GB2397025A

GB2397025A - Devices to deliver substances to the mucosa of the nose or mouth

Info

Publication number: GB2397025A
Application number: GB0400024A
Authority: GB
Inventors: Per Gisle Djupesland
Original assignee: Optinose AS
Current assignee: Optinose AS
Priority date: 2003-01-02
Filing date: 2004-01-02
Publication date: 2004-07-14
Anticipated expiration: 2024-01-02
Also published as: GB0400024D0; WO2004060433A3; WO2004060433A2; GB2397025B; GB0300008D0

Abstract

A delivery device and method for delivering substances as an aerosol to a subject via the nasal or oral mucosae. The delivery device comprising a nozzle for directing the aerosol at the mucosa, and a substance supply unit, characterised in that at least a fraction of the aerosol particles have a dimension and velocity such as to penetrate the mucosa. The nozzle may include a nosepiece which may be inflatable and has the effect of directing the aerosol at the mucosa. Actuation may be triggered in response to proximity to the mucosal surface or in response to breath or exhalation. A second delivery unit may deliver another substance to the other nostril. Also claimed is a delivery device comprising a nozzle and nosepiece wherein actuation is associated with initiation of the Hering-Breuer reflex by providing a flow of gas at the face of the user.

Description

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DELIVERY DEVICES

The present invention relates to delivery devices and methods for the nasal and oral delivery of substances to subjects, where human or animal subjects.

In one aspect 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.

In another aspect the present invention relates to a 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 a vaccine, to nasal or oral mucosa of a subject, and in particular transmucosal delivery through nasal or oral mucosa.

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 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 incarnation, 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 l 0 and 20 % of the population, with nasal congestion of the erectile tissues of the nasal conchs, lacrimation, secretion of watery mucus, sneezing and itching being the most e'ee.e cece::: t. all: 2 '. .': 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 or oral mucosa, the nasal pathway in particular 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 area of the nasal mucosa advantageously provides for rapid systemic uptake.

Mucosal delivery, in particular nasal mucosa delivery, is expected to be advantageous for the administration of medicaments requiring a rapid onset of action, for example, analgesics, anti-emetics, insulin, antiepileptics, sedatives and hypnotics, and also other pharmaceuticals, for example, cardio-vascular drugs.

Mucosal delivery, in particular nasal mucosa delivery, is also expected to 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 e i' ''.e::: .e l. cl': 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'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 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 both mucosal delivery and transmucosal delivery, and in particular the combination thereof, will allow for the effective delivery of substances, especially 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 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.

8e e' 'e'. ::: t' ele: 4 'a a': WO-A-00/51672 discloses a delivery device for delivering a substance, in particular a medicament, in a bidirectional 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 bidirectional 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 one aim of the present invention to provide 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.

It is another aim of the present invention to provide a 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 a vaccine, to nasal or oral mucosa of a subject, and in particular transmucosal delivery through nasal or oral mucosa to the nasal concha, in particular the middle nasal concha and the inferior nasal concha, and especially the head of the inferior nasal concha.

In one aspect the present invention provides a nasal delivery device for delivering a substance to a subject through nasal mucosa in a nasal cavity of the subject, the delivery device comprising: a nozzle for delivering a particulate aerosol containing a substance to nasal mucosa in the nasal cavity; and a substance supply unit actuatable to supply substance to the nozzle; wherein at least a fraction of the particles of the aerosol has a dimension and velocity such as to penetrate through the nasal mucosa.

Preferably, the aerosol comprises liquid particles.

Preferably, the aerosol comprises solid particles, such as powder particles or coated particles.

e e' t.. :: I' lie: 'a a' : Preferably, the nasal mucosa comprises the superior region of the inferior nasal concha.

More preferably, the nasal mucosa comprises the head region of the inferior nasal concha.

Preferably, the substance comprises a vaccine.

In one embodiment the aerosol includes a fraction of particles having a dimension and velocity which is such as to deposit on the nasal mucosa.

In another embodiment the delivery device further comprises: a further nozzle for delivering a particulate aerosol containing the substance to nasal mucosa in the nasal cavity, the aerosol including a fraction of particles having a dimension and velocity which is such as to deposit on the nasal mucosa.

Preferably, the delivery device comprises: a nosepiece for fitting in the nasal cavity of the subject, the nosepiece comprising the or each nozzle.

More preferably, the nosepiece is configured to position the or each nozzle at a region of the nasal mucosa.

Yet more preferably, the nosepiece includes an expandable cuff member which, when expanded, acts to position the or each nozzle at a region of the nasal mucosa.

Preferably, the delivery device further comprises: a sensing unit for sensing a surface of the nasal mucosa at a predeterminable proximity and causing actuation of the substance supply unit in response to detection of the same.

Preferably, the substance supply unit is a breath-actuated unit.

In another aspect the present invention provides a method of delivering a substance to a subject through nasal mucosa in a nasal cavity of the subject, the method comprising the steps of: providing a nozzle for delivering a particulate aerosol containing a substance; J 1 6 "'' "';.' ',"'.,' positioning the nozzle at a region of nasal mucosa in the nasal cavity; and supplying substance to the nozzle such as to generate an aerosol having at least a fraction of particles having a dimension and velocity such as to penetrate through the nasal mucosa.

S Preferably, the aerosol comprises liquid particles.

Preferably, the nasal mucosa comprises the superior region of the inferior nasal concha.

Preferably, the substance comprises a vaccine.

In another embodiment the method further comprises the steps of: providing a further nozzle for delivering a particulate aerosol containing the substance; positioning the further nozzle at a region of nasal mucosa in the nasal cavity; and supplying substance to the further nozzle such as to generate an aerosol having a dimension and velocity which is such as to deposit on the nasal mucosa.

Preferably, the method further comprises the step of: sensing a surface of the nasal mucosa at a predeterminable proximity, wherein the or each substance supplying step is performed in response to detection of the same.

Preferably, the method further comprises the step of: the subject exhaling through a mouthpiece, wherein the or each substance supplying step is performed in response to detection of the same.

7 ale; t'tIce d In a further aspect the present invention provides an oral delivery device for delivering a substance to a subject through oral mucosa in an oral cavity of the subject, the delivery device comprising: a nozzle for delivering a particulate aerosol containing a substance to oral mucosa in the oral cavity; and a substance supply unit actuatable to supply substance to the nozzle; wherein at least a fraction of the particles of the aerosol has a dimension and velocity such as to penetrate through the oral mucosa.

Preferably, the aerosol comprises liquid particles.

Preferably, the substance comprises a vaccine.

IS In one embodiment the aerosol includes a fraction of particles having a dimension and velocity which is such as to deposit on the oral mucosa.

In another embodiment the delivery device further comprises: a further nozzle for delivering a particulate aerosol containing the substance to oral mucosa in the oral cavity, the aerosol including a fraction of particles having a dimension and velocity which is such as to deposit on the oral mucosa.

Preferably, the delivery device further comprises: a sensing unit for sensing a surface of the oral mucosa at a predeterminable proximity and causing actuation of the substance supply unit in response to detection of the same.

In a yet further aspect the present invention provides a method of delivering a substance to a subject through oral mucosa in an oral cavity of the subject, the method comprising the steps of: providing a nozzle for delivering a particulate aerosol containing a substance; positioning the nozzle at a region of oral mucosa in the oral cavity; and supplying substance to the nozzle such as to generate an aerosol having at least a fraction of particles having a dimension and velocity such as to penetrate through the oral mucosa. t

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Preferably, the aerosol comprises liquid particles.

