GB2391482A

GB2391482A - Nasal delivery devices

Info

Publication number: GB2391482A
Application number: GB0316009A
Authority: GB
Inventors: Per Gisle Djupesland
Original assignee: Optinose AS
Current assignee: Optinose AS
Priority date: 2001-06-12
Filing date: 2002-06-12
Publication date: 2004-02-11
Anticipated expiration: 2022-06-12
Also published as: GB0316009D0; GB2391482B

Abstract

A nasal delivery device for and a method of delivering substance to a nasal airway of a subject, the delivery device comprising: a nosepiece 77 for fitting to a nostril of a subject, the nosepiece including a first delivery outlet 82 through which substance is in use delivered to the nasal airway of the subject, and at least one second delivery outlet 83 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 85 for delivering substance through the first delivery outlet of the nosepiece; and a gas supply unit 87 for supplying a gas flow through the at least one second delivery outlet of the nosepiece. The second outlet 83 maybe annular and surround the first outlet 82. The substance maybe a powder, a liquid or an aerosol or a solution or a suspension.

Description

NASAL DEVICES 2391 482

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 5 containing a medicament, especially systemic or topical pharmaceuticals, or a vaccine to the nasal airway of a subject.

Referring to Figure 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 10 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 nasopharyruc 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 15 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 20 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 nonallergic 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 25 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.

30 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-inflmnmatory 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 5 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 analgesics, such as anti-migraine compositions, as the high blood flow and large surface 15 area of the nasal mucosa advantageously provides for rapid systemic uptake.

Nasal delivery is also expected to be advantageous for the administration of medicarnents requiring a rapid onset of action, for example, analgesics, anti-emetics, insulin, anti-epileptics, sedatives and hypnotics, and also other pharmaceuticals, for 20 example, cardiovascular 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 costefficient 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's, Parkinson'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 5 it is possible to circumvent the blood-to-brain barrier (BBB) and enable communication with the cerebrospinal fluid (CSF) and the brain.

AISO, 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 practiced 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 20 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 25 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 30 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 5 nasal delivery methods for providing for the improved delivery of a substance to a nasal cavity of subject. D 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 10 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 15 gas flow through the at least one second delivery outlet of the nosepiece.

In another 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, 20 through at least one second delivery outlet into the nasal airway of the subject.

Preferred embodiments of the present invention will now be described hereinbelow by way of example only with reference to the accompanying drawings, in which: 25 Figure 1 schematically illustrates the anatomy of the upper respiratory tract of a human subject; Figure 2 schematically illustrates a nasal delivery device in accordance with a first embodiment of the present invention, illustrated in the inoperative configuration; Figure 3 schematically illustrates the delivery device of Figure 2 where the driving unit is primed for actuation;

s Figure 4 schematically illustrates the delivery device of Figure 2 inserted in a nasal cavity of a subject for operation; 5 Figure 5 schematically illustrates the delivery device of Figure 2 during actuation where the subject has commenced exhaling and the delivery device is at the point of actuation; Figure 6 schematically illustrates the delivery device of Figure 2 during actuation; 10 Figure 7 schematically illustrates a nasal delivery device in accordance with a second embodiment of the present invention, illustrated in the inoperative configuration; Figure 8 schematically illustrates the delivery device of Figure 7 where the driving unit is primed for actuation; Figure 9 schematically illustrates the delivery device of Figure 7 inserted in a nasal cavity of a subject for operation; Figure 10 schematically illustrates the delivery device of Figure 7 where the subject has 20 commenced exhaling and the delivery device is at the point of actuation; Figure 11 schematically illustrates the delivery device of Figure 7 where the driving unit has been actuated, the driving unit having initiated actuation of the gas supply unit and being at the point of initiating actuation of the substance supply unit; Figure 12 schematically illustrates the delivery device of Figure 7 during full actuation; Figure 13 schematically illustrates a nasal delivery device in accordance with a third embodiment of the present invention, illustrated in the inoperative configuration; Figure 14 schematically illustrates the delivery device of Figure 13 where the driving unit is primed for actuation;

