US20140166008A1 - Nasal delivery - Google Patents
Nasal delivery Download PDFInfo
- Publication number
- US20140166008A1 US20140166008A1 US14/047,390 US201314047390A US2014166008A1 US 20140166008 A1 US20140166008 A1 US 20140166008A1 US 201314047390 A US201314047390 A US 201314047390A US 2014166008 A1 US2014166008 A1 US 2014166008A1
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- US
- United States
- Prior art keywords
- nosepiece
- nasal
- subject
- nasal cavity
- delivery
- Prior art date
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- Abandoned
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Images
Classifications
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0001—Details of inhalators; Constructional features thereof
- A61M15/0021—Mouthpieces therefor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/009—Inhalators using medicine packages with incorporated spraying means, e.g. aerosol cans
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/0091—Inhalators mechanically breath-triggered
- A61M15/0098—Activated by exhalation
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- A—HUMAN NECESSITIES
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- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
- A61M15/08—Inhaling devices inserted into the nose
- A61M15/085—Fixing means therefor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M15/00—Inhalators
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Definitions
- 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.
- 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.
- nasal inflammation specifically rhinitis
- allergic and non-allergic inflammation of the nasal airway can typically effect between 10 and 20% of the population, with nasal congestion of the erectile tissues of the nasal concha, lacrimation, secretion of watery mucus, sneezing and itching being the most common symptoms.
- 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.
- 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.
- 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.
- 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 calcitonin, and analgetics, such as anti-migraine compositions, as the high blood flow and large surface area of the nasal mucosa advantageously provides for rapid systemic uptake.
- pharmaceuticals such as hormones, for example, oxytocin and calcitonin, and analgetics, such as anti-migraine compositions, as the high blood flow and large surface area of the nasal mucosa advantageously provides for rapid systemic uptake.
- Nasal delivery is also expected to be advantageous for the administration of medicaments requiring a rapid onset of action, for example, analgetics, anti-emetics, insulin, anti-epileptics, sedatives and hypnotica, and also other pharmaceuticals, for example, cardio-vascular drugs. It is envisaged that nasal administration will provide for a fast onset of action, at a rate similar to that of injection and at a rate much faster than that of oral administration. Indeed, for the treatment of many acute conditions, nasal administration is advantageous over oral administration, since gastric stasis can further slow the onset of action following oral administration.
- nasal delivery could provide an effective delivery route for the administration of proteins and peptides as produced by modern biotechnological techniques.
- the metabolism in the intestines and the first-pass-effect in the liver represent significant obstacles for reliable and cost-efficient delivery.
- 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.
- BBB blood-to-brain barrier
- CSF cerebrospinal fluid
- nasal delivery technique of the present invention will allow for the effective delivery of vaccines.
- liquids in particular saline solutions
- saline solutions are commonly practised to remove particles and secretions, as well as to improve the mucociliary activity of the nasal mucosa.
- WO-A-00/51672 discloses a delivery device for delivering a substance, in particular a medicament, in a bi-directional flow through the nasal cavities, that is, an air flow which passes into one nostril, around the posterior margin of the nasal septum and in the opposite direction out of the other nostril.
- This bi-directional air flow advantageously acts to stimulate the sensory nerves in the nasal mucosa, thereby conditioning the subject for the delivery and providing a more comfortable delivery situation.
- One particular aim of the present invention is to optimize the shape, direction and particle distribution of the plume of a delivered dose, in order to reach targeted regions and reduce deposition outside these regions.
- Another particular aim of the present invention is to provide for improved targeting of specific regions of the nasal airway and improved reproducibility and consistency of dosing.
- the present inventors have recognized that an increased delivery of substance to the posterior region of the nasal airway, and in particular the upper posterior region of the nasal airway, as illustrated in FIG. 1( b ), relative to the anterior region of the nasal airway, surprisingly provides for a disproportionately greater CNS effect, which is suggestive of a greater uptake of substance into the CNS than would be predicted from the blood plasma concentration of the substance.
- the posterior region of the nasal airway is that region which is posterior of the nasal valve NV, as illustrated in FIG. 1( b ).
- the nasal valve NV comprises the anterior bony cavum which contains inferior turbinate erectile tissue and septal erectile tissue, which are supported respectively by compliant ala tissue and the rigid cartilaginous septum (Cole). These elements combine to form a dynamic valve, which extends over several millimetres, that adjusts nasal airflow, and is stabilized by cartilage and bone, modulated by voluntary muscle and regulated by erectile tissue.
- the lumen of the nasal valve NV is the section of narrowest cross-sectional area between the posterior and anterior regions of the nasal airway, and is much longer and narrower dorsally than ventrally, and this lumen defines a triangular entrance which extends to the piriform region of the bony cavum.
- the nasal valve NV is lined in its anterior part with transitional epithelium, with a gradual transition posterior to respiratory epithelium.
- the nasal valve NV and anterior vestibule define roughly the anterior one-third of the nose.
- the upper lateral wall of the nasal valve NV collapses to form a collapsed region, as illustrated in FIG. 1( b ), which significantly narrows the upper part of the nasal valve NV and obstructs access to the upper posterior region of the nasal cavity, and in particular the olfactory region.
- This collapsed region in combination with the upper lateral wall of the nasal valve NV having a curved shape, makes the insertion of a rigid structure into the lumen of the nasal valve NV particularly difficult and uncomfortable.
- the posterior region of the nasal airway is that region which is lined with respiratory epithelium, which is ciliated, and olfactory epithelium, which comprises nerves which extend downwards through the cribiform plate CP from the olfactory bulb, whereas the anterior region of the nasal airway is that region which is lined with squamous epithelium, which is not ciliated, and transitional epithelium.
- the olfactory epithelium extends on both the lateral and medial sides of the nasal airway, and typically extends downwards about 1.5 to 2.5 cm.
- the upper posterior region is the region above the inferior meatus IM, as illustrated in FIG. 1( b ), and encompasses the middle turbinate, the sinus ostia in infundibulum (ostia to maxillary, frontal and ethmoidal sinuses), the olfactory region, and the upper branches of the trigeminal nerve, and is that region which includes veins which drain to the venous sinuses that surround the brain.
- the posterior region of the nasal airway is the nasal region posterior of an imaginary vertical plane VERT which is located at a position corresponding to the lower angle of the anterior nasal aperture (aperture piriformis), which corresponds substantially to one-quarter of the distance between the anterior nasal spine AnS, which is a pointed projection at the anterior extremity of the intermaxillary suture, and the posterior nasal spine PnS, which is the sharp posterior extremity of the nasal crest of the hard palate and represents the transition between the nose and the nasopharynx, which corresponds to a distance posterior of the anterior nasal spine AnS of between about 13 mm and about 14 mm (Rosenberger defines the distance between the anterior nasal spine AnS and the posterior nasal spine PnS as being 56 mm in eighteen year old boys and 53.3 mm in eighteen year old girls).
- the upper region of the nasal airway is an upper segment of the nasal airway which is bounded by the cribiform plate CP and a horizontal plane HORIZ which is located at a position corresponding to one-third of the distance between the nasal floor NF of the nasal airway and the cribiform plate CP, which corresponds to a height of typically between about 13 and about 19 mm above the nasal floor NF (Zacharek et al define the distance from the nasal floor NF to the cribiform plate CP as 46+/ ⁇ 4 mm).
- the upper posterior region is thus that upper posterior region which is bounded by the above-defined vertical and horizontal planes VERT, HORIZ.
- the present inventors have postulated that this increased concentration within the CNS arises as a result of the veins in the upper posterior region of the nasal airway draining backwards to the venous sinuses that surround the brain, which leads to a higher local concentration in the cerebrovasculature.
- the sinus cavernous is outside the blood-to-brain barrier
- animal models have shown that substances can be transported by a counter-current mechanism from the veins therein to the carotid artery which passes through the sinus cavernous.
- Other mechanisms have been proposed which include extra axonal transport along the surface of the olfactory and trigeminal nerves. This mode of transport is apparently quite rapid as compared to intra axonal transport.
- nasal spray administration systems have been determined initially to deliver largely to the anterior one-third of the nasal airway, that is, the nasal region anterior of the nasal valve, from which region drainage is mainly along the floor of the nose and in which region the veins drain to the external facial vein, which in turn drains to the external carotid and in turn to the peripheral circulation.
- the present invention provides a nosepiece which provides for expansion in the sagittal plane, opening the connection of the mucosal surfaces of the nasal valve and isthmus, in particular by expansion of the collapsed region at the upper lateral wall of the nasal valve.
- the present invention provides a nosepiece which includes a flexible tip to fit the cross-sectional shape of a nasal cavity.
