regions of the nasal cavity, where the flow resistance is the lowest, with only a minimal fraction, if any, of the particles being delivered to the olfactory region. 
     In this embodiment, by ensuring closure of the velum in delivery and optimizing both the particle size distribution so as to include a larger fraction of smaller particles, typically having a particle size of less than 10 μm, and the aerodynamic delivery conditions, the delivery device provides for the effective delivery of substance to the olfactory region. Such a delivery regime has not previously been known, and has been recognised by the present applicant as providing an improved delivery device and delivery method. 
     In this embodiment the at least one lobe  54  of the at least one cuff member  47  is configured such as to extend into, and thereby obstruct, a lower region of the nasal cavity of the subject, the at least one lobe  54  acting to force a delivered flow to follow a flow path defined by the superior meatus and in particular the olfactory region. The achievement of such a flow path, allied with an optimization of the particle size distribution, provides that a much larger fraction of substance can be delivered to sites in the superior meatus and in particular the olfactory region. 
     Operation of the delivery device is the same as for the above-described fourth embodiment. 
       FIGS. 23 to 26  illustrate an exhalation breath-actuated nasal delivery device in accordance with a seventh embodiment of the present invention. 
     The delivery device comprises a housing  55 , a nosepiece  57  for fitting in a nasal cavity of a subject, and a mouthpiece  59  through which the subject exhales to actuate the delivery device. 
     The nosepiece  57  comprises a guide member  60 , in this embodiment a frusto-conical element, for guiding the nosepiece  57  into a nasal cavity of the subject, and an outlet unit  61  for delivering substance into the nasal airway of the subject. In this embodiment the nosepiece  57  is a replaceable unit. 
     In this embodiment the outlet unit  61  comprises a delivery channel  63  which is in fluid communication with the mouthpiece  59  such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through the mouthpiece  59 , and a nozzle  65  for delivering substance to the nasal airway of the subject. In this embodiment the nozzle  65  is disposed in the delivery channel  63  co-axially with the same. In this embodiment the nozzle  65  is configured to provide an aerosol spray. In an alternative embodiment, for the delivery of a liquid, the nozzle  65  could be configured to deliver a liquid jet as a column of liquid. 
     In this embodiment the outlet unit  61  is movably coupled to the housing  55 , here as provided by a flexible coupling, such as to allow for the positioning of the outlet unit  61  in the nasal cavity of the subject, as will be described in more detail hereinbelow. 
     In an alternative embodiment the outlet unit  61  could be fixed to the housing  55 , and the mouthpiece  59  instead movably coupled to the housing  55 , here as provided by a flexible coupling, such as to allow for the positioning of the outlet unit  61  in the nasal cavity of the subject. 
     In this embodiment at least the tip of the delivery channel  63  comprises a tubular section of a flexible, preferably resilient, material. In a preferred embodiment the material is a semi-soft plastics material, such as silicone rubber. 
     In this embodiment at least the tip of the delivery channel  63  has a tapering section which narrows to the distal end thereof. The delivery channel  63 , in having a narrowing taper, acts, on insertion, to expand the narrow nasal valve of the nasal cavity of the subject. In a preferred embodiment the delivery channel  63  has an elliptical section, preferably an oval section. 
     In a preferred embodiment the distal end of the outlet unit  61  is configured to extend at least about 2 cm, preferably at least about 3 cm, and more preferably from about 2 cm to about 3 cm, into the nasal cavity of the subject. 
     The nosepiece  57  further comprises at least one expandable cuff member  67  for expansion in the nasal cavity of the subject. In this embodiment the at least one cuff member  67  comprises an inflatable member. 
     In this embodiment the at least one cuff member  67  is in fluid communication with the delivery channel  63 , whereby the air flow generated by the subject on exhalation through the mouthpiece  59  acts to inflate the at least one cuff member  67 . In an alternative embodiment the delivery device could include a separate pump unit for inflating the at least one cuff member  67  subsequent to fitting of the nosepiece  57 , and in a preferred embodiment subsequent to, preferably in response to, exhalation through the mouthpiece  59 . 