Preferably, the substance comprises a vaccine.

In one embodiment the aerosol includes a fraction of particles having a dimension and velocity which is such as to deposit on the oral mucosa.

In another embodiment the method further comprises the steps of: providing a further nozzle for delivering a particulate aerosol containing the substance; positioning the further nozzle at a region of oral mucosa in the oral cavity; and supplying substance to the further nozzle such as to generate an aerosol having a dimension and velocity which is such as to deposit on the oral mucosa.

Preferably, the method further comprises the step of: sensing a surface of the oral mucosa at a predeterminable proximity, wherein the or each substance supplying step is performed in response to detection of the same.

In a still further aspect the present invention provides a nasal delivery device for delivering substances to a subject through the nasal cavities of the subject, the delivery device comprising: a first delivery unit comprising a first nozzle for delivering a particulate aerosol containing a first substance to nasal mucosa in one nasal cavity, and a first substance supply unit actuatable to supply first substance to the first nozzle, wherein at least a fraction of the particles of the aerosol has a dimension and velocity such as to penetrate through the nasal mucosa; and a second delivery unit comprising a second l . . ; i.!.; nozzle for delivering a second substance to the other nasal cavity, and a second substance supply unit actuatable to supply second substance to the second nozzle.

Preferably, the aerosol comprises liquid particles. s

Preferably, the first substance comprises a vaccine.

In a further embodiment the first delivery unit further comprises a further nozzle for delivering a particulate aerosol containing the first substance to nasal mucosa in the one nasal cavity, the aerosol including a fraction of particles having a dimension and velocity which is such as to deposit on the nasal mucosa.

Preferably, the first delivery unit comprises a first nosepiece for fitting in the one nasal cavity of the subject, the first nosepiece comprising the or each nozzle of the first delivery unit.

More preferably, the first nosepiece is configured to position the or each nozzle of the first delivery unit at a region of the nasal mucosa.

Yet more preferably, the first nosepiece includes an expandable cuff member which, when expanded, acts to position the or each nozzle of the first delivery unit at a region of the nasal mucosa. l

I tat I Preferably, the first delivery unit further comprises a sensing unit for sensing a surface of the nasal mucosa at a predeterminable proximity and causing actuation of the first substance supply unit in response to detection of the same.

Preferably, the or each substance supply unit is a breath-actuated unit.

In a still yet further aspect the present invention provides a method of delivering substances to a subject through the nasal cavities of the subject, the method comprising the steps of: providing a first nozzle for delivering a particulate aerosol containing a first substance; positioning the first nozzle at a region of nasal mucosa in one nasal cavity; supplying first substance to the first nozzle such as to generate an aerosol having at least a fraction of particles having a dimension and velocity such as to penetrate through the nasal mucosa; providing a second nozzle for delivering a second substance; positioning the second nozzle in the other nasal cavity; and supplying second substance to the second nozzle such as to deliver second substance into the other nasal cavity.

Preferably, the aerosol comprises liquid particles.

Preferably, the first substance comprises a vaccine.

ce::: À .. cte: À:. e:. :: :: ee. À In another embodiment the method further comprises the steps of: providing a third nozzle for delivering a particulate aerosol containing the first substance; positioning the third nozzle at a region of nasal mucosa in the one nasal cavity; and supplying first substance to the third nozzle such as to generate an aerosol having a dimension and velocity which is such as to deposit on the nasal mucosa.

Preferably, the method further comprises the step of: sensing a surface of the nasal mucosa at a predeterminable proximity from the first nozzle, wherein the or each substance supplying step is performed in response to detection of the same.

In yet another aspect the present invention provides a nasal delivery device for delivering a substance to a nasal cavity of a subject, the delivery device comprising: a nosepiece for fitting in a nasal cavity of the subject, the nosepiece comprising a nozzle for delivering an aerosol spray to the nasal cavity; a substance supply unit actuatable to supply substance to the nozzle; a reflex fluid delivery unit actuatable to deliver a reflex fluid to the face of the subject such as to cause a Hering-Breuer reflex action; and a trigger mechanism for actuating the reflex fluid delivery unit and the substance supply unit, wherein the trigger mechanism is configured to actuate the reflex fluid delivery unit on or before actuation of the substance supply unit.

Preferably, the reflex fluid comprises a gas.

In still another aspect the present invention provides a delivery device for delivering a substance to a nasal or oral cavity of a subject, the delivery device comprising: an outlet unit including a nozzle for delivering an aerosol spray to the nasal or oral cavity; a substance supply unit actuatable to supply substance to the nozzle; a reflex fluid delivery unit actuatable to deliver a reflex fluid to the face of the subject such as to cause a Hering-Breuer reflex action; and a trigger mechanism for actuating the reflex fluid t: t.

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delivery unit and the substance supply unit, wherein the trigger mechanism is configured to actuate the reflex fluid delivery unit on or before actuation of the substance supply unit.

In still yet another aspect the present invention provides a method of delivering a substance to a nasal cavity of a subject, the method comprising the steps of: fitting a nosepiece in a nasal cavity of the subject, the nosepiece comprising a nozzle for delivering an aerosol spray to the nasal cavity; supplying substance to the nozzle; and on or before supplying substance to the nozzle, delivering a reflex fluid to the face of the subject such as to cause a Hering-Breuer reflex action.

Preferably, the reflex fluid comprises a gas.

Preferred embodiments of the present invention will now be described hereinbelow by way of example only with reference to the accompanying drawings, in which: Figure 1 schematically illustrates the anatomy of the upper respiratory tract of a human subject; Figures 2(a) to (d) schematically illustrate a delivery device in accordance with a first embodiment of the present invention; Figures 3(a) and (b) schematically illustrate a delivery device in accordance with a second embodiment of the present invention; Figures 4(a) and (b) schematically illustrate a delivery device in accordance with a third embodiment of the present invention; Figures 5(a) to (d) schematically illustrate a delivery device in accordance with a fourth embodiment of the present invention; e: l' as: À:e c: :: Figures 6(a) to (j) schematically illustrate a delivery device in accordance with a fifth embodiment of the present invention; and Figures 7(a) to (e) schematically illustrate a delivery device in accordance with a sixth embodiment of the present invention.

Figures 2(a) to (d) illustrate an exhalation breath-actuated nasal delivery device in accordance with a first embodiment of the present invention.

The delivery device comprises a housing 15, a nosepiece 17 for fitting in a nasal cavity of a subject, a breath-actuated trigger mechanism 18 for actuating the delivery device in response to exhalation by the subject, and a mouthpiece 19 which is in fluid communication with the trigger mechanism 18 and through which the subject exhales to actuate the delivery device. In this embodiment the delivery device is configured for use l 5 in relation to human subjects, but in an alternative embodiment finds equal application in relation to animal subjects.

The nosepiece 17 comprises a guide member 20, in this embodiment a frustoconical element, for guiding the nosepiece 17 into a nasal cavity of the subject, and an outlet unit 21 for delivering substance at a mucosal surface of the nasal airway. In this embodiment the nosepiece 17 is a replaceable unit.