- the nosepiece has an internal configuration, at least at the tip, which acts to prevent collapse and maintain a stable cross-sectional area and a relatively-stable resistance.
- the present invention provides a spray nozzle which provides an asymmetrical spray plume, where either a powder or a liquid.
- the present invention is particularly advantageous when used in combination with bi-directional nasal delivery, but is not restricted to such delivery.
- the present invention can be combined with delivery concepts which generate a mist, an aerosol, an aerosol spray of particles, either liquid or powder, drops, droplets, or a liquid jet or jets of liquid.
- An entraining flow can be provided by the exhalation breath of the subject or from an external flow source, such as from an air chamber or a compressed air supply.
- the delivery device can be triggered, such that one or both of the dose and gas flow are triggered by an intraoral pressure which is such as to close the oropharyngeal velum or by another event, which may or may not secure velum closure.
- the present invention also finds application in delivery systems which do not utilize an auxiliary gas flow and even with inhalation environments which provide for nasal inhalation or a sniffing manoeuvre through one or both of the nostrils.
- the devices can be a multi-dose or single-dose.
- U.S. Pat. No. 6,647,980 discloses a device which utilizes a modified plume in order to attempt to decrease lateral deposition, and thereby increase the amount of the dose which reaches the upper region of the nasal airway.
- this device may provide for reduced deposition in the anterior part of the nasal cavity which is lined by squamous epithelium, owing to the narrower cone angle, only a moderate increase in deposition in the upper region of the nose is expected to be achieved, owing to the difficult and protected access to this region.
- narrowing of the nose during inhalation, as caused by the Bernoulli effect will further narrow the nasal cavity to increase the fraction deposited in valve region.
- the present invention provides for a bi-directional air flow in the nasal passages in which optimally-sized particles are entrained and subsequently delivered to appropriate target sites in the nasal airway.
- the present invention aims further to improve upon the devices as disclosed in the applicant's earlier WO-A-03/000310, the content of which is herein incorporated by reference.
- the present invention provides for optimisation of the delivery to upper parts of the nasal airway, including the olfactory region, by configuring the nosepiece, in particular the shape and position thereof, and the emitted plume of particles or liquid jet or jets in conjunction.
- the present invention provides for significantly enhanced access and deposition in the upper region of the nasal airway, and thereby improved dose-to-dose consistency and repeatability of drug delivery to this region of the nasal airway.
- the present invention provides for expansion of the nasal airway in the vertical or sagittal plane and the delivery of an asymmetric plume which has the greater spray angle in the vertical plane, and this particular mode of expansion of the nasal airway in combination with the particular geometrical arrangement of the spray plume has been found to be particularly advantageous in achieving targeted delivery to posterior regions, in particular the olfactory region, of the nasal airway.
- the delivery device of the present invention provides both for positioning of the outlet nozzle and the expansion of the upper lateral and medial surfaces of the valve region of a nasal cavity.
- the nosepiece By configuring the external and internal shape of the nosepiece, the nosepiece both ensures the correct positioning of the outlet nozzle and optimizes the vertical expansion of the nasal cavity.
- the operative function of the nosepiece of the present invention in vertically expanding the nasal cavity, can be contrasted to that of a conventional, frusto-conical nosepiece, which, during insertion into a nasal cavity, has been found by the present inventor to push the soft, nasal tissue rearwardly, which is particularly disadvantageous where attempting delivery to posterior regions of the nasal airway.
- a conventional, frusto-conical nosepiece which, during insertion into a nasal cavity, has been found by the present inventor to push the soft, nasal tissue rearwardly, which is particularly disadvantageous where attempting delivery to posterior regions of the nasal airway.
- One such nosepiece is disclosed in WO-A-1999/049984.
- nosepiece geometries are known for nasal delivery devices, such as disclosed in US-A-2003/0101992, U.S. Pat. No. 6,561,193 and WO-A-2004/108197, but none of these nosepieces are configured to provide for vertical or sagittal expansion of the nasal cavity, in particular at the nasal valve.
- the present invention provides a narrow nosepiece which can be easily slid into a nasal cavity beyond the nasal valve to the required depth, before expansion in the vertical or sagittal plane.
- This expanding movement of the nosepiece can either be to the upper part, the lower part or both the upper and lower parts.
- the nosepiece comprises two members, that is, an upper and a lower member, where one or both of the members are movable relative to the supporting body.
- Such members are exemplified by a pair of scissors, a pair of pliers and expansion screws.
- the nosepiece could comprise an expanding cuff-like member, which comprises one or both of upper and lower cuff members which expand in the vertical plane.
- the nosepiece can comprise a moderately-flexible anterior part such as to allow the nosepiece to adapt to the curved shape of a nasal passage, and thereby facilitate deeper insertion into the nasal slit, and even into the bony part thereof.
- the nosepiece includes internal features, such as ribs, which prevent collapse of the flow path and prevents substantial reduction in the internal cross-sectional area, which would otherwise lead to an increase in flow resistance.
- This flexibility enables the nosepiece to conform, at least in part, to the different shapes and directions of the nasal passage in this region, but at the same time assists in expanding the isthmus.
- shape of the anterior part of the nasal passage normally varies within a pre-defined range, pathological deviations may cause more pronounced changes which otherwise may create problems for insertion and positioning of the nosepiece, and hence efficient delivery.
- this adaptation of the anterior shape of the nosepiece to conform to the nasal passage provides for reduced turbulence, which would otherwise lead to unwanted deposition in the zone of turbulence.
- the present invention also provides for a nozzle, such as the swirl chamber of a spray pump or a pMDI or a nebulizer, which delivers a modified, asymmetric plume of particles.
- a nozzle such as the swirl chamber of a spray pump or a pMDI or a nebulizer, which delivers a modified, asymmetric plume of particles.
- the plume is an asymmetric plume which is relatively flat, with a small dimension in one axis and much greater in the other axis.
- Such a shaped plume reduces deposition in the anterior part of the valve region and increases the fraction of the dose entering into the upper, more posterior region of the nasal passage including the olfactory region and the sinus ostia, which is located below the middle meatus.
- the present invention also extends to means for securing a correct and reproducible positioning of nosepiece.
- Positioning of the delivery device can be achieved by the function of the mouthpiece or an exit resistor in the exit nostril of a bi-directional device, or as a separate feature with the main function of assisting positioning of the nosepiece.
- Triangular-shaped nose pieces assist in achieving the correct positioning.
- the mouthpiece of a device intended for bi-directional delivery also assists in achieving a reproducible positioning of the nosepiece.
- the provision of a nosepiece in the contralateral nostril also assists in achieving a reproducible positioning of the nosepiece.
- the provision of a special cap or the like as applied to the exterior of the exterior nose also assists in achieving a reproducible positioning of the nosepiece.
- tape or vacuum can be used to assist in positioning of the nosepiece and potentially in addition helps expanding the valve region by external action, such as an external dilator used to open the nose (“Breath-Right” nasal strip).
- the present invention extends to devices which are adapted to bi-directional delivery where driven by the exhalation breath of the subject or an auxiliary gas source, and conventional nasal delivery devices which do not utilize an auxiliary gas flow.
- the present invention can be adapted to any traditional delivery modality, including but not restricted to a spray pump, a pMDI, a nebulizer or any other means of delivering liquid jets, particles or drops, either in powder or liquid form.
- the present invention provides for expansion in the vertical or sagittal plane, but the expansion is not restricted to this plane.
- the expansion can be a combination of movement in different planes.
- the expansion can be only or predominantly to the upper part or the lower part of a nasal cavity, or the upper and lower parts in combination.
- the expansion can be achieved by any possible movement, such as pushing, pulling, lifting, pressing, rotating, expanding, flexing, suction (vacuum) and even by secondary chemical reactions initiated by, for example, pressure, moisture and temperature which create the desired movement of retraction of a mass or volume.
- the nosepiece comprises two movable members in the form of a speculum
- one of the members can provide a delivery channel through which substance is delivered into the nasal airway
- the other member can include a pressure-sensitive release valve or an open channel which allows for the venting of particles from the nasal airway.
- the substance includes relatively-large particles
- those particles will due to their momentum travel forward and deposit on an opposing surface, whereas the air flow will deviate and flow towards the exit valve.
- the valve can have a filter to prevent the particles from escaping to the atmosphere. Using large particles, such as from about 100 ⁇ m to about 200 ⁇ m, will also avoid or at least reduce this problem.
- the positioning of the nosepiece should preferably occur prior to release of substance, but could also occur in sequence immediately prior to or simultaneously with the releasing action.
- the preferred action is as follows.