Figure 15 schematically illustrates the delivery device of Figure 13 inserted in a nasal cavity of a subject for operation; Figure 16 schematically illustrates the delivery device of Figure 13 where the subject has commenced exhaling and the delivery device is at the point of actuation; Figure 17 schematically illustrates the delivery device of Figure 13 where the driving unit has been actuated, the driving unit having initiated actuation of the gas supply unit 10 and being at the point of initiating actuation of the substance supply unit; and Figure 18 schematically illustrates the delivery device of Figure 13 during full actuation.

Figures 2 to 6 illustrate an exhalation breath-actuated nasal delivery device in 15 accordance with a first 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 frustoconical 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 30 substance and altering the characteristics of Me 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.

5 In this embodiment the nozzle 82 is disposed in the delivery channel 83 co-axial1y 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.

10 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.

15 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 20 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.

25 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 Figures 2 to 5) 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 30 Figure 6) 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 farther comprises a load biasing element 101, in this embodiment a 5 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 Figure 2) in which the 10 load biasing element 101 is not loaded thereby, and a second, operative position (as illustrated in Figures 3 to 6) in which the load 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 15 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.

20 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 25 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 linkage biasing element 112, in this embodiment a resilient element, particularly a tension spring, for biasing the linkage 30 assembly 107 to a locking configuration (as illustrated in Figures 2 to 4) 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 107is in the locking configuration, is biased to a rest 5 position (as illustrated in Figures 2 to 4) in which the flow path through the mouthpiece 79 is substantially closed, the one arm 1 15 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 10 other, second ann 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 1 17 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 15 on the side opposite to the first arm 115 of the first link element 109, whereby the second ann 1 17 of the first link element 109 and the second link element 1 1 1 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 20 Figures 3 to 6 of the accompanying drawings.

In a first step, as illustrated in Figure 3, the loading member 103 is operated to bias the load biasing element 101 and load the drive member 97 of the driving unit 9S with the actuation force.

Referring to Figure 4, the nosepiece 77 is then first inserted into a nasal cavity of a subject until the cuff member 80 is fitted in the Dares 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 ann 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 5 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 Figure 5, 10 the rotation of the first arm 115 of the first link element 109 is such as to rotate the second arm 1 17 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 Figure 6, this collapse of the linkage assembly 107 enables the drive 15 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, 20 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.

25 The loading member 103 of the driving unit 9S is then returned to the inoperative position, and the drive member 97 of the driving unit 9S 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 resumed 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 e configuration, the delivery device is ready for further use.

Figures 7 to 12 illustrate an exhalation breath-actuated nasal delivery device in 5 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

10 designating like parts.

The delivery device of this embodiment differs from that of the abovedescribed first embodiment only in the configuration of the driving unit 95.

15 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-descnbed first 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 20 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 8S is achieved by 25 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 30 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 corurnon 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 first 5 embodiment.

Figures 13 to 18 illustrate an exhalation breath-actuated nasal delivery device in I accordance with a third embodiment of the present invention.

10 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.

15 The delivery device of this embodiment differs from that of the abovedescribed first embodiment only in the configuration of the outlet unit 81 and in the integration of the I substance supply unit 85 and the gas supply unit 87.

In this embodiment the outlet unit 81 includes a second delivery channel 120, here an 20 annular channel which is disposed co-axially about the nozzle 82 thereof, through which an air flow from an exhalation breath of a subject is delivered, such as to entrain with I 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 I 25 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 30 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 5 124 being driven forwardly, the substance contained between the pistons 124, 125 being substantially incompressible. The forward piston 124 is a puncturable member which is punctured by the needle 123 of the nozzle 82 on being driven onto the same, with the I 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 125 of the substance supply unit 85, is required to be driven a predetermined distance before the forward piston 125 of 15 the substance supply unit 85 is punctured and substance is delivered through the nozzle 82. this way, actuation of the gas supply unit 87 is initiated prior to the actuation of I 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 I nozzle 82 and then during the delivery of substance from the nozzle 82 such as to 20 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.