In this embodiment the outlet unit 21 comprises a nozzle 25 for delivering substance at a mucosal surface of the nasal airway, in this embodiment the superior region of the inferior nasal concha, and specifically the head of the inferior nasal concha. In this embodiment the nozzle 25 is configured to provide a focused, liquid aerosol spray, where the particles have a dimension and velocity such as to penetrate the mucosa; this transmucosal delivery providing for the direct delivery of the substance into the blood stream provided by the vascular structure beneath the mucosa.

t: t' . : À À ec: :. À:e.: :: À À 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, for example, as similarly 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 outlet unit 21 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 outlet unit 21 has a tapering section which narrows to the distal end thereof. The outlet unit 21, 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 outlet unit 21 has an elliptical section, preferably an oval section.

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 mouthpiece l 9, 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. I: ld

cee. eee. :: t.: '.. À' : 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 on exhalation through the mouthpiece, with the at least one cuff member 27 deflating on the subject ceasing exhalation. 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 at the mouthpiece 19, with the at least one cuff member 27 returning to the original, deflated configuration on the subject ceasing to exhale through the mouthpiece 19.

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 theporous 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 mouthpiece 19, whereby the pressure developed in the mouthpiece 19 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 cuffmember 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.

À r À 8.' 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 positioning of the outlet unit 21 in the nasal cavity of the subject, and in particular the positioning of the distal end of the outlet unit 21 at a mucosal surface in the nasal airway.

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 engage 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 engage 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 is coupled to the trigger mechanism 18 such that, when the trigger mechanism 18 is actuated by the exhalation breath of the subject, the resilient element is released to actuate the substance supply unit 29 to deliver a metered dose of a substance through the nozzle 25 as a focused, liquid aerosol spray, the particles of which have a dimension and velocity which provides for penetration through the mucosa and the direct delivery into the blood stream provided by the vascular structure beneath the mucosa.

e't;: A:: ::e tee 17 À In this embodiment the trigger mechanism 18 is configured to cause actuation of the substance supply unit 29 on generation of a predetermined pressure thereat.

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 on actuation thereof.

Operation of the delivery device will now be described hereinbelow with reference to Figures 2(b) to (d) of the accompanying drawings.

Referring to Figure 2(b), 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 to a mucosal surface in the nasal cavity, 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. Exhalation through the mouthpiece 19 also acts to inflate the at least one cuff member 27. As illustrated in Figure 2(c), the expansion of the at least one cuff member 27 acts to position the outlet unit 21 in relation to the nasal cavity of the subject, in particular the distal end of the outlet unit 21 in the nasal cavity adjacent a desired mucosal surface, in this embodiment at the superior region of the inferior nasal concha, and especially the head of the inferior nasal concha. As will be noted from Figure 2(c), 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 pressure developed at the mouthpiece 19 reaches a predetermined value, the release mechanism 18 is triggered to actuate the substance t: lI' #' cIt À. ::: .. ce tt: supply unit 29 to deliver a metered dose of a substance to the nozzle 25, with the nozzle generating a focused, liquid aerosol spray, the particles of which penetrate through the mucosa and enter into the blood stream provided by the vascular structure beneath the mucosa.

Following exhalation, the at least one cuff member 27 deflates, as illustrated in Figure 2(d), 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.

In an alternative embodiment the at least one cuff member 27 could be 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 21 is correctly positioned. In one embodiment the at least one cuff member 27 could comprise a sponge member, for example, a foam member. In an alternative embodiment the at least one cuff member 27 could comprise a gel-filled member, such as a silicone-filled member.

In this embodiment the at least one cuff member 27 comprises a single annular cuff member 27 which is disposed about the outlet unit 21.

In an alternative embodiment the at least one cuff member 27 could comprise a plurality of cuff members 27 which are disposed about the outlet unit 21. : ll

ete' 't cee. .: ..e tete ec. : In an alternative embodiment the nozzle 25 could be configured such as to deliver an aerosol spray which has first and second fractions of particles, the first fraction of particles having a dimension and velocity which is such as to penetrate the mucosa and the second fraction of particles having a dimension and velocity which is such as to deposit on, and not penetrate, the mucosa. This combined mucosal and transmucosal delivery, which provides for direct, transmucosal vascular delivery and indirect, systemic delivery, is envisaged as being particularly advantageous in the delivery of vaccines.

Figures 3(a) and (b) 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 quite similar to that 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 parts being designated by like reference signs.

The delivery device of this embodiment differs from that of the abovedescribed first embodiment in that the outlet unit 21 includes first and second nozzles 25a, 25b, with the first nozzle 25a being configured to deliver a first aerosol, the particles of which have a dimension and velocity which is such as to penetrate the mucosa, and the second nozzle 25b being configured to deliver a second aerosol, the particles of which have a dimension and velocity which is such as to deposit on the mucosa and not penetrate the same. This combined mucosal and transmucosal delivery, which provides for direct, transmucosal vascular delivery and indirect, systemic delivery, is envisaged as being particularly advantageous in the delivery of vaccines.

Operation of this delivery device is the same as for the delivery device of the above- described first embodiment, where, as illustrated in Figure 3(b), the first and second nozzles 25a, 25b of the outlet unit 21 deliver first and second aerosols, with the particles of the first aerosol having a dimension and velocity which is such as to penetrate the mucosa, and the particles of the second aerosol having a dimension and velocity which is such as to deposit on the mucosa and not penetrate the same. f

f,.e À, " À' Figures 4(a) and (b) illustrate an exhalation breathactuated nasal delivery device in accordance with a third embodiment of the present invention.

The delivery device of this embodiment differs from that of the abovedescribed first embodiment in that the delivery device comprises first and second nosepieces 17a, 17b for fitting to respective nasal cavities of a subject, where the first nosepiece 17a has the same construction as the nosepiece 17 of the delivery device of the first-described embodiment and the second nosepiece 17b comprises a guide member 20, as a frusto conical element, for guiding the second nosepiece 17b into the respective, other nasal cavity of the subject. By positioning the delivery device relative to both nasal cavities of the subject, the delivery device can be more accurately and reliably positioned.

Operation of this delivery device is the same as for the delivery device of the above described first embodiment.

Figures 5(a) to (d) illustrate an exhalation breath-actuated nasal delivery device in accordance with a fourth embodiment of the present invention.

The delivery device of this embodiment differs from that of the abovedescribed first embodiment in further comprising a sensing mechanism 31 which is operative to sense the proximity of a mucosal surface and cause the actuation of the substance supply unit ete' t' '.::e.' Il: 21 "' À': 29 when the distal end of the outlet unit 21 is at a required distance from the mucosal surface. The nasal mucosa can be tender to touch, and by including such a sensing mechanism 31, the delivery device can be actuated either without requiring contact with the mucosal surface or only a very light sensing force. In this embodiment the sensing mechanism 31 includes an optical sensor, but in an alternative embodiment could include a mechanical sensor.

Operation of this delivery device, as illustrated in Figures 5(b) to (d), is the same as for the delivery device of the above-described first embodiment, but where the substance supply unit 29 is actuated in response to the sensing mechanism 31 sensing the mucosal surface at a predetermined proximity.

Figures 6(a) to (j) illustrate an exhalation breath-actuated nasal delivery device in accordance with a fifth embodiment of the present invention.