- the positioning and expansion of the specialized nozzle can be achieved by a finger action. When complete, this action will also open the flow path permitting delivery of substance into the nasal airway, preferably by bi-directional delivery, but alternatively also even in the absence of bi-directional delivery.
- a pre-charged spring or similar can be released when the nosepiece is inserted into a nostril to the correct position.
- a valve is opened, making it possible to blow through the device or alternatively release the force from a gas chamber or another stored force, or alternatively allowing a mechanical action by hand compression, similar to actuation of a spray pump.
- the two actions of expansion and release of substance from, for example, a spray pump can be integrated.
- the first part of the mechanical action/compression of a lever by the finger will secure the expansion of the lever and positioning of the nosepiece.
- the finger force will result in the generation of a spray or release of a compressed gas by exhalation against a resistor or from a pressurized compartment or the combination thereof.
- This region plays a key role in ventilation of the sinuses and in the development of sinus pathology and consequently for the treatment of pathology in this region.
- Delivery of topically-acting substances such as decongestants, steroids and antihistamines, which can reduce the mucosal swelling in the entrances to and in the narrow slit like passages of the upper part of the nose in order to improve olfaction or reverse anosmia.
- FIG. 1( a ) schematically illustrates the anatomy of the upper respiratory tract of a human subject
- FIG. 1( b ) illustrates the segmentation of a nasal cavity in accordance with a preferred embodiment of the present invention
- FIG. 2 illustrates a nasal delivery device in accordance with a first embodiment of the present invention
- FIG. 3 illustrates the delivery device of FIG. 2 prior to insertion into a nasal cavity of a subject
- FIG. 4 illustrates the delivery device of FIG. 2 inserted into a nasal cavity of the subject prior to operation
- FIG. 5 illustrates the delivery device of FIG. 2 following operation of the actuating members of the nosepiece assembly to expand the upper and lower walls of the nasal cavity of the subject;
- FIG. 6 illustrates the delivery device of FIG. 2 following actuation of the substance supply unit
- FIGS. 7( a ) and ( b ) illustrate the tip of a delivery element as one modified embodiment of the delivery device of FIG. 2 , where illustrated in respective ones of the rest or uncompressed state and the operative or compressed state;
- FIG. 8 illustrates a nasal delivery device in accordance with a second embodiment of the present invention
- FIG. 9 illustrates a cross sectional view (along section I-I in FIG. 8 ) of the nosepiece assembly of the delivery device of FIG. 8 ;
- FIG. 10 illustrates the delivery device of FIG. 8 prior to insertion into a nasal cavity of a subject
- FIG. 11 illustrates the delivery device of FIG. 8 inserted into a nasal cavity of a subject prior to operation
- FIG. 12 illustrates a cross sectional view (along section II-II in FIG. 11 ) of the nosepiece assembly of the delivery device of FIG. 8 inserted into the nasal cavity of the subject for operation;
- FIG. 13 illustrates the delivery device of FIG. 8 following actuation of the substance supply unit
- FIG. 14 illustrates a nasal delivery device in accordance with a third embodiment of the present invention.
- FIG. 15 illustrates a fragmentary perspective view of the nosepiece of the delivery device of FIG. 14 (other side symmetrical);
- FIG. 16 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device of FIG. 14 (other side symmetrical);
- FIG. 17 illustrates a fragmentary plan view of the nosepiece of the delivery device of FIG. 14 (other side symmetrical);
- FIG. 18 illustrates the delivery device of FIG. 14 prior to insertion into a nasal cavity of a subject
- FIG. 19 illustrates the delivery device of FIG. 14 inserted into a nasal cavity of the subject prior to operation
- FIG. 20 illustrates the delivery device of FIG. 14 following actuation of the substance supply unit
- FIG. 21 illustrates a nasal delivery device in accordance with a fourth embodiment of the present invention.
- FIG. 22 illustrates a fragmentary perspective view of the nosepiece of the delivery device of FIG. 21 (other side symmetrical);
- FIG. 23 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device of FIG. 21 (other side symmetrical);
- FIG. 24 illustrates a fragmentary plan view of the nosepiece of the delivery device of FIG. 21 (other side symmetrical);
- FIG. 25 illustrates the delivery device of FIG. 21 prior to insertion into a nasal cavity of a subject
- FIG. 26 illustrates the delivery device of FIG. 21 inserted into a nasal cavity of the subject prior to operation
- FIG. 27 illustrates the delivery device of FIG. 21 following actuation of the substance supply unit
- FIG. 28 illustrates a nasal delivery device in accordance with a fifth embodiment of the present invention.
- FIG. 29 illustrates a fragmentary perspective view of the nosepiece of the delivery device of FIG. 28 (other side symmetrical);
- FIG. 30 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device of FIG. 28 (other side symmetrical);
- FIG. 31 illustrates a fragmentary plan view of the nosepiece of the delivery device of FIG. 28 (other side symmetrical);
- FIG. 32 illustrates the delivery device of FIG. 28 prior to insertion into a nasal cavity of a subject
- FIG. 33 illustrates the delivery device of FIG. 28 inserted into a nasal cavity of the subject prior to operation
- FIG. 34 illustrates the delivery device of FIG. 28 following actuation of the substance supply unit
- FIG. 35 illustrates a nasal delivery device in accordance with a sixth embodiment of the present invention.
- FIG. 36 illustrates a fragmentary perspective view of the nosepiece of the delivery device of FIG. 35 (other side symmetrical);
- FIG. 37 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device of FIG. 35 (other side symmetrical);
- FIG. 38 illustrates a fragmentary plan view of the nosepiece of the delivery device of FIG. 35 (other side symmetrical);
- FIG. 39 illustrates the delivery device of FIG. 35 prior to insertion into a nasal cavity of a subject
- FIG. 40 illustrates the delivery device of FIG. 35 inserted into a nasal cavity of the subject prior to operation
- FIG. 41 illustrates the delivery device of FIG. 35 following actuation of the substance supply unit
- FIG. 42 illustrates a nasal delivery device in accordance with a seventh embodiment of the present invention.
- FIG. 43 illustrates a fragmentary perspective view of the nosepiece of the delivery device of FIG. 42 (other side symmetrical);
- FIG. 44 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device of FIG. 42 (other side symmetrical);
- FIG. 45 illustrates a fragmentary plan view of the nosepiece of the delivery device of FIG. 42 (other side symmetrical);
- FIG. 46 illustrates the delivery device of FIG. 42 prior to insertion into a nasal cavity of a subject
- FIG. 47 illustrates the delivery device of FIG. 42 inserted into a nasal cavity of the subject prior to operation
- FIG. 48 illustrates the delivery device of FIG. 42 following actuation of the substance supply unit
- FIG. 49 illustrates a nasal delivery device in accordance with an eighth embodiment of the present invention.
- FIG. 50 illustrates a fragmentary perspective view of the nosepiece of the delivery device of FIG. 49 (other side symmetrical);
- FIG. 51 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device of FIG. 49 (other side symmetrical);
- FIG. 52 illustrates a fragmentary plan view of the nosepiece of the delivery device of FIG. 49 (other side symmetrical);
- FIG. 53 illustrates a fragmentary perspective view of the nozzle of the outlet unit of the delivery device of FIG. 49 ;
- FIG. 54 illustrates a vertical sectional view (along section III-III in FIG. 53 ) of the nozzle of FIG. 53 ;
- FIG. 55 illustrates an enlarged view of detail A in FIG. 54 ;
- FIG. 56 illustrates the delivery device of FIG. 49 prior to insertion into a nasal cavity of a subject
- FIG. 57 illustrates the delivery device of FIG. 49 inserted into a nasal cavity of the subject prior to operation
- FIG. 58 illustrates the delivery device of FIG. 49 following actuation of the substance supply unit
- FIG. 59 illustrates a nasal delivery device in accordance with a ninth embodiment of the present invention.
- FIG. 60 illustrates a fragmentary perspective view of the nosepiece of the delivery device of FIG. 59 (other side symmetrical);
- FIG. 61 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device of FIG. 59 (other side symmetrical);
- FIG. 62 illustrates a fragmentary plan view of the nosepiece of the delivery device of FIG. 59 (other side symmetrical);
- FIG. 63 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device of FIG. 59 where twisted about the longitudinal axis of the nosepiece;
- FIG. 64 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device of FIG. 59 where bent about an axis orthogonal to the longitudinal axis of the nosepiece and extending in the plane of the support member of the nosepiece;
- FIG. 65 illustrates the delivery device of FIG. 59 prior to insertion into a nasal cavity of a subject
- FIG. 66 illustrates the delivery device of FIG. 59 inserted into a nasal cavity of the subject prior to operation
- FIG. 67 illustrates the delivery device of FIG. 59 following actuation of the substance supply unit
- FIG. 68 illustrates a fragmentary perspective view of a nosepiece as one modification of the nosepiece of the delivery device of FIG. 42 (other side symmetrical);
- FIG. 69 illustrates a fragmentary, sectional perspective view of the nosepiece of FIG. 68 (other side symmetrical).