     In this embodiment the at least one cuff member  67  is an inflatable member which is inflated on exhalation by the subject. In an alternative embodiment the at least one cuff member  67  could be inflated on the nosepiece  57  being located in the correct position. 
     In this embodiment the at least one cuff member  67  comprises a flexible balloon element which is inflated by the generation of a pressure in the delivery channel  63 , with the at least one cuff member  67  deflating on the release of pressure from the delivery channel  63 . In the alternative embodiment, where the at least one cuff member  67  is inflated by a separate pump unit, the at least one cuff member  67  could equally be deflated by the evacuation of gas therefrom using the same pump unit. 
     In one embodiment the at least one cuff member  67  could comprise a resilient balloon element which is inflated by the generation of a pressure in the delivery channel  63 , with the at least one cuff member  67  returning to the original, deflated configuration on the release of pressure from the delivery channel  63 . 
     In another embodiment the at least one cuff member  67  could comprise an inflatable sponge element, in one embodiment a foam element having an encapsulating sealing layer, which can be compressed, in this embodiment by evacuation, to adopt a compact configuration to allow for insertion into a nasal cavity of the subject and inflated, in this embodiment by breaking the vacuum, to allow for the introduction of a gas into the porous structure of the sponge element. In one embodiment such a cuff member  67  could be in selective fluid communication with the atmosphere. In another embodiment such a cuff member  67  could be in selective fluid communication with the delivery channel  63 , whereby the pressure developed in the delivery channel  63  would assist in the inflation of the cuff member  67 . In the alternative embodiment which includes a separate pump unit, the pump unit could be employed to assist in inflating such a cuff member  67  and in deflating the cuff member  67  by the evacuation of gas therefrom. In one embodiment the inflation could be triggered on exhalation by the subject. In another embodiment the inflation could be triggered on the nosepiece  57  being located in the correct position in the nasal cavity of the subject. 
     The at least one cuff member  67  is disposed to an outer surface of the outlet unit  61  such as, on expansion, to engage the inner wall of the nasal cavity of the subject. The at least one cuff member  67 , in being expandable, provides for the expansion of the narrow nasal valve of the nasal cavity of the subject, the sealing of the nosepiece  57  in the nasal cavity of the subject, and the positioning, in particular the direction, of the outlet unit  61  in the nasal cavity of the subject. 
     In this embodiment the at least one cuff member  67  comprises a single annular cuff member  67  which is located about the outlet unit  61  such as to provide a seal between the delivery channel  63  and the inner wall of the nasal cavity of the subject when inflated. 
     In an alternative embodiment the at least one cuff member  67  could comprise a plurality of cuff members  67  which together provide a seal between the delivery channel  63  and the inner wall of the nasal cavity of the subject when inflated. 
     In this embodiment the at least one cuff member  67  is configured such that, when inserted in the nasal cavity, the outlet unit  61  is directed at a lower region of the nasal cavity of the subject. In preferred embodiments the at least one cuff member  67  can be configured to direct the outlet unit  61  at any region of the inferior meatus and the inferior region of the middle meatus, whereby substance can be targeted in particular at the inferior nasal concha, and the adenoids and tubal ostia in the superior region of the epipharynx. 
     Regions in the nasal airway adjacent the inferior meatus and the inferior region of the middle meatus represent the regions in the nasal airway which provide the path of least flow resistance therethrough. With existing nasal spray systems, the delivery is such that the delivered substance flows along the floor of the nasal cavity, with the result that the substance does not reach the adenoids or the tubal ostia. 
     In this embodiment the at least one cuff member  67  includes at least one lobe  74 , here a single lobe  74 , which is configured such as to extend into, and thereby obstruct, an upper region of the nasal cavity of the subject, the at least one lobe  74  acting to force the delivered flow to follow a flow path defined by the inferior meatus and the inferior region of the middle meatus. The achievement of such a flow path, allied with an optimization of the particle size distribution, provides that a much larger fraction of substance can be delivered to sites in the inferior meatus and the inferior region of the middle meatus. 