The delivery device comprises a housing 35, first and second delivery units 37, 39 for delivering substance to the respective nasal cavities of a subject, a breath-actuated trigger mechanism 40 for actuating the delivery units 37, 39 in response to exhalation by the subject, and a mouthpiece 41 which is in fluid communication with the trigger mechanism 40 and through which the subject exhales to actuate the delivery device. In this embodiment the delivery device is configured for use with human subjects, but in an alternative embodiment finds equal application in relation to animal subjects.

The first delivery unit 37 comprises a nosepiece 43 which comprises a guide member 45, in this embodiment a frusto-conical element, for guiding the nosepiece 43 into one nasal cavity of the subject, and an outlet unit 47 for delivering substance at a mucosal surface of the nasal airway. In this embodiment the nosepiece 43 is a replaceable unit.

In this embodiment the outlet unit 47 comprises a nozzle 49 for delivering substance at a mucosal surface of the nasal airway, here the superior region of the inferior nasal concha, and especially the head of the inferior nasal concha. In this embodiment the nozzle 49 is configured to provide a focused, liquid aerosol spray, where the particles of the generated l tlel I' .e:: tc t' Il: aerosol have a dimension and velocity which is such as to penetrate the mucosa; this transmucosal delivery providing for the direct delivery of the substance to the blood stream provided by the vascular structure beneath the mucosa.

In this embodiment the outlet unit 47 is movably coupled to the housing 35, here as provided by a flexible coupling, such as to allow for the positioning of the outlet unit 47 in the one nasal cavity of the subject, as will be described in more detail hereinbelow.

In an alternative embodiment the outlet unit 47 could be fixed to the housing 35, and the mouthpiece 41 instead movably coupled to the housing 35, similarly as provided by a flexible coupling, such as to allow for the positioning of the outlet unit 47 in the one nasal cavity of the subject.

In this embodiment at least the tip of the outlet unit 47 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 outlet unit 47 has a tapering section which narrows to the distal end thereof. The outlet unit 47, in having a narrowing taper, acts, on insertion, to expand the narrow nasal valve of the one nasal cavity of the subject. In a preferred embodiment the outlet unit 47 has an elliptical section, preferably an oval section.

The nosepiece 43 further comprises at least one expandable cuff member 51 for expansion in the one nasal cavity of the subject. In this embodiment the at least one cuff member 51 comprises an inflatable member.

In this embodiment the at least one cuff member 51 is in fluid communication with the mouthpiece 41, whereby the air flow generated by the subject on exhalation through the mouthpiece 41 acts to inflate the at least one cuff member 51. In an alternative embodiment the delivery device could include a separate pump unit for inflating the at least one cuff member 51 subsequent to fitting of the nosepiece 43, and in a preferred P. It1 I' l.e I' I: embodiment subsequent to, preferably in response to, exhalation through the mouthpiece 41.

In this embodiment the at least one cuff member 51 is an inflatable member which is inflated on exhalation by the subject. In an alternative embodiment the at least one cuff member 51 could be inflated on the nosepiece 43 being located in the correct position.

In this embodiment the at least one cuff member 51 comprises a flexible balloon element which is inflated on exhalation through the mouthpiece 41, with the at least one cuff member 51 deflating on the subject ceasing exhalation. In the alternative embodiment, where the at least one cuff member 51 is inflated by a separate pump unit, the at least one cuff member 51 could equally be deflated by the evacuation of gas therefrom using the same pump unit.

In one embodiment the at least one cuff member 51 could comprise a resilient balloon element which is inflated by the generation of a pressure at the mouthpiece 41, with the at least one cuff member 51 returning to the original, deflated configuration on the subject ceasing to exhale through the mouthpiece 41.

In another embodiment the at least one cuff member 51 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 one 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 51 could be in selective fluid communication with the atmosphere. In another embodiment such a cuff member 51 could be in selective fluid communication with the mouthpiece 41, whereby the pressure developed in the mouthpiece 41 would assist in the inflation of the cuff member 51. In the alternative embodiment which includes a separate pump unit, the pump unit could be employed to assist in inflating such a cuff member 51 and in deflating the cuff member 51 by the evacuation of gas therefrom. In one embodiment the inflation could be triggered on exhalation by the subject. In another embodiment the inflation cI' ce.. :: .e tl: 24 À'. À ': could be triggered on the nosepiece 43 being located in the correct position in the one nasal cavity of the subject.

The at least one cuff member 51 is disposed to an outer surface of the outlet unit 47 such as, on expansion, to engage the inner wall of the one nasal cavity of the subject. The at least one cuff member 51, in being expandable, provides for the positioning of the outlet unit 47 in the one nasal cavity of the subject, and in particular the distal end of the outlet unit 47 at a mucosal surface of the nasal airway.

In this embodiment the at least one cuff member 51 comprises a single annular cuff member 51 which is located about the outlet unit 47 such as to engage the inner wall of the one nasal cavity of the subject when inflated.

In an alternative embodiment the at least one cuff member 51 could comprise a plurality of cuff members 51 which together engage the inner wall of the one nasal cavity of the subject when inflated.

The delivery device further comprises a substance supply unit 53 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 49 to deliver substance from the nosepiece 43, in this embodiment as a focused, liquid aerosol spray.

In this embodiment the substance supply unit 53 is a multi-dose unit for delivering a plurality of metered doses of substance. In another embodiment the substance supply unit 53 could be a single-dose unit for delivering a single metered dose of substance.

The substance supply unit 53 is pre-primeable, in this embodiment by loading a resilient element, and is coupled to the trigger mechanism 40 such that, when the trigger mechanism 40 is actuated by the exhalation breath of the subject, the resilient element is released to actuate the substance supply unit 53 to deliver a metered dose of a substance c: t' . : . A: t:' e:e:: :e ". À' : through the nozzle 49 as a focused, aerosol spray, the particles of which have a dimension and velocity which is such as to penetrate the mucosa. In this embodiment the trigger mechanism 40 is configured to cause actuation of the substance supply unit 53 on generation of a predetermined pressure thereat.

In an alternative embodiment the substance supply unit 53 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 53 could comprise a dry powder delivery unit which delivers metered doses of a substance on actuation thereof.

In an alternative embodiment the at least one cuff member 51 could be a resilient member which is deformable to allow for insertion into the one nasal cavity of the subject and, on insertion, expansion to adopt the required position in the one nasal cavity, in which position the outlet unit 47 is correctly positioned. In one embodiment the at least one cuff member 51 could comprise a sponge member, for example, a foam member. In an alternative embodiment the at least one cuff member 51 could comprise a gel-filled member, such as a silicone-filled member.

In one such alternative embodiment the at least one cuff member 51 could comprise a single annular cuff member 51 which is disposed about the outlet unit 47.

In another such alternative embodiment the at least one cuff member 51 could comprise a plurality of cuff members 51 which are disposed about the outlet unit 47.

In an alternative embodiment the nozzle 49 could be configured such as to deliver an aerosol spray which has first and second fractions of particles, with the first fraction of particles having a dimension and velocity which is such as to penetrate the mucosa and the second fraction of particles having a dimension and velocity which is such as to deposit on, and not penetrate, the mucosa. This combined mucosal and transmucosal t t t it it.. I ee 26 c delivery, which provides for direct, transmucosal vascular delivery and indirect, systemic delivery, is envisaged as being particularly advantageous in the delivery of vaccines.