- FIG. 70 illustrates a fragmentary plan view of the nosepiece of FIG. 68 (other side symmetrical).
- FIGS. 2 to 6 illustrate a nasal delivery device in accordance with a first embodiment of the present invention.
- the delivery device comprises a housing 15 , a nosepiece assembly 17 for fitting in a nasal cavity of a subject, and a mouthpiece unit 19 through which the subject exhales to actuate the delivery device.
- the nosepiece assembly 17 comprises first and second nosepiece units 20 , 24 which are movably coupled, in this embodiment pivotally coupled, to the housing 15 and are operable by the subject, in this embodiment by gripping the same between one of the fingers and the thumb, to expand the nasal cavity of the subject in the vertical or sagittal plane.
- the first nosepiece unit 20 comprises a lower, guide element 26 which acts to guide the nosepiece assembly 17 when fitted in the nasal cavity of the subject, and an actuating arm 28 which extends rearwardly of the guide element 26 and is operated by the subject, in this embodiment by gripping the same, to position the guide element 26 .
- the second nosepiece unit 24 comprises an upper, delivery element 32 which acts to guide the nosepiece assembly 17 when fitted in the nasal cavity of the subject, an outlet unit 34 which is disposed within the delivery element 32 for delivering substance into the nasal airway of the subject, and an actuating arm 36 which extends rearwardly of the delivery element and is operated by the subject, in this embodiment by gripping the same, to position the delivery element 32 .
- the delivery element 32 has a relatively-narrow section in the horizontal plane so as to facilitate insertion beyond the narrow nasal valve of the nasal cavity of the subject and a tapering section in the vertical plane which narrows to the distal end thereof.
- the outlet unit 34 comprises a delivery channel 43 which is in fluid communication with the mouthpiece unit 19 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through the mouthpiece unit 19 , and a nozzle 45 for delivering substance to the nasal airway of the subject.
- the nozzle 45 is disposed in the delivery channel 43 co-axially with the same.
- the nozzle 45 is configured to provide an aerosol spray.
- the nozzle 45 could be configured to deliver a liquid jet as a column of liquid.
- outlet unit 34 is coupled to the housing 15 by a flexible coupling, such as to allow for the positioning of the delivery element 32 in the nasal cavity of the subject, as will be described in more detail hereinbelow.
- the delivery element 32 could be fixed to the housing 15 , and the mouthpiece unit 19 instead movably coupled to the housing 15 , typically by a flexible coupling, such as to allow for the positioning of the delivery element 32 in the nasal cavity of the subject.
- At least the tip of the delivery element 32 can comprise a tubular section of a flexible, preferably resilient, material, which is such as to expand in the vertical axis when compressed in the horizontal axis.
- the material is a semi-soft plastics material, such as silicone rubber.
- the tip of the delivery element 32 is configured such that the lateral sections thereof preferentially flex when compressed in the horizontal axis, but yet exhibit sufficient rigidity as to drive the upper and lower sections thereof to expand in the vertical axis.
- the tip of the delivery element 32 includes supporting elements 46 , 47 which are disposed to the inner surface at the lateral sections of the tip of the delivery element 32 , and act to prevent compression of the lateral sections of the tip of the delivery element 32 beyond a predetermined separation, which is that required to achieve an optimal flow profile through the nosepiece 120 .
- operation of the actuating arms 28 , 36 of the first and second nosepiece units 20 , 24 in this embodiment by gripping the same between ones of the fingers and the thumb, causes the expansion of the guide element 26 of the first nosepiece unit 20 relative to the delivery element 32 of the second nosepiece unit 24 to an expanded state.
- This expansion acts to engage the lower and upper walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure as compared to the lower wall of the nasal cavity of the subject, which is a relatively-firm structure, and also position the delivery element 32 of the second nosepiece unit 24 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion.
- This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the delivery element 32 of the second nosepiece unit 24 .
- the nozzle 45 of the outlet unit 34 is configured to deliver an asymmetric aerosol spray, with the aerosol spray having a significantly greater spray angle in the vertical plane ⁇ than in the horizontal plane ⁇ .
- Such an aerosol spray has been found to be particularly advantageous in the delivery of substance to posterior regions of the nasal cavities, in particular the olfactory region.
- the spray angle in the vertical plane ⁇ is greater than 35°, and more preferably greater than 40°.
- the aerosol spray presents an elliptical spray zone.
- the aerosol spray could present a substantially rectangular spray zone.
- the nosepiece assembly 17 further comprises a sealing member 48 , in this embodiment a tapered, annular ring of a resilient material, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of the outlet unit 34 of the second nosepiece unit 24 of the nosepiece assembly 17 into the nasal cavity of the subject.
- a sealing member 48 in this embodiment a tapered, annular ring of a resilient material, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of the outlet unit 34 of the second nosepiece unit 24 of the nosepiece assembly 17 into the nasal cavity of the subject.
- the distal end of the outlet unit 34 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably at least about 4 cm, and preferably from about 2 cm to about 4 cm, into the nasal cavity of the subject.
- the delivery device further comprises a substance supply unit 49 for delivering metered doses of a substance, in this embodiment an aerosol canister for delivering metered volumes of a propellant, preferably a hydrofluoroalkane (HFA) propellant or the like, containing medicament, either as a suspension or solution, which is fluidly connected to the nozzle 45 of the outlet unit 34 to deliver substance from the nosepiece assembly 17 , in this embodiment as an aerosol spray.
- a substance supply unit 49 for delivering metered doses of a substance
- an aerosol canister for delivering metered volumes of a propellant, preferably a hydrofluoroalkane (HFA) propellant or the like, containing medicament, either as a suspension or solution, which is fluidly connected to the nozzle 45 of the outlet unit 34 to deliver substance from the nosepiece assembly 17 , in this embodiment as an aerosol spray.
- a propellant preferably a hydrofluoroalkane (HFA) propellant or the like
- the substance supply unit 49 is a multi-dose unit for delivering a plurality of metered doses of substance.
- the substance supply unit 49 could be a single-dose unit for delivering a single metered dose of substance.
- the substance supply unit 49 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism 51 which, when triggered, releases the resilient element and actuates the substance supply unit 49 to deliver a metered dose of substance through the nozzle 45 of the outlet unit 34 .
- the release mechanism 51 is configured to cause actuation of the substance supply unit 49 on generation of a predetermined flow rate through the delivery channel 43 of the delivery element 32 .
- the release mechanism 51 could be configured to cause actuation of the substance supply unit 49 on generation of a predetermined pressure within the delivery channel 43 of the delivery element 32 .
- the release mechanism 51 could be configured to cause actuation of the substance supply unit 49 on generation of either one of a predetermined flow rate through the delivery channel 43 of the delivery element 32 or a predetermined pressure within the delivery channel 43 of the delivery element 32 .
- the substance supply unit 49 could comprise a mechanical delivery pump, in particular a liquid delivery pump or a powder delivery pump, which delivers metered doses of a substance on actuation thereof.
- the substance supply unit 49 could comprise a dry powder delivery unit which delivers metered doses of a substance, as a dry powder, on actuation thereof.
- the substance supply unit 49 could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof.
- the nosepiece assembly 17 is first inserted into one of the nasal cavities of a subject until the sealing member 48 abuts the nares of the nostril of the subject, at which point the distal end of the outlet unit 34 typically extends from about 2 cm to about 4 cm into the nasal cavity of the subject, and the mouthpiece unit 19 is then gripped in the lips of the subject.
- the subject then operates the actuating arms 28 , 36 of the first and second nosepiece units 20 , 24 , in this embodiment by gripping the same between ones of the fingers and the thumb, to cause the expansion of the guide element 26 of the first nosepiece unit 20 relative to the delivery element 32 of the second nosepiece unit 24 to an expanded state.
- This expansion acts to engage the lower and upper walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and position the delivery element 32 of the second nosepiece unit 24 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject being a relatively-hard structure, which acts as a reference for the expansion.
- This expansion also acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls to be urged into sealing contact with the delivery element 32 of the second nosepiece unit 24 .
- the subject then begins to exhale through the mouthpiece unit 19 , which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through the delivery channel 43 of the outlet unit 34 , with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject.