     In this embodiment the at least one cuff member  67  comprises a single annular cuff member  67  which is disposed about the outlet unit  61 . 
     In an alternative embodiment the at least one cuff member  67  could comprise a plurality of cuff members  67  which are disposed about the outlet unit  61 . 
     The delivery device further comprises a substance supply unit  69  for delivering metered doses of a substance, in this embodiment an aerosol canister for delivering metered volumes of a propellant, preferably a hydrofluoroalkane (HFA) propellant or the like, containing medicament, either as a suspension or solution, which is fluidly connected to the nozzle  65  to deliver substance from the nosepiece  57 , in this embodiment as an aerosol spray. 
     In this embodiment the substance supply unit  69  is a multi-dose unit for delivering a plurality of metered doses of substance. In another embodiment the substance supply unit  69  could be a single-dose unit for delivering a single metered dose of substance. 
     The substance supply unit  69  is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism  71  which, when triggered, releases the resilient element and actuates the substance supply unit  69  to deliver a metered dose of a substance through the nozzle  65 . 
     In this embodiment the trigger mechanism  71  is configured to cause actuation of the substance supply unit  69  on generation of a predetermined flow rate through the delivery channel  63 . 
     In another embodiment the trigger mechanism  71  could be configured to cause actuation of the substance supply unit  69  on generation of a predetermined pressure within the delivery channel  63 . 
     In a further embodiment the trigger mechanism  71  could be configured to cause actuation of the substance supply unit  69  on generation of either one of a predetermined flow rate through the delivery channel  63  or a predetermined pressure within the delivery channel  63 . 
     In an alternative embodiment the substance supply unit  69  could comprise a mechanical delivery pump, in particular a liquid delivery pump or a powder delivery pump, which delivers metered doses of a substance on actuation thereof. 
     In another alternative embodiment the substance supply unit  69  could comprise a dry powder delivery unit which delivers metered doses of a substance, as a dry powder, on actuation thereof. 
     In yet another alternative embodiment the substance supply unit  69  could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof. 
     Operation of the delivery device will now be described hereinbelow with reference to  FIGS. 24 to 26  of the accompanying drawings. 
     Referring to  FIG. 24 , the nosepiece  57  is first inserted into one of the nasal cavities of a subject until the guide member  60  abuts the nares of the nostril, at which point the distal end of the outlet unit  61  extends about 2 cm into the nasal cavity of the subject, and the mouthpiece  59  is gripped in the lips of the subject. 
     The subject then begins to exhale through the mouthpiece  59 , which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through the delivery channel  63  of the outlet unit  61 , with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject. Exhalation through the mouthpiece  59  acts to develop a pressure in the delivery channel  63 , which pressure acts to inflate the at least one cuff member  67 . As illustrated in  FIG. 25 , the expansion of the at least one cuff member  67  acts to expand the nasal valve in the nasal cavity, seal the delivery channel  63  to the inner wall of the nasal cavity, and position the outlet unit  61  in relation to the nasal cavity of the subject. As will be noted from  FIG. 25 , the outlet unit  61  is forced to adopt the required position by the at least one cuff member  67 , in this embodiment as accommodated by flexing of the outlet unit  61 . 
     In this embodiment, when the flow rate developed through the delivery channel  63  reaches a predetermined value, the release mechanism  71  is triggered to actuate the substance supply unit  69  to deliver a metered dose of a substance to the nozzle  65  and into the nasal cavity of the subject. In the alternative embodiment the release mechanism  71  could be triggered on the generation of a predetermined pressure in the delivery channel  63 . 
     Following exhalation, the pressure in the delivery channel  63  decreases and the at least one cuff member  67  deflates, as illustrated in  FIG. 26 , at which point the mouthpiece  59  is released and the nosepiece  57  withdrawn from the nasal cavity of the subject. 
     In one embodiment, where the delivery device is a single-dose device, the device can be discarded. 