The second delivery unit 39 comprises a nosepiece 63 which comprises a guide member 65, in this embodiment a frusto-conical element, for guiding the nosepiece 63 into the other nasal cavity of the subject, and an outlet unit 67 for delivering substance into the nasal airway of the subject. In this embodiment the nosepiece 63 is a replaceable unit, and preferably integrally formed with the nosepiece 43 of the first delivery unit 37.

In this embodiment the outlet unit 67 comprises a delivery channel 68 which is in fluid communication with the mouthpiece 41 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through the mouthpiece 41, and a nozzle 69 for delivering substance to the nasal airway of the subject. In this embodiment the nozzle 69 is disposed in the delivery channel 68 co axially with the same. In this embodiment the nozzle 69 is configured to provide an aerosol spray. In an alternative embodiment, for the delivery of a liquid, the nozzle 69 could be configured to deliver a liquid jet as a column of liquid.

In this embodiment the outlet unit 67 is movably coupled to the housing 35, here as provided by a flexible coupling, such as to allow for the positioning of the outlet unit 67 in the other nasal cavity of the subject, as will be described in more detail hereinbelow.

In an alternative embodiment the outlet unit 67 could be fixed to the housing 35, and the mouthpiece 41 instead movably coupled to the housing 35, similarly as provided by a flexible coupling, such as to allow for the positioning of the outlet unit 67 in the other nasal cavity of the subject.

In this embodiment at least the tip of the delivery channel 68 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. I' l r r 27. ;

In this embodiment at least the tip of the delivery channel 68 has a tapering section which narrows to the distal end thereof. The delivery channel 68' in having a narrowing taper, acts, on insertion, to expand the narrow nasal valve of the other nasal cavity of the subject. In a preferred embodiment the delivery channel 68 has an elliptical section, preferably an oval section.

In a preferred embodiment the distal end of the outlet unit 67 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 other nasal cavity of the subject.

The nosepiece 63 further comprises at least one expandable cuff member 71 for expansion in the other nasal cavity of the subject. In this embodiment the at least one cuffmember 71 comprises an inflatable member.

In this embodiment the at least one cuff member 71 is in fluid communication with the delivery channel 68, whereby the air flow generated by the subject on exhalation through the mouthpiece 41 acts to inflate the at least one cuff member 71. In an alternative embodiment the delivery device could include a separate pump unit for inflating the at least one cuff member 71 subsequent to fitting of the nosepiece 63' and in a preferred embodiment subsequent to, preferably in response to, exhalation through the mouthpiece 41.

In this embodiment the at least one cuff member 71 is an inflatable member which is inflated on exhalation by the subject. In an alternative embodiment the at least one cuff member 71 could be inflated on the nosepiece 63 being located in the correct position.

In this embodiment the at least one cuff member 71 comprises a flexible balloon element which is inflated by the generation of a pressure in the delivery channel 68' with the at least one cuff member 71 deflating on the release of pressure from the delivery channel 68. In the alternative embodiment, where the at least one cuffmember 71 is inflated by a separate pump unit, the at least one cuff member 71 could equally be deflated by the evacuation of gas therefrom using the same pump unit. V,, 1

In one embodiment the at least one cuff member 71 could comprise a resilient balloon element which is inflated by the generation of a pressure in the delivery channel 68, with the at least one cuff member 71 returning to the original, deflated configuration on the release of pressure from the delivery channel 68.

In another embodiment the at least one cuff member 71 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 the other 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 71 could be in selective fluid communication with the atmosphere. In another embodiment such a cuff member 71 could be in selective fluid communication with the delivery channel 68, whereby the pressure developed in the delivery channel 68 would assist in the inflation of the cuff member 71. In the alternative embodiment which includes a separate pump unit, the pump unit could be employed to assist in inflating such a cuff member 71 and in deflating the cuff member 71 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 63 being located in the correct position in the other nasal cavity of the subject.

The at least one cuff member 71 is disposed to an outer surface of the outlet unit 67 such as, on expansion, to engage the inner wall of the other nasal cavity of the subject. The at least one cuff member 71, in being expandable, provides for the expansion of the narrow nasal valve of the other nasal cavity of the subject, the sealing of the nosepiece 63 in the other nasal cavity of the subject, and the positioning, in particular the direction, of the outlet unit 67 in the other nasal cavity of the subject.

In this embodiment the at least one cuff member 71 comprises a single annular cuff member 71 which is located about the outlet unit 67 such asto provide a seal between the Ott, ,5 delivery channel 68 and the inner wall of the other nasal cavity of the subject when inflated.

In an alternative embodiment the at least one cuff member 71 could comprise a plurality of cuff members 71 which together provide a seal between the delivery channel 68 and the inner wall of the other nasal cavity of the subject when inflated.

The delivery device further comprises a substance supply unit 73 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 69 to deliver substance from the nosepiece 63, in this embodiment as an aerosol spray.

In this embodiment the substance supply unit 73 is a multi-dose unit for delivering a plurality of metered doses of substance. In another embodiment the substance supply unit 73 could be a single-dose unit for delivering a single metered dose of substance.

The substance supply unit 73 is pre-primeable, in this embodiment by loading a resilient element, and is coupled to the trigger mechanism 40 such that, when the trigger mechanism 40 is actuated by the exhalation breath of the subject, the resilient element is released to actuate the substance supply unit 73 to deliver a metered dose of a substance through the nozzle 69.

In this embodiment the trigger mechanism 40 is configured to cause actuation of the substance supply unit 73 on generation of a predetermined flow rate through the delivery channel 68.

In another embodiment the trigger mechanism 40 could be configured to cause actuation of the substance supply unit 73 on generation of a predetermined pressure within the delivery channel 68.

Àe a. Àe.: eec: ce cce e.: '': In a further embodiment the trigger mechanism 40 could be configured to cause actuation of the substance supply unit 73 on generation of either one of a predetermined flow rate through the delivery channel 68 or a predetermined pressure within the delivery channel 68.

In an alternative embodiment the substance supply unit 73 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 73 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 73 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 Figures 6(c) to (j) of the accompanying drawings.

Referring to Figures 6(c) and (d), the nosepieces 43, 63 of the first and second delivery units 37, 39 are first inserted into the respective nasal cavities of a subject until the guide members 45, 65 thereof abut the Hares of the nostrils, at which point the distal end of the outlet unit 47 of the first delivery unit 37 is disposed adjacent a mucosal surface of the one nasal cavity of the subject and the outlet unit 67 of the second delivery unit 39 extends about 2 cm into the other nasal cavity of the subject, and the mouthpiece 41 is gripped in the lips of the subject.

The subject then begins to exhale through the mouthpiece 41, which exhalation acts to close the oropharyugeal velum of the subject and drive an air flow through the delivery channel 68 of the outlet unit 67 of the second delivery unit 39, with the air flow passing into the other nasal cavity, around the posterior margin of the nasal septum and out of the l À . one nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject, and also inflate the cuff members 51, 71 of the first and second delivery units 37, 39. As illustrated in Figures 6(e) and (f), the expansion of the cuff members S1, 71 acts to position the respective outlet units 47, 67 in relation to the respective nasal cavities of the subject, in particular the distal end of the outlet unit 47 of the first delivery unit 37 adjacent a desired mucosal surface, in this embodiment the superior region of the inferior nasal concha, and especially the head of the inferior nasal concha, and the direction of the outlet unit 67 of the second delivery unit 39. As will be noted from Figures 6(e) and (I), the outlet units 47, 67 are forced to adopt the required positions by the respective cuff members 51, 71, in this embodiment as accommodated by flexing of the outlet units 47, 67.