- the release mechanism 51 when the flow rate developed through the delivery channel 43 of the delivery element 32 reaches a predetermined value, the release mechanism 51 is triggered to actuate the substance supply unit 49 to deliver a metered dose of a substance to the nozzle 45 of the outlet unit 34 and into the nasal cavity of the subject, in this embodiment as an asymmetric aerosol spray.
- the release mechanism 51 could be triggered on the generation of a predetermined pressure in the delivery channel 43 of the delivery element 32 .
- the subject then releases the actuating arms 28 , 36 of the first and second nosepiece units 20 , 24 , which causes the guide element 26 of the first nosepiece unit 20 and the delivery element 32 of the second nosepiece unit 24 to return to the contracted state, at which point the mouthpiece unit 19 is released and the nosepiece assembly 17 is withdrawn from the nasal cavity of the subject.
- the device can be discarded.
- the delivery device is a multi-dose device
- the device is ready for further use following priming of the substance supply unit 49 .
- FIGS. 8 to 13 illustrate a nasal delivery device in accordance with a second embodiment of the present invention.
- the delivery device comprises a housing 115 , a nosepiece assembly 117 for fitting in a nasal cavity of a subject, and a mouthpiece unit 119 through which the subject exhales to actuate the delivery device.
- the nosepiece assembly 117 comprises a nosepiece 120 which is attached to the housing 115 and defines a delivery channel 123 which is in fluid communication with the mouthpiece unit 119 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through the mouthpiece unit 119 , and an outlet unit 124 which is disposed within the nosepiece 120 for delivering substance into the nasal airway of the subject.
- the nosepiece 120 is frusto-conical in shape and semi-flexible, here formed of a semi-soft plastics material, such as to expand in the vertical axis when compressed in the horizontal axis.
- the nosepiece 120 is configured such that the lateral sections thereof preferentially flex when compressed in the horizontal axis, but yet exhibit sufficient rigidity as to drive the upper and lower sections thereof to expand in the vertical axis.
- the nosepiece 120 includes upper and lower re-inforcing elements 127 , 129 which are disposed to the inner surface at the upper and lower sections of the nosepiece 120 , and provide for the application of the expansion force to upper and lower regions of the nasal cavity of the subject.
- the nosepiece 120 includes supporting elements 131 , 133 which are disposed to the inner surface at the lateral sections of the nosepiece 120 , and act to prevent compression of the lateral sections of the nosepiece 120 beyond a predetermined separation, which is that required to achieve an optimal flow profile through the nosepiece 120 .
- the outlet unit 124 comprises a nozzle 145 for delivering substance to the nasal airway of the subject.
- the nozzle 145 is disposed to the upper re-inforcing element 127 .
- the nozzle 145 is configured to provide an aerosol spray.
- the nozzle 145 could be configured to deliver a liquid jet as a column of liquid.
- outlet unit 124 is coupled to the housing 115 by a flexible coupling, such as to allow for the positioning of the nosepiece 120 in the nasal cavity of the subject, as will be described in more detail hereinbelow.
- insertion of the nosepiece 120 into the nasal cavity of the subject acts to compress the lateral sections of the nosepiece 120 by engagement with the relatively-narrow passage as presented at the nasal valve, which in turn acts to cause the expansion of the upper and lower sections of the nosepiece 120 in the vertical axis.
- This expansion acts to engage upper and lower walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position the nosepiece 120 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion.
- This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the nosepiece 120 .
- the nozzle 145 of the outlet unit 124 is configured to deliver an asymmetric aerosol spray, with the aerosol spray having a significantly greater spray angle in the vertical plane ⁇ than in the horizontal plane ⁇ .
- Such an aerosol spray has been found to be particularly advantageous in the delivery of substance to posterior regions of the nasal cavities, in particular the olfactory region.
- the spray angle in the vertical plane ⁇ is greater than 35°, and more preferably greater than 40°.
- the aerosol spray presents an elliptical spray zone.
- the aerosol spray could present a substantially rectangular spray zone.
- the nosepiece assembly 117 further comprises a sealing member 148 , in this embodiment a tapered, annular ring of a resilient material, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of the outlet unit 124 of the nosepiece assembly 117 into the nasal cavity of the subject.
- the distal end of the outlet unit 124 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably at least about 4 cm, and preferably from about 2 cm to about 4 cm, into the nasal cavity of the subject.
- the delivery device further comprises a substance supply unit 149 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 145 of the outlet unit 124 to deliver substance from the nosepiece assembly 117 , in this embodiment as an aerosol spray.
- a substance supply unit 149 for delivering metered doses of a substance
- 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 145 of the outlet unit 124 to deliver substance from the nosepiece assembly 117 , in this embodiment as an aerosol spray.
- a propellant preferably a hydrofluoroalkane (HFA) propellant or the like
- the substance supply unit 149 is a multi-dose unit for delivering a plurality of metered doses of substance.
- the substance supply unit 149 could be a single-dose unit for delivering a single metered dose of substance.
- the substance supply unit 149 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism 151 which, when triggered, releases the resilient element and actuates the substance supply unit 149 to deliver a metered dose of substance through the nozzle 145 of the outlet unit 124 .
- the release mechanism 151 is configured to cause actuation of the substance supply unit 149 on generation of a predetermined flow rate through the delivery channel 123 of the nosepiece 120 .
- the release mechanism 151 could be configured to cause actuation of the substance supply unit 149 on generation of a predetermined pressure within the delivery channel 123 of the nosepiece 120 .
- the release mechanism 151 could be configured to cause actuation of the substance supply unit 149 on generation of either one of a predetermined flow rate through the delivery channel 123 of the nosepiece 120 or a predetermined pressure within the delivery channel 123 of the nosepiece 120 .
- the substance supply unit 149 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.
- the substance supply unit 149 could comprise a dry powder delivery unit which delivers metered doses of a substance, as a dry powder, on actuation thereof.
- the substance supply unit 149 could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof.
- the nosepiece assembly 117 is first inserted into one of the nasal cavities of a subject until the sealing member 148 abuts the nares of the nostril of the subject, at which point the distal end of the outlet unit 124 typically extends from about 2 cm to about 4 cm into the nasal cavity of the subject, and the mouthpiece unit 119 is then gripped in the lips of the subject.
- insertion of the nosepiece 120 into the nasal cavity of the subject acts to compress the lateral sections of the nosepiece 120 by engagement with the relatively-narrow passage as presented at the nasal valve, which in turn acts to cause the expansion of the upper and lower sections of the nosepiece 120 in the vertical axis, with the extent of the compression being determined by the supporting elements 131 , 133 .
- This expansion acts to engage upper and lower walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position the nosepiece 120 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion.
- This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the nosepiece 120 .
- the subject then begins to exhale through the mouthpiece unit 119 , which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through the delivery channel 123 of the nosepiece 120 , with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject.
- the release mechanism 151 when the flow rate developed through the delivery channel 123 of the nosepiece 120 reaches a predetermined value, the release mechanism 151 is triggered to actuate the substance supply unit 149 to deliver a metered dose of a substance to the nozzle 145 of the outlet unit 124 and into the nasal cavity of the subject, in this embodiment as an asymmetric aerosol spray.
- the release mechanism 151 could be triggered on the generation of a predetermined pressure in the delivery channel 123 of the nosepiece 120 .
- the subject then releases the mouthpiece unit 119 and the nosepiece assembly 117 is withdrawn from the nasal cavity of the subject.
- the device can be discarded.
- the delivery device is a multi-dose device
- the device is ready for further use following priming of the substance supply unit 149 .
- FIGS. 14 to 20 illustrate a nasal delivery device in accordance with a third embodiment of the present invention.
- the delivery device comprises a housing 215 , a nosepiece assembly 217 for fitting in a nasal cavity of a subject, and a mouthpiece unit 219 through which the subject exhales to actuate the delivery device.
- the nosepiece assembly 217 comprises a nosepiece 220 which is attached to the housing 115 and defines a delivery channel 223 which is in fluid communication with the mouthpiece unit 219 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through the mouthpiece unit 219 , and an outlet unit 224 which is disposed within the nosepiece 220 for delivering substance into the nasal airway of the subject.
- the nosepiece 220 is generally frusto-conical in shape and includes a tip element 225 of asymmetric, elongate section, in having a dimension d 1 in a first, sagittal direction which is substantially greater than a dimension d 2 in a second, lateral direction which is orthogonal to the first, sagittal direction.
- the dimension d 1 in the sagittal direction is at least twice that of the dimension d 2 in the lateral direction.
- the dimension d 2 in the lateral direction is not more than 6 mm and more preferably not more than 4 mm.
- the tip element 225 extends substantially axially to the longitudinal axis of the nosepiece 220 .
- the nosepiece 220 further comprises a sealing element 248 , in this embodiment a tapered, annular section, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of the outlet unit 224 of the nosepiece assembly 217 into the nasal cavity of the subject.