     In another embodiment, where the delivery device is a multi-dose device, the device is ready for further use following priming of the substance supply unit  69 . In a preferred embodiment, where the nosepiece  57  is replaceable, the nosepiece  57  can be replaced with a new nosepiece  57 . 
       FIGS. 27 to 30  illustrate an exhalation breath-actuated nasal delivery device in accordance with an eighth embodiment of the present invention. 
     The delivery device of this embodiment is very similar to the delivery device of the above-described seventh embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts. 
     The delivery device of this embodiment differs from that of the above-described seventh embodiment only in the configuration of the outlet unit  61  and the at least one cuff member  67 . 
     In this embodiment the at least one cuff member  67  is configured such that, when inserted in the nasal cavity of the subject, the outlet unit  61  is directed at a middle region of the nasal cavity of the subject. In a preferred embodiment the at least one cuff member  67  can be configured to direct the outlet unit  61  at any region of the middle meatus and the inferior region of the superior meatus, whereby substance can be targeted in particular at the middle nasal concha, the sinus infundibulum and the sinus ostia 
     The middle meatus is the region of the nasal cavity located under and lateral to the middle nasal concha, with the sinus infundibulum and the sinus ostia representing the sites of the main pathologies in many very common diseases, such as chronic sinusitis, which affects about 10 to 15% of the population and has no FDA approved treatment, and nasal polyposis. The only known treatment of these conditions is the application of drops during a rigorous and complex procedure involving severe neck extension and the so-called “Mecca” position. As will be appreciated, however, owing to the complicated and often painful procedure, compliance is very poor. Existing nasal spray systems are ineffective in delivering substance to this region of the nasal cavity. 
     In this embodiment the at least one cuff member  67  includes upper and lower lobes  74   a ,  74   b  which are configured such as to extend into, and thereby obstruct, respective ones of the upper and lower regions of the nasal cavity of the subject, the lobes  74   a ,  74   b  acting to force a delivered flow to follow a flow path defined by the middle meatus and the inferior region of the superior meatus. The achievement of such a flow path, allied with an optimization of the particle size distribution, provides that a much larger fraction of substance can be delivered to sites in the middle meatus and the inferior region of the middle meatus. 
     Operation of the delivery device is the same as for the above-described seventh embodiment. 
       FIGS. 31 to 34  illustrate an exhalation breath-actuated nasal delivery device in accordance with a ninth embodiment of the present invention. 
     The delivery device of this embodiment is very similar to the delivery device of the above-described seventh embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts. 
     The delivery device of this embodiment differs from that of the above-described seventh embodiment only in the configuration of the outlet unit  61  and the at least one cuff member  67 . 
     In this embodiment the at least one cuff member  67  is configured such that, when inserted in the nasal cavity of the subject, the outlet unit  61  is directed at a superior region of the nasal cavity of the subject. In a preferred embodiment the at least one cuff member  67  can be configured to direct the outlet unit  61  at any region of the superior meatus, and in particular provide for the targeting of the superior nasal concha and the olfactory region. 
     The olfactory region is located in the superior region of the nasal cavity and typically has a surface area of from about 4 to 6 cm 2 . The olfactory region represents the only region where it is possible to circumvent the blood-to-brain barrier (BBB) and enable communication with the cerebrospinal fluid (CSF) and the brain. Such delivery is necessary to enable effective treatment of neurological diseases, such as Alzheimer&#39;s and Parkinson&#39;s disease, psychiatric diseases and intracerebral infections. 
     The olfactory region is reached through narrow slit-like passages and the delivery of substance to this region is not possible using existing nasal delivery systems. 
     In existing nasal spray systems, substantially all of the particles are far too large to pass through the passages in communication with the olfactory region. Indeed, such spray systems are specifically designed to deliver particles having an average diameter of greater than 10 μm in order to comply with the FDA requirements which require that the maximum fraction of particles having an average diameter of less than 10 μm be 5% of the total fraction. The reason for this requirement is that, where the velum is not closed, as would be the case where a subject inhales through the nose as prescribed for delivery, particles having an average diameter of less than 10 μm could escape from the nasal cavity and be inhaled into the lungs. 