In this embodiment, as illustrated in Figure 6(g), when the pressure developed at the mouthpiece 41 reaches a predetermined value, the trigger mechanism 40 is triggered to actuate the substance supply unit 53 of the first delivery unit 37 to deliver a metered dose of a substance to the nozzle 49, with the nozzle 49 generating a focused, liquid aerosol spray which penetrates the mucosa such as to deliver the substance directly into the blood stream provided by the vascular structure beneath the mucosa.

In this embodiment, as illustrated in Figure 6(h), following actuation of the first delivery unit 37, and provided the flow rate developed through the delivery channel 68 is at a predetermined value, the release mechanism 40 is triggered to actuate the substance supply unit 73 of the second delivery unit 39 to deliver a metered dose of a substance to the nozzle 69 and into the other nasal cavity of the subject. In the alternative embodiment the trigger mechanism 40 could be triggered on the generation of a predetermined pressure in the delivery channel 68.

Following exhalation, the cuff members 51, 71 deflate, as illustrated in Figures 6(i) and (.1), at which point the mouthpiece 41 is released and the nosepieces 43, 63 of the first and second delivery units 37, 39 are withdrawn from the nasal cavities of the subject.

a. 6e À . .e In one embodiment, where the delivery device is a singledose 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 units 53, 73. In a preferred embodiment, where the nosepieces 43, 63 are replaceable, the nosepieces 43, 63 can be replaced with new nosepieces 43, 63.

Figures 7(a) to (e) illustrate a nasal delivery device in accordance with a sixth 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 trigger mechanism 80 which is actuatable to provide for actuation of the delivery device.

The nosepiece 77 comprises a sealing member 81, in this embodiment a frusto-conical element, for providing a fluid tight seal in the nasal cavity of the subject, and an outlet unit 82 for delivering substance into the nasal airway of the subject. In this embodiment the nosepiece 77 is a replaceable unit.

In this embodiment the outlet unit 82 comprises a delivery channel 83 through which a gas flow is delivered into the nasal airway of the subject, and a nozzle 85 for delivering a substance into the nasal cavity of the subject. In this embodiment the nozzle 85 is disposed in the delivery channel 83 co-axially with the same. In this embodiment the nozzle 85 is configured to provide an aerosol spray. In an alternative embodiment, for the delivery of a liquid, the nozzle 85 could be configured to deliver a liquid jet as a column of liquid.

In this embodiment at least the tip of the delivery channel 83 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.

cle. .e ce:: ee.e tee.

In this embodiment at least the tip of the delivery channel 83 has a tapering section which narrows to the distal end thereof. The delivery channel 83, 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 83 has an elliptical section, preferably an oval section.

In a preferred embodiment the outlet unit 82 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 delivery device further comprises a reflex fluid delivery unit 87 for delivering a reflex-inducing fluid, in this embodiment a gas, such as air, to the face of the subject, in this embodiment a region surrounding the eyes, prior to the delivery of a substance to the nasal cavity. The reflex fluid delivery unit 87 is coupled to the trigger mechanism 80 such as to be actuated at the onset, or just immediately prior, to the delivery of substance.

The delivery of a fluid, typically gas or water, to the face of a subject, particularly an infant, is such as to cause a reflex action, known as the Hering-Breuer reflex, which causes the vocal chords to close off the larynx. By co-ordinating the reflex action and the delivery of substance such that the reflex action is elicited at the onset of delivery, the inhalation of substance can be prevented. In providing for this reflex action to prevent inhalation, improved delivery to non-compliant subjects, who may not provide velum closure, can be achieved. Such subjects are typically infants, and also animal subjects. It is envisaged that the delivery device could also possibly be utilized with unconscious subjects, non-cooperating human subjects, typically epileptics or comatosed patients, The delivery device further comprises an entraining gas delivery unit 88 for delivering an entraining gas through the delivery channel 83.

The delivery device further comprises a substance supply unit 89 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 85 to deliver substance from the nosepiece 77, in this embodiment as an aerosol spray.

In this embodiment the substance supply unit 89 is a multi-dose unit for delivering a S plurality of metered doses of substance. In another embodiment the substance supply unit 89 could be a single-dose unit for delivering a single metered dose of substance.

The substance supply unit 89 is pre-primeable, in this embodiment by loading a resilient element, and is coupled to the trigger mechanism 80 such that, when the trigger mechanism 80 is actuated, the resilient element is released to actuate the substance supply unit 89 to deliver a metered dose of a substance through the nozzle 85.

In an alternative embodiment the substance supply unit 89 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 89 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 89 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 Figures 7(b) to (e) of the accompanying drawings.

Referring to Figure 7(b), the nosepiece 77 is first inserted into a nasal cavity of a subject until the sealing member 81 abuts the Hares of the nostril, at which point the distal end of the outlet unit 82 extends about 2 cm into the nasal cavity of the subject.

of: c:. i: e': c: . e. :e The trigger mechanism 80 is then actuated, as illustrated in Figure 7(c), such as to actuate the reflex fluid delivery unit 87 to deliver a reflex fluid to the face of the subject, in this embodiment a region about the eyes of the subject, to cause the HeringBreuer reflex and the closure of the vocal chords against the larynx, and simultaneously cause the actuation of the entraining gas delivery unit 88 to deliver an entraining gas into the nasal airway and the substance supply unit 89 to deliver a metered dose of a substance to the nozzle 85 and into the nasal cavity of the subject, as illustrated in Figure 7(d).

Following operation of the delivery device, as illustrated in Figure 7(e), the nosepiece 77 is withdrawn from the nasal cavity of the subject.

In one embodiment, where the delivery device is a single-dose device, the delivery 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 89. In a preferred embodiment, where the nosepiece 77 is replaceable, the nosepiece 77 can be replaced with a new nosepiece 77.

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, in the described embodiments liquid and powder particles are exemplified as substance particles. Other particles, such as coated solid particles, which provide for transmucosal delivery could, however, be utilized.

In one modification, the delivery device of the first-described embodiment can be utilized for the transmucosal delivery of a substance through the oral mucosa. In such an embodiment the component parts for fitting the device in a nasal cavity of a subject ct' ct. c:: .e le would be omitted, with the outlet unit 21 instead being applied directly to a region of the oral mucosa.

In the above-described first to fifth embodiments the mouthpieces 19, 41 are configured to be gripped in the lips of a subject. In alternative embodiments the mouthpieces 19, 41 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 19, 41 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 17, 17a, 17b, 43, 63 to be reliably inserted in the same position in the nasal cavity.

In the fifth-described embodiment the second delivery unit 39 is configured to deliver substance 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 an alternative embodiment the second delivery unit 39 could be configured to deliver substance at a reduced pressure which is not sufficient to achieve bi-directional delivery through the nasal cavities. Such an embodiment is still advantageous as compared to known delivery devices in providing for velum closure and being capable of achieving targeted delivery.

In one embodiment the nosepieces 43, 63 of the first and second delivery units 37, 39 of the delivery device of the fifth-described embodiment can be configured such as to clamp the delivery device to the nasal septum. In addition to positioning the delivery device, it is envisaged that this clamping of the delivery device will be effective in allowing control over animal subjects, where compliance is required to effect delivery.