- the distal end of the outlet unit 224 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably at least about 4 cm, and preferably from about 2 cm to about 4 cm, into the nasal cavity of the subject.
- the nosepiece 220 is formed as a substantially rigid structure, here formed of a plastics material.
- the outlet unit 224 comprises a nozzle 245 for delivering substance to the nasal airway of the subject.
- the nozzle 245 is configured to provide an aerosol spray, either as a liquid or powder aerosol.
- the nozzle 245 could be configured to deliver a jet as a column of substance, either as a liquid or powder jet.
- the longer, sagittal section of the tip element 225 of the nosepiece 220 becomes aligned in the sagittal plane and acts to engage upper and lower walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position the nosepiece 220 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion.
- This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the nosepiece 220 .
- the nozzle 245 of the outlet unit 224 is configured to deliver an asymmetric aerosol spray, with the aerosol spray having a significantly greater spray angle in the vertical, sagittal plane ⁇ than in the horizontal plane ⁇ .
- Such an aerosol spray has been found to be particularly advantageous in the delivery of substance to posterior regions of the nasal cavities, in particular the olfactory region.
- the spray angle in the vertical, sagittal plane ⁇ is greater than about 35°, more preferably greater than about 40°, still more preferably greater than about 45° and yet more preferably greater than about 50°.
- the spray angle in the horizontal plane ⁇ is not more than about 35°, more preferably not more than about 30°, still more preferably not more than about 25°, yet more preferably not more than about 20°, and still yet more preferably not more than about 15°.
- the aerosol spray presents an elliptical spray zone.
- the aerosol spray could present a substantially rectangular spray zone.
- the delivery device further comprises a substance supply unit 249 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 245 of the outlet unit 224 to deliver substance from the nosepiece assembly 217 , in this embodiment as an aerosol spray.
- a substance supply unit 249 for delivering metered doses of a substance
- 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 245 of the outlet unit 224 to deliver substance from the nosepiece assembly 217 , in this embodiment as an aerosol spray.
- a propellant preferably a hydrofluoroalkane (HFA) propellant or the like
- the substance supply unit 249 is a multi-dose unit for delivering a plurality of metered doses of substance.
- the substance supply unit 249 could be a single-dose unit for delivering a single metered dose of substance.
- the substance supply unit 249 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism 251 which, when triggered, releases the resilient element and actuates the substance supply unit 249 to deliver a metered dose of substance through the nozzle 245 of the outlet unit 224 .
- the release mechanism 251 is configured to cause actuation of the substance supply unit 249 on generation of a predetermined flow rate through the delivery channel 223 of the nosepiece 220 .
- the release mechanism 251 could be configured to cause actuation of the substance supply unit 249 on generation of a predetermined pressure within the delivery channel 223 of the nosepiece 220 .
- the release mechanism 251 could be configured to cause actuation of the substance supply unit 249 on generation of either one of a predetermined flow rate through the delivery channel 223 of the nosepiece 220 or a predetermined pressure within the delivery channel 223 of the nosepiece 220 .
- the substance supply unit 249 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.
- the substance supply unit 249 could comprise a dry powder delivery unit which delivers metered doses of a substance, as a dry powder, on actuation thereof.
- the substance supply unit 249 could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof.
- the nosepiece assembly 217 is first inserted into one of the nasal cavities of a subject until the sealing member 248 abuts the nares of the nostril of the subject, at which point the distal end of the outlet unit 224 typically extends from about 2 cm to about 4 cm into the nasal cavity of the subject, and the mouthpiece unit 219 is then gripped in the lips of the subject.
- insertion of the nosepiece 220 into the nasal cavity of the subject acts to cause the longer, sagittal section of the tip element 225 of the nosepiece 220 to become aligned in the sagittal plane and engage upper and lower walls of the nasal cavity of the subject, which engagement causes the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position the nosepiece 220 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion.
- This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the nosepiece 220 .
- the subject then begins to exhale through the mouthpiece unit 219 , which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through the delivery channel 223 of the nosepiece 220 , with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject.
- the release mechanism 251 when the flow rate developed through the delivery channel 223 of the nosepiece 220 reaches a predetermined value, the release mechanism 251 is triggered to actuate the substance supply unit 249 to deliver a metered dose of a substance to the nozzle 245 of the outlet unit 224 and into the nasal cavity of the subject, in this embodiment as an asymmetric aerosol spray.
- the release mechanism 251 could be triggered on the generation of a predetermined pressure in the delivery channel 223 of the nosepiece 220 .
- the subject then releases the mouthpiece unit 219 and the nosepiece assembly 217 is withdrawn from the nasal cavity of the subject.
- the device can be discarded.
- the delivery device is a multi-dose device
- the device is ready for further use following priming of the substance supply unit 249 .
- FIGS. 21 to 27 illustrate a nasal delivery device in accordance with a fourth embodiment of the present invention.
- the delivery device of this embodiment is quite similar to the delivery device of the above-described third embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts.
- the delivery device of this embodiment differs from that of the above-described third embodiment in the release mechanism 251 being a manually-actuated unit and the mouthpiece unit 219 being omitted. With this configuration, a gas flow is not delivered into the nasal cavity of the subject, but the device still advantageously provides for delivery to the olfactory region by virtue of the operation of the nosepiece 220 of the nosepiece unit 217 .
- Operation of the delivery device is the same as for the above-described third embodiment, except that a gas flow is not delivered into the nasal cavity.
- FIGS. 28 to 34 illustrate a nasal delivery device in accordance with a fifth embodiment of the present invention.
- the delivery device of this embodiment is very similar to the delivery device of the above-described third embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts.
- the delivery device of this embodiment differs from that of the above-described third embodiment in further comprising an oral exhalation breath-actuatable gas supply unit 257 for delivering a gas flow through the delivery channel 223 of the outlet unit 221 in response to exhalation by a subject, and in that the mouthpiece unit 219 is not in fluid communication with the delivery channel 223 of the outlet unit 221 , whereby a gas flow, separate to the exhalation breath of the subject, is delivered to the delivery channel 223 of the outlet unit 221 , and hence the nasal airway of the subject, in response to exhalation through the mouthpiece unit 219 .
- Operation of the delivery device is the same as for the above-described third embodiment, with a gas flow, separate to the exhalation breath of the subject, being delivered to the delivery channel 223 of the outlet unit 221 in response to exhalation through the mouthpiece unit 219 .
- the release mechanism 251 could be a manually-actuated unit and the mouthpiece unit 219 omitted.
- FIGS. 35 to 41 illustrate a nasal delivery device in accordance with a sixth embodiment of the present invention.
- the delivery device of this embodiment is very similar to the delivery device of the above-described third embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts.
- the delivery device of this embodiment differs from that of the above-described third embodiment in the configuration of the nosepiece 220 of the nosepiece unit 217 .
- the tip element 225 of the nosepiece 220 is inclined, in this embodiment upwardly, in the vertical, sagittal plane relative to the longitudinal axis of the nosepiece 220 . As illustrated in FIGS. 40 and 41 , this configuration is such as to provide for greater deflection of the upper surface of the nasal cavity relative to the bony and substantially rigid structure at the lower surface of the nasal cavity. With this configuration, the tip element 225 of the nosepiece 220 is inserted generally more caudally into the nasal opening, and subsequently rotated to the correct position by rotation.
- FIGS. 42 to 48 illustrate a nasal delivery device in accordance with a seventh embodiment of the present invention.
- the delivery device of this embodiment is very similar to the delivery device of the above-described third embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts.
- the delivery device of this embodiment differs from that of the above-described third embodiment in the configuration of the nosepiece 220 of the nosepiece unit 217 .
- the nosepiece 220 is attached to the housing 215 by a flexible coupling 259 , in this embodiment a resilient coupling, which allows for limited movement of the nosepiece 220 relative to the housing 215 , which facilitates the fitting of the nosepiece 220 in a nasal cavity of the subject.
- the nosepiece 220 includes a lateral gas flow outlet 261 , which is in fluid communication with the delivery channel 223 and disposed rearwardly of the distal end thereof, such as to allow for a gas flow through the delivery channel 223 in the event that the distal end of the delivery channel 223 becomes obstructed.
- FIGS. 49 to 58 illustrate a nasal delivery device in accordance with an eighth embodiment of the present invention.
- the delivery device comprises a housing 315 , a nosepiece assembly 317 for fitting in a nasal cavity of a subject, and a mouthpiece unit 319 through which the subject exhales to actuate the delivery device.