25 Operation of the delivery device is the same as for the abovedescribed first 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 30 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.

In the described embodiments the mouthpieces are configured to be gripped in the lips 5 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 10 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 15 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, 20 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 25 delivery devices via the nosepieces and the mouthpieces.

Claims

1. A nasal delivery device for delivering substance to a nasal airway of a subject, comprising: 5 a nosepiece for fitting to a nostril 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 Visas flow, separate to an exhalation breath of the subject, is in use delivered to the nasal airway of the subject; 10 a delivery unit for delivering substance through the first delivery outlet of the nosepiece; and a gas supply unit for supplying a gas flow through the at least one second delivery outlet of the nosepiece.; 15 2. The delivery device of claim 1, further comprising: a mouthpiece unit through which the subject in use exhales to cause closure of 3 the oropharyngeal velum of the subject.

3. The delivery device of claim 1 or 2, wherein the at least one second delivery À 20 outlet is disposed such that the at least one gas flow delivered therefrom interacts with the substance delivered through the first delivery outlet.

4. The delivery device of claim 3, wherein the at least one gas flow delivered from the at least one second delivery outlet is such as to guide the substance delivered 25 through the first delivery outlet.

5. The delivery device of any of claims 1 to 4, wherein the at least one second delivery outlet comprises a substantially annular outlet.

30 6. The delivery device of claim 5, wherein the annular delivery outlet is disposed about the first delivery outlet.

7. The delivery device of any of claims I to 6, further comprising: an actuation mechanism for actuating the delivery unit and the gas supply unit on exhalation by the subject.

5 8. The delivery device of any of claims 1 to 7, wherein actuation of the gas supply unit is initiated prior to the deliver unit, whereby a gas flow is delivered through the at least one second delivery outlet prior to substance being delivered through the first delivery outlet.

10 9. The delivery device of any of claims I to 8, wherein the substance comprises a powder. 10. The delivery device of claim 9, wherein the substance is delivered as a powder aerosol. 11. The delivery device of any of claims I to 8, wherein the substance comprises a liquid. 12. The delivery device of claim 11, wherein the liquid is one of a solution or a 20 suspension. 13. The delivery device of claim 11 or 12, wherein the substance is delivered as a liquid aerosol.

25 14. The delivery device of claim 11 or 12, wherein the substance is delivered as a liquid jet.

15. The delivery device of any of claims 9 to 14, wherein a major fraction of the particle size distribution is in the range of from 1 rim to 80 Fun.

16. The delivery device of claim 15, wherein a major fraction of the particle size distribution is in the range of from 1 lam to 50 m.

17. The delivery device of claim 16, wherein a major fraction of the particle size distribution is in the range of from I 1lm to 30 1lm.

5 18. The delivery device of claim 17, wherein a major fraction of the particle size distribution is in the range of from 10,um to 30 m.

19. The delivery device of claim 18, wherein a major fraction of the particle size distribution is in the range of from 10 lam to 20,um.

20. The delivery device of claim IS, wherein a major fraction of the particle size distribution is in the range of from 15 lam to 30 m.

21. The delivery device of any of claims I to 20, wherein the gas supply unit 15 comprises a gas pump unit for delivering a gas flow, the gas pump unit including a chamber containing a gas and a piston member which is movable in the chamber to deliver a gas flow from the chamber through the at least one second delivery outlet.

20 22. The delivery device of any of claims 1 to 21, wherein the delivery unit includes a substance pump unit for delivering a flow of substance to the first delivery outlet, the substance pump unit including a chamber containing substance and a piston member which is movable in the chamber to deliver a flow of substance from the chamber through the first delivery outlet.

23. The delivery device of claims 21 and 22, wherein the gas supply unit and the delivery unit are formed as an integrated unit and actuatable by a common driving unit.