In another modification, the concept of the sixth-described embodiment can be applied to the other-described embodiments. Indeed, the modification of the delivery devices of the above-described first to fourth embodiments and the first delivery unit 37 of the above- described fifth embodiment, which provide for transmucosal delivery, to include a reflex ' fluid delivery unit 87 as in the sixth-described embodiment would be advantageous in enabling actuation of the delivery device where exhalation cannot be reliably achieved.

In another embodiment the nosepieces 17, 17a, 17b, 43, 63, 77 of the above-described delivery devices could include a manually-actuatable expansion unit for expanding the nasal valve in a nasal cavity to which the nosepiece 17, 1 7a, 1 7b, 43, 63, 77 is introduced.

In one embodiment the expansion unit comprises first and second members which are biased such as to force apart the lateral sections which define the nasal valve. In one preferred embodiment the expansion unit includes a biasing element which biases the first and second expansion members thereof to a closed position, in which position the expansion unit can be inserted into a nasal valve, and is acted upon by a user against the bias of the biasing element to open the nasal valve, with the expansion unit including a latch to latch the expansion members when in an open position, as defined by a predetermined spacing therebetween. In another preferred embodiment the expansion unit includes a biasing element which biases the first and second expansion members thereof to an open position, in which position the expansion members have a predetermined spacing, and is acted upon by a user against the bias of the biasing element to close the expansion members, in which position the expansion unit can be inserted into a nasal valve, and thereafter the expansion members are allowed to be biased to the open position. a preferred embodiment the expansion unit can be configured such as to prevent actuation of the delivery device until the expansion members of the expansion unit are in the open position, thereby providing an interlock which requires the proper fitting of the delivery device.

Claims

e: s: Be: a. # 38 '

1. A nasal delivery device for delivering a substance to a subject through nasal mucosa in a nasal cavity of the subject, the delivery device comprising: a nozzle for delivering a particulate aerosol containing a substance to nasal mucosa in the nasal cavity; and a substance supply unit actuatable to supply substance to the nozzle; wherein at least a fraction of the particles of the aerosol has a dimension and velocity such as to penetrate through the nasal mucosa.

2. The delivery device of claim 1, wherein the aerosol comprises liquid particles.

3. The delivery device of claim 1 or 2, wherein the aerosol comprises solid particles, such as powder particles or coated particles.

4. The delivery device of any of claims 1 to 3, wherein the nasal mucosa comprises the superior region of the inferior nasal concha.

5. The delivery device of claim 4, wherein the nasal mucosa comprises the head region of the inferior nasal concha.

6. The delivery device of any of claims I to 5, wherein the substance comprises a vaccine.

7. The delivery device of any of claims 1 to 6, wherein the aerosol includes a fraction of particles having a dimension and velocity which is such as to deposit on the nasal mucosa.

8. The delivery device of any of claims 1 to 6, further comprising: a further nozzle for delivering a particulate aerosol containing the substance to nasal mucosa in the nasal cavity, the aerosol including a fraction of particles having a dimension and velocity which is such as to deposit on the nasal mucosa.

9. The delivery device of any of claims 1 to 8, comprising: a nosepiece for fitting in the nasal cavity of the subject, the nosepiece comprising the or each nozzle.

10. The delivery device of claim 9, wherein the nosepiece is configured to position the or each nozzle at a region of the nasal mucosa.

11. The delivery device of claim 10, wherein the nosepiece includes an expandable cuff member which, when expanded, acts to position the or each nozzle at a region of the nasal mucosa.

12. The delivery device of any of claims 1 to 1 1, further comprising: a sensing unit for sensing a surface of the nasal mucosa at a predeterminable proximity and causing actuation of the substance supply unit in response to detection of the same.

13. The delivery device of any of claims 1 to 12, wherein the substance supply unit is a breath-actuated unit.

14. A method of delivering a substance to a subject through nasal mucosa in a nasal cavity of the subject, the method comprising the steps of: providing a nozzle for delivering a particulate aerosol containing a substance; positioning the nozzle at a region of nasal mucosa in the nasal cavity; and supplying substance to the nozzle such as to generate an aerosol having at least a fraction of particles having a dimension and velocity such as to penetrate through the nasal mucosa.

15. The method of claim 14, wherein the aerosol comprises liquid particles.

16. The method of claim 14 or 15, wherein the aerosol comprises solid particles, such as powder particles or coated particles.

17. The method of any of claims 14 to 16, wherein the nasal mucosa comprises the superior region of the inferior nasal concha.

18. The method of claim 17, wherein the nasal mucosa comprises the head region of the inferior nasal concha.

1 9. The method of any of claims 1 4 to 18, wherein the substance comprises a vaccine.

20. The method of any of claims 14 to 19, wherein the aerosol includes a fraction of particles having a dimension and velocity which is such as to deposit on the nasal mucosa.

21. The method of any of claims 14 to 19, further comprising the steps of: providing a further nozzle for delivering a particulate aerosol containing the substance; positioning the further nozzle at a region of nasal mucosa in the nasal cavity; and supplying substance to the further nozzle such as to generate an aerosol having a dimension and velocity which is such as to deposit on the nasal mucosa.

22. The method of any of claims 14 to 21, further comprising the step of: sensing a surface of the nasal mucosa at a predeterminable proximity, wherein the or each substance supplying step is performed in response to detection of the same.

23. The method of any of claims 14 to 22, further comprising the step of: the subject exhaling through a mouthpiece, wherein the or each substance supplying step is performed in response to detection of the same.

24. An oral delivery device for delivering a substance to a subject through oral mucosa in an oral cavity of the subject, the delivery device comprising: l ' a nozzle for delivering a particulate aerosol containing a substance to oral mucosa in the oral cavity; and a substance supply unit actuatable to supply substance to the nozzle; wherein at least a fraction of the particles of the aerosol has a dimension and velocity such as to penetrate through the oral mucosa.

25. The delivery device of claim 24, wherein the aerosol comprises liquid particles.

26. The delivery device of claim 24 or 25, wherein the aerosol comprises solid particles, such as powder particles or coated particles.

27. The delivery device of any of claims 24 to 26, wherein the substance comprises a vaccine.

28. The delivery device of any of claims 24 to 27, wherein the aerosol includes a fraction of particles having a dimension and velocity which is such as to deposit on the oral mucosa.

29. The delivery device of any of claims 24 to 27, further comprising: a further nozzle for delivering a particulate aerosol containing the substance to oral mucosa in the oral cavity, the aerosol including a fraction of particles having a dimension and velocity which is such as to deposit on the oral mucosa.

30. The delivery device of any of claims 24 to 29, further comprising: a sensing unit for sensing a surface of the oral mucosa at a predeterminable proximity and causing actuation of the substance supply unit in response to detection of the same.

31. A method of delivering a substance to a subject through oral mucosa in an oral cavity of the subject, the method comprising the steps of: providing a nozzle for delivering a particulate aerosol containing a substance; positioning the nozzle at a region of oral mucosa in the oral cavity; and l 42 ' supplying substance to the nozzle such as to generate an aerosol having at least a fraction of particles having a dimension and velocity such as to penetrate through the oral mucosa.

32. The method of claim 31, wherein the aerosol comprises liquid particles.

33. The method of claim 31 or 32, wherein the aerosol comprises solid particles, such as powder particles or coated particles.