- the nosepiece assembly 317 comprises a nosepiece 320 which is attached to the housing 315 and defines a delivery channel 323 which is in fluid communication with the mouthpiece unit 319 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through the mouthpiece unit 319 , and an outlet unit 324 which is disposed within the nosepiece 320 for delivering substance into the nasal airway of the subject.
- the nosepiece 320 is generally frusto-conical in shape and includes a tip element 325 of asymmetric, elongate section, in having a dimension d 1 in a first, sagittal direction which is substantially greater than a dimension d 2 in a second, lateral direction which is orthogonal to the first, sagittal direction.
- the dimension d 1 in the sagittal direction is at least twice that of the dimension d 2 in the lateral direction.
- the dimension d 2 in the lateral direction is not more than 6 mm and more preferably not more than 4 mm.
- the tip element 325 extends substantially axially to the longitudinal axis of the nosepiece 320 .
- the nosepiece 320 further comprises a sealing element 326 , in this embodiment a tapered, annular section, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of the outlet unit 324 of the nosepiece assembly 317 into the nasal cavity of the subject.
- the distal end of the outlet unit 324 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably at least about 4 cm, and preferably from about 2 cm to about 4 cm, into the nasal cavity of the subject.
- the nosepiece 320 is formed as a substantially rigid structure, here formed of a plastics material.
- the longer, sagittal section of the tip element 325 of the nosepiece 320 becomes aligned in the sagittal plane and acts to engage upper and lower walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position the nosepiece 320 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion.
- This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the nosepiece 320 .
- the outlet unit 324 comprises a nozzle 345 for delivering substance to the nasal airway of the subject.
- the nozzle 345 includes a plurality of nozzle outlets 347 which provide a plurality of jets as columns of substance, either as a liquid or powder jet.
- the nozzle 345 of the outlet unit 324 is configured to deliver an asymmetric profile, with the jet spray having a significantly greater spray angle in the vertical, sagittal plane ⁇ than in the horizontal plane ⁇ .
- Such jets have been found to be particularly advantageous in the delivery of substance to posterior regions of the nasal cavities, in particular the olfactory region.
- the jet spray angle in the vertical, sagittal plane ⁇ is greater than about 35°, more preferably greater than about 40°, still more preferably greater than about 45° and yet more preferably greater than about 50°.
- the nozzle outlets are aligned in the vertical, sagittal direction and thus the jet angle in the horizontal plane ⁇ approaches 0°.
- the jet angle in the horizontal plane ⁇ is not more than about 35°, more preferably not more than about 30°, still more preferably not more than about 25°, yet more preferably not more than about 20°, still yet more preferably not more than about 15°, yet further more preferably not more than about 10° and still yet further more preferably not more than about 5°.
- the jet spray presents a substantially rectangular spray zone.
- the delivery device further comprises a substance supply unit 349 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 345 of the outlet unit 324 to deliver substance from the nosepiece assembly 317 , in this embodiment as a plurality of liquid jets.
- a substance supply unit 349 for delivering metered doses of a substance
- 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 345 of the outlet unit 324 to deliver substance from the nosepiece assembly 317 , in this embodiment as a plurality of liquid jets.
- a propellant preferably a hydrofluoroalkane (HFA)
- the substance supply unit 349 is a multi-dose unit for delivering a plurality of metered doses of substance.
- the substance supply unit 349 could be a single-dose unit for delivering a single metered dose of substance.
- the substance supply unit 349 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism 351 which, when triggered, releases the resilient element and actuates the substance supply unit 349 to deliver a metered dose of substance through the nozzle 345 of the outlet unit 324 .
- the release mechanism 351 is configured to cause actuation of the substance supply unit 349 on generation of a predetermined flow rate through the delivery channel 323 of the nosepiece 320 .
- the release mechanism 351 could be configured to cause actuation of the substance supply unit 349 on generation of a predetermined pressure within the delivery channel 323 of the nosepiece 320 .
- the release mechanism 351 could be configured to cause actuation of the substance supply unit 349 on generation of either one of a predetermined flow rate through the delivery channel 323 of the nosepiece 320 or a predetermined pressure within the delivery channel 323 of the nosepiece 320 .
- the substance supply unit 349 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.
- the substance supply unit 239 could comprise a dry powder delivery unit which delivers metered doses of a substance, as a dry powder, on actuation thereof.
- the substance supply unit 349 could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof.
- the nosepiece assembly 317 is first inserted into one of the nasal cavities of a subject until the sealing member 327 abuts the nares of the nostril of the subject, at which point the distal end of the outlet unit 324 typically extends from about 2 cm to about 4 cm into the nasal cavity of the subject, and the mouthpiece unit 319 is then gripped in the lips of the subject.
- insertion of the nosepiece 320 into the nasal cavity of the subject acts to cause the longer, sagittal section of the tip element 325 of the nosepiece 320 to become aligned in the sagittal plane and engage upper and lower walls of the nasal cavity of the subject, which engagement causes the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position the nosepiece 320 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion.
- This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the nosepiece 320 .
- the subject then begins to exhale through the mouthpiece unit 319 , which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through the delivery channel 323 of the nosepiece 320 , with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject.
- the release mechanism 351 when the flow rate developed through the delivery channel 323 of the nosepiece 320 reaches a predetermined value, the release mechanism 351 is triggered to actuate the substance supply unit 349 to deliver a metered dose of a substance to the nozzle 345 of the outlet unit 324 and into the nasal cavity of the subject, in this embodiment as an asymmetric jet spray comprising a plurality of liquid jets.
- the release mechanism 351 could be triggered on the generation of a predetermined pressure in the delivery channel 323 of the nosepiece 320 .
- the subject then releases the mouthpiece unit 319 and the nosepiece assembly 317 is withdrawn from the nasal cavity of the subject.
- the device can be discarded.
- the delivery device is a multi-dose device
- the device is ready for further use following priming of the substance supply unit 349 .
- FIGS. 59 to 67 illustrate a nasal delivery device in accordance with a ninth embodiment of the present invention.
- the delivery device comprises a housing 415 , a nosepiece assembly 417 for fitting in a nasal cavity of a subject, and a mouthpiece unit 419 through which the subject exhales to actuate the delivery device.
- the nosepiece assembly 417 comprises a nosepiece 420 which is attached to the housing 415 and defines a delivery channel 423 which is in fluid communication with the mouthpiece unit 419 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through the mouthpiece unit 419 , and an outlet unit 424 which is disposed within the nosepiece 420 for delivering substance into the nasal airway of the subject.
- the nosepiece 420 comprises a nosepiece member 425 which acts to engage the nasal cavity of the subject and a support member 426 which acts structurally to support the nosepiece member 425 , such as to confer a required rigidity in the sagittal plane, as will be described in more detail hereinbelow.
- the nosepiece member 425 is generally frusto-conical in shape and includes a tip element 427 of asymmetric, elongate section, in having a dimension d 1 in a first, sagittal direction which is substantially greater than a dimension d 2 in a second, lateral direction which is orthogonal to the first, sagittal direction.
- the dimension d 1 in the sagittal direction is at least twice that of the dimension d 2 in the lateral direction.
- the dimension d 2 in the lateral direction is not more than 6 mm and more preferably not more than 4 mm.
- the tip element 427 extends substantially axially to the longitudinal axis of the nosepiece 420 .
- the nosepiece member 425 further includes a sealing element 428 , in this embodiment a tapered, annular section, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of the outlet unit 424 of the nosepiece assembly 417 into the nasal cavity of the subject.
- the distal end of the outlet unit 424 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably at least about 4 cm, and preferably from about 2 cm to about 4 cm, into the nasal cavity of the subject.
- the distal end of the outlet unit 424 extends into the bony part of the nasal valve, or at least as far into the nasal cavity as possible with the outlet unit 424 aligned with the nasal slit, such that the outlet unit 424 targets substance at the upper posterior region of the nasal cavity, and in particular the olfactory region.
- the nosepiece member 425 is formed as a flexible or semi-rigid structure, here formed of a plastics material, which allows the nosepiece 420 to conform to the nasal cavity of the subject, where the nasal cavities of different subjects can differ quite markedly.
- the support member 426 confers rigidity to the nosepiece member 425 in both the axial direction, such as to prevent the collapse of the nosepiece 420 on insertion into the nasal cavity, and the vertical, sagittal plane along the elongate, sagittal direction of the tip element 427 of the nosepiece member 425 , such as to enable expansion of the nasal cavity in the vertical, sagittal plane, as will be described in more detail hereinbelow.
- the support member 426 comprises an elongate plate, here a plastics plate, which extends along a length of the nosepiece member 425 in the elongate, sagittal direction of the tip element 427 of the nosepiece member 425 .