30 24. The delivery device of claim 23, wherein the piston member of the gas supply unit is operative to drive the piston member of the delivery unit.

25. The delivery device of claim 23, wherein the piston members of the gas supply unit and the delivery unit are integrally formed.

26. The delivery device of any of claims 23 to 25, further comprising: 5 a driving unit for driving the piston members of the gas supply unit and the substance supply unit to deliver gas and substance flows.

27. The delivery device of claim 26, wherein the driving unit is operative to drive the piston members of the gas supply unit and the substance supply unit in a 10 single action.

28. The delivery device of claim 27, wherein the driving unit is operative, in a single action, first to drive the piston member of the gas supply unit and subsequently drive the piston members of the gas supply unit and the substance supply unit in 15 unison. 29. The delivery device of any of claims 1 to 28, wherein the delivery unit comprises a liquid pump unit for supplying a liquid substance.

20 30. The delivery device of any of claims I to 28, wherein the delivery unit comprises a powder pump unit for supplying a powdered substance.

31. The delivery device of any of claims 1 to 30, wherein the first delivery outlet comprises a nozzle outlet for generating an aerosol.

32. The delivery device of claim 31, wherein the aerosol is a liquid aerosol.

33. The delivery device of claim 31, wherein the aerosol is a powder aerosol.

30 34. The delivery device of any of claims 1 to SO, wherein the first delivery outlet comprises a nozzle outlet for generating a jet.

35. The delivery device of any of claims 1 to 20, wherein the delivery unit comprises a nebulizer for supplying an aerosol.

36. The delivery device of any of claims I to 20, wherein the delivery unit comprises 5 an aerosol canister for supplying an aerosol.

37. The delivery device of any of claims 1 to 36, wherein the nosepiece includes at least one third delivery outlet through which an air flow from the exhalation breath from a subject is in use delivered, the delivered air flow acting to entrain 10 the substance delivered through the first delivery outlet.

38. The delivery device of claim 37, wherein the at least one third delivery outlet comprises a substantially annular channel disposed about the first delivery outlet.

15 39. 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.

40. The method of claim 39, further comprising the steps of: providing a mouthpiece unit; the subject exhaling through the mouthpiece unit to cause closure of the oropharyngeal velum of the subject.

41. The method of claim 39 or 40, wherein the at least one second delivery outlet is disposed such that the at least one gas flow delivered therefrom interacts with the substance delivered through the first delivery outlet.

30 42. The method of claim 41, wherein the at least one gas flow delivered from the at least one second delivery outlet is such as to guide the substance delivered through the first delivery outlet.

43. The method of any of claims 39 to 42, wherein the at least one second delivery outlet comprises a substantially annular outlet and the at least one gas flow is a substantially annular gas flow s 44. The method of any of claims 39 to 43, wherein the substance and the at least one gas flow are delivered in response to exhalation by the subject.

45. The method of any of claims 39 to 44, wherein delivery of the at least one gas 10 flow is initiated prior to delivery of the substance, whereby at least one gas flow is delivered through the at least one second delivery outlet prior to substance being delivered through the first delivery outlet.; 46. The method of any of claims 1 to 45, wherein the substance comprises a powder.

47. The method of claim 46, wherein the substance is delivered as a powder aerosol.

48. The method of any of claims 1 to 45, wherein the substance comprises a liquid.

20 49. The method of claim 48, wherein the liquid is one of a solution or a suspension.

50. The method of claim 48 or 49, wherein the substance is delivered as a liquid aerosol. 25 51. The method of claim 48 or 49, wherein the substance is delivered as a liquid jet.

52. A nasal delivery device for delivering a substance to a nasal cavity of a subject substantially as hereinbefore described with reference to any of Figures 2 to 6, Figures 7 to 12 or Figures 13 to 18 of the accompanying drawings.

53. A method of delivering a substance to a nasal cavity of a subject substantially as hereinbefore described with reference to any of Figures 2 to 6, Figures 7 to 12 or Figures 13 to 18 of the accompanying drawings.