     In addition, in existing nasal spray systems, the flow rate of particles delivered into the nasal cavity is too great to enable delivery through the passages communicating with the olfactory region. 
     Furthermore, inhalation by a subject during delivery causes the particles to be drawn into the inferior and middle regions of the nasal cavity, where the flow resistance is the lowest, with only a minimal fraction, if any, of the particles being delivered to the olfactory region. 
     In this embodiment, by ensuring closure of the velum in delivery and optimizing both the particle size distribution so as to include a larger fraction of smaller particles, typically having a particle size of less than 10 μm, and the aerodynamic delivery conditions, the delivery device provides for the effective delivery of substance to the olfactory region. Such a delivery regime has not previously been known, and has been recognised by the present applicant as providing an improved delivery device and delivery method. 
     In this embodiment the at least one lobe  74  of the at least one cuff member  67  is configured such as to extend into, and thereby obstruct, a lower region of the nasal cavity of the subject, the at least one lobe  74  acting to force a delivered flow to follow a flow path defined by the superior meatus and in particular the olfactory region. The achievement of such a flow path, allied with an optimization of the particle size distribution, provides that a much larger fraction of substance can be delivered to sites in the superior meatus and in particular the olfactory region. 
     Operation of the delivery device is the same as for the above-described seventh embodiment. 
       FIGS. 35 to 39  illustrate an exhalation breath-actuated nasal delivery device in accordance with a tenth embodiment of the present invention. 
     The delivery device comprises a housing  75 , a nosepiece  77  for fitting in a nasal cavity of a subject, and a mouthpiece  79  through which the subject exhales to actuate the delivery device. 
     The nosepiece  77  comprises a cuff member  80 , in this embodiment a frusto-conical element, for positioning the nosepiece  77  in the nasal cavity of the subject and providing a fluid-tight seal therewith, and an outlet unit  81  for delivering substance into the nasal airway of the subject. 
     In this embodiment the outlet unit  81  comprises a nozzle  82  from which substance is delivered into the nasal cavity of the subject, and a delivery channel  83  through which a gas flow, separate from the exhalation breath of the subject, is delivered to interact with the substance delivered from the nozzle  82 . This configuration, in interacting with the substance and altering the characteristics of the delivered substance, advantageously provides for improved delivery of the substance. 
     In this embodiment the nozzle  82  is configured to provide an aerosol spray. In an alternative embodiment, for the delivery of a liquid, the nozzle  82  could be configured to deliver a liquid jet as a column of liquid. 
     In this embodiment the nozzle  82  is disposed in the delivery channel  83  co-axially with the same. In this embodiment the delivery channel  83  is an annular channel which surrounds the nozzle  82  such as to define an annular gas flow which interacts with the substance delivered from the nozzle  82 . 
     The delivery device further comprises a substance supply unit  85  which is fluidly connected to the nozzle  82  such as to deliver a metered dose of a substance on actuation thereof. In this embodiment the substance supply unit  85  comprises a mechanical pump for delivering a metered dose of a substance on actuation thereof. 
     The delivery device further comprises a gas supply unit  87  which is fluidly connected to the delivery channel  83  for supplying a gas flow therethrough. The gas supply unit  87  comprises a cylinder  89 , a piston  91  which is movably disposed within the cylinder  89  and defines a chamber  93  forward thereof which contains a gas, with a volume of the contained gas, typically about 5 ml, being expelled from the chamber  93  on actuation of the gas supply unit  87 . 
     The delivery device further comprises a driving unit  95  which is actuatable to actuate the substance supply unit  85  and the gas supply unit  87 . 