34. The method of any of claims 31 to 33, wherein the substance comprises a vaccine.

35. The method of any of claims 31 to 34, wherein the aerosol includes a fraction of particles having a dimension and velocity which is such as to deposit on the oral mucosa.

36. The method of any of claims 31 to 34, further comprising the steps of: providing a further nozzle for delivering a particulate aerosol containing the substance; positioning the further nozzle at a region of oral mucosa in the oral cavity; and supplying substance to the further nozzle such as to generate an aerosol having a dimension and velocity which is such as to deposit on the oral mucosa.

37. The method of any of claims 31 to 36, further comprising the step of: sensing a surface of the oral mucosa at a predeterminable proximity, wherein the or each substance supplying step is performed in response to detection of the same.

38. The method of any of claims 31 to 37, further comprising the step of: the subject exhaling through a mouthpiece, wherein the or each substance supplying step is performed in response to detection of the same. l r

39s A nasal delivery device for delivering substances to a subject through the nasal cavities of the subject, the delivery device comprising: a first delivery unit comprising a first nozzle for delivering a particulate aerosol containing a first substance to nasal mucosa in one nasal cavity, and a first substance supply unit actuatable to supply first substance to the first nozzle, wherein at least a fraction of the particles of the aerosol has a dimension and velocity such as to penetrate through the nasal mucosa; and a second delivery unit comprising a second nozzle for delivering a second substance to the other nasal cavity, and a second substance supply unit actuatable to supply second substance to the second nozzle.

40. The delivery device of claim 39' wherein the aerosol comprises liquid particles.

41. The delivery device of claim 39 or 40, wherein the aerosol comprises solid particles, such as powder particles or coated particles.

42. The delivery device of any of claims 39 to 41, wherein the nasal mucosa comprises the superior region of the inferior nasal concha.

43. The delivery device of claim 42, wherein the nasal mucosa comprises the head region of the inferior nasal concha.

44. The delivery device of any of claims 39 to 43, wherein the first substance comprises a vaccine.

45. The delivery device of any of claims 39 to 44, wherein the aerosol includes a fraction of particles having a dimension and velocity which is such as to deposit on the nasal mucosa.

46. The delivery device of any of claims 39 to 44' wherein the first delivery unit further comprises a further nozzle for delivering a particulate aerosol containing the first substance to nasal mucosa in the one nasal cavity, the aerosol including a f ,, fraction of particles having a dimension and velocity which is such as to deposit on the nasal mucosa.

47. The delivery device of any of claims 39 to 46, wherein the first delivery unit comprises a first nosepiece for fitting in the one nasal cavity of the subject, the first nosepiece comprising the or each nozzle of the first delivery unit.

48. The delivery device of claim 47, wherein the first nosepiece is configured to position the or each nozzle of the first delivery unit at a region of the nasal 1 0 mucosa.

49. The delivery device of claim 48, wherein the first nosepiece includes an expandable cuff member which, when expanded, acts to position the or each nozzle of the first delivery unit at a region of the nasal mucosa.

50. The delivery device of any of claims 39 to 49, wherein the first delivery unit further comprises a sensing unit for sensing a surface of the nasal mucosa at a predeterminable proximity and causing actuation of the first substance supply unit in response to detection of the same.

51. The delivery device of any of claims 39 to 50, wherein the or each substance supply unit is a breath-actuated unit.

52. A method of delivering substances to a subject through the nasal cavities of the subject, the method comprising the steps of: providing a first nozzle for delivering a particulate aerosol containing a first substance; positioning the first nozzle at a region of nasal mucosa in one nasal cavity; supplying first substance to the first nozzle such as to generate an aerosol having at least a fraction of particles having a dimension and velocity such as to penetrate through the nasal mucosa; providing a second nozzle for delivering a second substance; r r positioning the second nozzle in the other nasal cavity; and supplying second substance to the second nozzle such as to deliver second substance into the other nasal cavity.

53. The method of claim 52, wherein the aerosol comprises liquid particles.

54. The method of claim 52 or 53, wherein the aerosol comprises solid particles, such as powder particles or coated particles.

55. The method of any of claims 52 to 54, wherein the nasal mucosa comprises the superior region of the inferior nasal concha.

56. The method of claim 55, wherein the nasal mucosa comprises the head region of the inferior nasal concha.

57. The method of any of claims 52 to 56, wherein the first substance comprises a vaccine.

58. The method of any of claims 52 to 57, wherein the aerosol includes a fraction of particles having a dimension and velocity which is such as to deposit on the nasal mucosa.

59. The method of any of claims 52 to 57, further comprising the steps of: providing a third nozzle for delivering a particulate aerosol containing the first substance; positioning the third nozzle at a region of nasal mucosa in the one nasal cavity; and supplying first substance to the third nozzle such as to generate an aerosol having a dimension and velocity which is such as to deposit on the nasal mucosa.

60. The method of any of claims 52 to 59, further comprising the step of: 1, c c c c e c c; À À sensing a surface of the nasal mucosa at a predeterminable proximity from the first nozzle, wherein the or each substance supplying step is performed in response to detection of the same.

61. The method of any of claims 52 to 60' further comprising the step of: the subject exhaling through a mouthpiece, wherein the or each substance supplying step is performed in response to detection of the same.

62. A nasal delivery device for delivering a substance to a nasal cavity of a subject, the delivery device comprising: a nosepiece for fitting in a nasal cavity of the subject, the nosepiece comprising a nozzle for delivering an aerosol spray to the nasal cavity; a substance supply unit actuatable to supply substance to the nozzle; a reflex fluid delivery unit actuatable to deliver a reflex fluid to the face of the subject such as to cause a Hering-Breuer reflex action; and a trigger mechanism for actuating the reflex fluid delivery unit and the substance supply unit, wherein the trigger mechanism is configured to actuate the reflex fluid delivery unit on or before actuation of the substance supply unit.

63. The delivery device of claim 62' wherein the reflex fluid comprises a gas.

64. A delivery device for delivering a substance to a nasal or oral cavity of a subject, the delivery device comprising: an outlet unit including a nozzle for delivering an aerosol spray to the nasal or oral cavity; a substance supply unit actuatable to supply substance to the nozzle; a reflex fluid delivery unit actuatable to deliver a reflex fluid to the face of the subject such as to cause a Hering-Breuer reflex action; and a trigger mechanism for actuating the reflex fluid delivery unit and the substance supply unit, wherein the trigger mechanism is configured to actuate the reflex fluid delivery unit on or before actuation of the substance supply unit.

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65. A method of delivering a substance to a nasal cavity of a subject, the method comprising the steps of: fitting a nosepiece in a nasal cavity of the subject, the nosepiece comprising a nozzle for delivering an aerosol spray to the nasal cavity; supplying substance to the nozzle; and on or before supplying substance to the nozzle, delivering a reflex fluid to the face of the subject such as to cause a Hering-Breuer reflex action.

66. The method of claim 65, wherein the reflex fluid comprises a gas.

67. A delivery device substantially as hereinbefore described with reference to Figure 2, Figure 3, Figure 4, Figure 5, Figure 6 or Figure 7 of the accompanying drawings.

68. A method of delivering substance substantially as hereinbefore described with reference to Figure 2, Figure 3, Figure 4, Figure 5, Figure 6 or Figure 7 of the accompanying drawings.