     The driving unit  95  comprises a drive member  97 , in this embodiment a block, which is coupled, here commonly coupled, to the body of the substance supply unit  85  and the piston  91  of the gas supply unit  87  and movable between a first, rest position (as illustrated in  FIGS. 35 to 38 ) in which the substance supply unit  85  and the gas supply unit  87  are in the non-actuated positions and a second, actuated position (as illustrated in  FIG. 39 ) in which the body of the substance supply unit  85  and the piston  91  of the gas supply unit  87  are advanced to the actuated positions, and a return biasing element  99 , in this embodiment a resilient element, particularly a compression spring, for returning the drive member  97  to the rest position. 
     The driving unit  95  further comprises a load biasing element  101 , in this embodiment a resilient element, particularly a compression spring, for biasing the drive member  97  in an actuating direction when in the rest position, and a loading member  103 , in this embodiment a lever, for loading the load biasing element  101  such as to bias the drive member  97  when in the rest position with an actuation force. The loading member  103  is movable between a first, inoperative position (as illustrated in  FIG. 35 ) in which the load biasing element  101  is not loaded thereby, and a second, operative position (as illustrated in  FIGS. 36 to 38 ) in which the biasing element  101 , when restrained, loads the drive member  97  with the actuation force. 
     The delivery device further comprises a trigger mechanism  105  which is configured normally to lock the drive member  97  of the driving unit  95  in the rest position and release the same on exhalation by the subject through the mouthpiece  79 , which drive member  97 , when loaded by the load biasing element  101 , once released acts commonly to actuate the substance supply unit  85  and the gas supply unit  87 . 
     In this embodiment the trigger mechanism  105  is configured to cause actuation of the driving unit  95  on generation of a predetermined flow rate through the mouthpiece  79 . 
     In another embodiment the trigger mechanism  105  could be configured to cause actuation of the driving unit  95  on generation of a predetermined pressure within the mouthpiece  79 . 
     In this embodiment the trigger mechanism  105  comprises a linkage assembly  107  which includes first and second link elements  109 ,  111 , and a biasing element  112 , in this embodiment a resilient element, particularly a tension spring, for biasing the linkage assembly  107  to a locking configuration (as illustrated in  FIGS. 35 to 37 ) in which the linkage assembly  107  acts to lock the drive member  97  of the driving unit  95  in the rest position and prevent movement thereof when loaded by the load biasing element  101 . 
     One of the link elements  109  includes a pivot  113  about which the same is rotatable, and first and second arms  115 ,  117 . One of the arms  115  extends into the mouthpiece  79  and, when the linkage assembly  107  is in the locking configuration, is biased to a rest position (as illustrated in  FIGS. 35 to 37 ) in which the flow path through the mouthpiece  79  is substantially closed, the one arm  115  thereby providing a vane to be acted upon by the exhalation breath of the subject. 
     The other of the link elements  111  is pivotally coupled at one end to the distal end of the other, second arm  117  of the first link element  109  and at the other end to the drive member  97  of the driving unit  95 ; the second arm  117  of the first link element  109  being angularly positioned relative to the first arm  115  thereof such that, when the linkage assembly  107  is in the locking configuration, the second arm  117  of the first link element  109  and the second link element  111  enclose an angle of less than 180 degrees on the side opposite to the first arm  115  of the first link element  109 , whereby the second arm  117  of the first link element  109  and the second link element  111  are over-centered and support the drive member  97  of the driving unit  95  when loaded. 
     Operation of the delivery device will now be described hereinbelow with reference to  FIGS. 36 to 39  of the accompanying drawings. 
     In a first step, as illustrated in  FIG. 36 , the loading member  103  is operated to bias the biasing element  101  and load the drive member  97  of the driving unit  95  with the actuation force. 
     Referring to  FIG. 37 , the nosepiece  77  is then first inserted into a nasal cavity of a subject until the cuff member  80  is fitted in the nares of the nostril, at which point the distal end of the outlet unit  81  extends about 2 cm into the nasal cavity of the subject, and the mouthpiece  79  is gripped in the lips of the subject. 
     The subject then begins to exhale through the mouthpiece  79 , which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow over the first arm  115  of the first link element  109  of the linkage assembly  107  which extends into the mouthpiece  79 . While the flow rate developed is not sufficient to actuate the trigger mechanism  105 , the linkage assembly  107  of the trigger mechanism  105  acts to retain the drive member  97  of the driving unit  95  in the locked position, whereby the substance supply unit  85  and the gas supply unit  87  are not actuated. When the flow rate developed reaches a predetermined value, as illustrated in  FIG. 38 , the rotation of the first arm  115  of the first link element  109  is such as to rotate the second arm  117  of the first link element  109  to a position in which the support provided together with the second link element  111  is unstable and collapses. Referring to  FIG. 39 , this collapse of the linkage assembly  107  enables the drive member  97  of the driving unit  95  to be moved by the load biasing element  101  to the actuated position, which movement actuates the substance supply unit  85  to deliver a metered dose of a substance through the nozzle  82  and the gas supply unit  87  to deliver a metered volume of a gas through the delivery channel  83 , which gas flow interacts with the delivered substance to modify the characteristics of the delivered substance, and thereby provide for improved delivery to the nasal airway of the subject. 
     Following actuation, the mouthpiece  79  is released and the nosepiece  77  is withdrawn from the nasal cavity of the subject. 
     The loading member  103  of the driving unit  95  is then returned to the inoperative position, and the drive member  97  of the driving unit  95  is returned to the rest position by the return biasing element  99 . The return of the drive member  97  to the rest position causes the body of the substance supply unit  85  and the piston  91  of the gas supply unit  87  to be returned to the rest positions. 
     Following the return of the drive member  97  to the rest position, the linkage assembly  107  again adopts the locking configuration, with the linkage assembly  107  being maintained in the locking configuration by the linkage biasing element  112 . In this configuration, the delivery device is ready for further use. 
       FIGS. 40 to 45  illustrate an exhalation breath-actuated nasal delivery device in accordance with an eleventh embodiment of the present invention. 
     The delivery device of this embodiment is very similar to the delivery device of the above-described tenth embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts. 
     The delivery device of this embodiment differs from that of the above-described tenth embodiment only in the configuration of the driving unit  95 . 
     In this embodiment the drive member  97  of the drive unit  95  is not configured to commence actuation of the substance supply unit  85  and the gas supply unit  87  at the same instant as in the above-described tenth embodiment, but rather is configured such that actuation of the gas supply unit  87  is commenced prior to the actuation of the substance supply unit  85 , whereby an interacting gas flow is delivered from the delivery channel  83  of the outlet unit  81  prior to the delivery of substance from the nozzle  82  and then during the delivery of substance from the nozzle  82  such as to interact with the same. 
     In this embodiment the delayed actuation of the substance supply unit  85  is achieved by configuring the drive member  97  such as to be spaced from the body of the substance supply unit  85  when the drive member  97  is in the rest position, whereby the drive member  97  has to be advanced a predetermined distance, corresponding to a predetermined time period, prior to common actuation of the substance supply unit  85  and the gas supply unit  87 . In this embodiment the substance supply unit  85  includes a biasing element  119  for returning the substance supply unit  85  to the rest position following actuation. With this configuration, the interval between actuation of the gas supply unit  87  and the common actuation of the substance supply unit  85  and the gas supply unit  87  can be controlled by altering the spacing between the drive member  97  and the body of the substance supply unit  85 . 
     Operation of the delivery device is the same as for the above-described tenth embodiment. 
       FIGS. 46 to 51  illustrate an exhalation breath-actuated nasal delivery device in accordance with a twelfth embodiment of the present invention. 
     The delivery device of this embodiment is very similar to the delivery device of the above-described tenth embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts. 
     The delivery device of this embodiment differs from that of the above-described tenth embodiment only in the configuration of the outlet unit  81  and in the integration of the substance supply unit  85  and the gas delivery unit  87 . 
     In this embodiment the outlet unit  81  includes a second delivery channel  120 , here an annular channel which is disposed co-axially about the nozzle  82 , through which an air flow from an exhalation breath of a subject is delivered, such as to entrain with the substance delivered from the nozzle  82 . In this embodiment the second delivery channel  120  is fluidly connected to the mouthpiece  79  downstream of the trigger mechanism, and the mouthpiece  79  includes a pressure-release valve which allows for the development of a flow above the release pressure of the pressure-release valve where a flow, or at least not a sufficient flow, cannot be developed through the nasal airway of the subject. 
     In this embodiment the substance supply unit  85  comprises a piston unit which is disposed within the chamber  93  of the gas supply unit  87 . The substance supply unit  85  comprises a cylinder  121  which defines a chamber  122  and into one, forward end of which a hollow needle  123  extends as an extension of the nozzle  82 . The substance supply unit  85  further comprises first and second pistons  124 ,  125  which contain a volume of substance therebetween and are movably disposed within the chamber  122 . 
     With this configuration, the forward, piston  125  is driven forwardly on the rear, piston  124  being driven forwardly, the substance contained between the pistons  124 ,  125  being substantially incompressible. The forward piston  125  is a puncturable member which is punctured by the needle  123  of the nozzle  82  on being driven onto the same, with the needle  123  of the nozzle  82  being in fluid communication with the substance contained between the pistons  124 ,  125  on puncturing the forward piston  125 . 
     In this embodiment the forward piston  125  of the substance supply unit  85  is spaced from the needle  123  of the nozzle  82  by a predetermined distance such that the piston  91  of the gas supply unit  87 , which drives the rear piston  124  of the substance supply unit  85 , is required to be driven a predetermined distance before the forward piston  125  of the substance supply unit  85  is ruptured and substance is delivered through the nozzle  82 . In this way, actuation of the gas supply unit  87  is initiated prior to the actuation of the substance supply unit  85 , whereby an interacting gas flow is delivered from the delivery channel  83  of the outlet unit  81  prior to the delivery of substance from the nozzle  82  and then during the delivery of substance from the nozzle  82  such as to interact with the same. In this embodiment the interval between actuation of the gas supply unit  87  and the common actuation of the substance supply unit  85  and the gas supply unit  87  can be controlled by altering the spacing between the forward piston  125  of the substance supply unit  85  and the needle  123  of the nozzle  82 . 
     Operation of the delivery device is the same as for the above-described tenth embodiment. 
     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. 
     In particular, it should be understood that features of any of the embodiments could be incorporated in any other of the embodiments. For example, the second and third embodiments could incorporate features of the first embodiment, in particular the at least one expandable cuff member  23  as in the first embodiment. 
     Also, in embodiments where an entraining gas flow is not required through the nasal airways of subjects, ones of the embodiments could be modified to include no such gas flow. For example, the first-described embodiment could be modified such that the outlet unit  21  includes only the nozzle  23  and no delivery channel  23 . 
     In the described embodiments the mouthpieces are configured to be gripped in the lips of a subject. In alternative embodiments the mouthpieces could be configured to be gripped by the teeth of a subject and sealed by the lips of the subject. In preferred embodiments the mouthpieces could be specifically configured to have one or both of a shape or geometry which allows the delivery devices to be gripped repeatedly in the same position, thereby providing for the respective nosepieces to be reliably inserted in the same position in the nasal cavity. 
     In preferred embodiments the delivery devices are configured to deliver substance through one nostril of a subject at such a pressure as to flow around the posterior margin of the nasal septum and out of the other nostril of the subject, thereby achieving bi-directional delivery through the nasal cavities as disclosed in WO-A-00/51672. In alternative embodiments the, delivery device could be configured to deliver substance at a reduced pressure which is not sufficient to achieve bi-directional delivery through the nasal cavities. Such embodiments are still advantageous as compared to known delivery devices in providing for velum closure and being capable of achieving targeted delivery, particularly when certain regions of the nasal cavity are obstructed by cuff members. 
     Also, in another modification, the delivery devices could include two nosepieces, in one embodiment configured for the simultaneous delivery to each of the nasal cavities. Such embodiments would advantageously provide for three-point fixation of the delivery devices via the nosepieces and the mouthpieces.