- This plate is flexible in allowing for torsional flexing, as illustrated in FIG. 63 , and flexing over the major surface thereof, as illustrated in FIG. 64 , but presents a substantially rigid structure in the plane of the plate, such as not to allow for flexing in the plane of the plate.
- the support member 426 could take the form of a living hinge, which comprises a plurality of rigid elements interconnected by flexible elements, which allow for torsional and bending moments.
- the outlet unit 424 comprises a nozzle 445 for delivering substance to the nasal airway of the subject.
- the nozzle 445 is attached to the support member 426 , and can be integrally formed therewith in one embodiment.
- the nozzle 445 is configured to provide an aerosol spray, either as a liquid or powder aerosol.
- the nozzle 445 could be configured to deliver a jet as a column of substance, either as a liquid or powder jet.
- the flexibility of the nosepiece 420 facilitates the longer, sagittal section of the tip element 427 of the nosepiece member 425 in becoming aligned in the sagittal plane and acts to engage upper and lower walls of the nasal cavity of the subject and, by virtue of the rigidity of the nosepiece 420 in the sagittal plane, cause the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position the nosepiece 420 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion.
- This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the nosepiece 420 .
- the nozzle 445 of the outlet unit 424 is configured to deliver an asymmetric aerosol spray, with the aerosol spray having a significantly greater spray angle in the vertical, sagittal plane ⁇ than in the horizontal plane ⁇ .
- Such an aerosol spray has been found to be particularly advantageous in the delivery of substance to posterior regions of the nasal cavities, in particular the olfactory region.
- the spray angle in the vertical, sagittal plane ⁇ is greater than about 35°, more preferably greater than about 40°, still more preferably greater than about 45° and yet more preferably greater than about 50°.
- the spray angle in the horizontal plane ⁇ is not more than about 35°, more preferably not more than about 30°, still more preferably not more than about 25°, yet more preferably not more than about 20°, and still yet more preferably not more than about 15°.
- the aerosol spray presents an elliptical spray zone.
- the aerosol spray could present a substantially rectangular spray zone.
- the delivery device further comprises a substance supply unit 449 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 445 of the outlet unit 424 to deliver substance from the nosepiece assembly 417 , in this embodiment as an aerosol spray.
- a substance supply unit 449 for delivering metered doses of a substance
- 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 445 of the outlet unit 424 to deliver substance from the nosepiece assembly 417 , in this embodiment as an aerosol spray.
- a propellant preferably a hydrofluoroalkane (HFA) propellant or the like
- the substance supply unit 449 is a multi-dose unit for delivering a plurality of metered doses of substance.
- the substance supply unit 449 could be a single-dose unit for delivering a single metered dose of substance.
- the substance supply unit 449 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism 451 which, when triggered, releases the resilient element and actuates the substance supply unit 449 to deliver a metered dose of substance through the nozzle 445 of the outlet unit 424 .
- the release mechanism 451 is configured to cause actuation of the substance supply unit 449 on generation of a predetermined flow rate through the delivery channel 423 of the nosepiece 420 .
- the release mechanism 451 could be configured to cause actuation of the substance supply unit 449 on generation of a predetermined pressure within the delivery channel 423 of the nosepiece 420 .
- the release mechanism 451 could be configured to cause actuation of the substance supply unit 449 on generation of either one of a predetermined flow rate through the delivery channel 423 of the nosepiece 420 or a predetermined pressure within the delivery channel 423 of the nosepiece 420 .
- the substance supply unit 449 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.
- the substance supply unit 449 could comprise a dry powder delivery unit which delivers metered doses of a substance, as a dry powder, on actuation thereof.
- the substance supply unit 449 could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof.
- the nosepiece assembly 417 is first inserted into one of the nasal cavities of a subject until the sealing element 428 of the nosepiece member 425 abuts the nares of the nostril of the subject, at which point the distal end of the outlet unit 424 typically extends from about 2 cm to about 4 cm into the nasal cavity of the subject, and the mouthpiece unit 419 is then gripped in the lips of the subject.
- insertion of the nosepiece 420 into the nasal cavity of the subject acts to cause the longer, sagittal section of the tip element 427 of the nosepiece member 425 to become aligned in the sagittal plane and engage upper and lower walls of the nasal cavity of the subject, which engagement causes the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position the nosepiece 420 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion.
- This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the nosepiece 420 .
- the subject then begins to exhale through the mouthpiece unit 419 , which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through the delivery channel 423 of the nosepiece 420 , with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject.
- the release mechanism 451 when the flow rate developed through the delivery channel 423 of the nosepiece 420 reaches a predetermined value, the release mechanism 451 is triggered to actuate the substance supply unit 449 to deliver a metered dose of a substance to the nozzle 445 of the outlet unit 424 and into the nasal cavity of the subject, in this embodiment as an asymmetric aerosol spray.
- the release mechanism 451 could be triggered on the generation of a predetermined pressure in the delivery channel 423 of the nosepiece 420 .
- the subject then releases the mouthpiece unit 419 and the nosepiece assembly 417 is withdrawn from the nasal cavity of the subject.
- the device can be discarded.
- the delivery device is a multi-dose device
- the device is ready for further use following priming of the substance supply unit 449 .
- the nosepieces of the above-described third to eighth embodiments could be other than elliptical in section, such as an elongate, triangular section, with the base of the triangle defining a lower edge of the nosepiece.
- outlet units of the above-described embodiments could be configured such that the nozzles thereof are extendable in a forward direction following insertion of the nosepieces, for example, in the manner of a telescopic element, such as to extend further posterior into the nasal cavity.
- the flexible coupling 259 can be integrated with the support member 226 of the nosepiece 220 .
- FIGS. 68 to 70 illustrate one such embodiment.
- the flexible coupling 259 , the support member 226 and the outlet unit 224 are formed as a single, integral unit, typically of a plastics material.
- the flexible coupling 259 allows for limited axial compression of the nosepiece 220 by compression of the flexible coupling 259 and also allows for limited bending of the support member 226 about the flexible coupling 259 , which assist in insertion of the nosepiece 220 into the nasal cavity.
- the upper part of the support member 226 is still substantially rigid in the plane thereof, such as to provide for vertical, sagittal expansion of the nasal cavity, in particular the collapsed region at the upper, lateral wall of the nasal cavity.
- the flexible coupling 259 could have a simpler geometric shape, in one example as a section of the support member 226 of reduced thickness, which confers the limited compressibility and flexibility to the flexible coupling 259 , but yet which confers the required rigidity to the support member 226 , in particular the upper part thereof, as to achieve the vertical, sagittal expansion of the nasal cavity.
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Abstract
A nasal delivery device for and method of delivering substance to a nasal cavity of a subject, the delivery device comprising: a nosepiece unit including a nosepiece for fitting to a nostril of a subject and a nozzle through which substance is in use delivered, preferably substantially axially to a longitudinal axis of the nosepiece, to the respective nasal cavity, wherein at least a tip element of the nosepiece has, at least in one configuration, an elongate lateral section which has a longer dimension in a first, sagittal direction than a second direction orthogonal to the sagittal direction, such that, when the nosepiece is inserted in the nasal cavity of the subject, the longer dimension of the nosepiece acts to engage lower and upper surfaces of the nasal cavity, preferably at the nasal valve, and expand the same in the sagittal plane; and a delivery unit for delivering substance through the nozzle of the nosepiece.
Description
- This application is a continuation application of U.S. application Ser. No. 12/281,894, filed on Jun. 12, 2009, which is a U.S. national phase application of PCT/IB07/01709, filed on Mar. 6, 2007, which in turn claims priority to GB 0604444.0, filed on Mar. 6, 2006.
- 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.
- Referring to
FIG. 1( a), thenasal airway 1 comprises the two nasal cavities separated by the nasal septum, whichairway 1 includes numerous ostia, such as theparanasal sinus ostia 3 and thetubal ostia 5, and olfactory cells, and is lined by the nasal mucosa. Thenasal airway 1 can communicate with thenasopharynx 7, the oral cavity 9 and thelower airway 11, with thenasal airway 1 being in selective communication with the anterior region of thenasopharynx 7 and the oral cavity 9 by opening and closing of theoropharyngeal velum 13. Thevelum 13, which is often referred to as the soft palate, is illustrated in solid line in the closed position, as achieved by providing a certain positive pressure in the oral cavity 9, such as achieved on exhalation through the oral cavity 9, and in dashed line in the open position. - There are many nasal conditions which require treatment. One such condition is nasal inflammation, specifically rhinitis, which can be allergic or non-allergic and is often associated with infection and prevents normal nasal function. By way of example, allergic and non-allergic inflammation of the nasal airway can typically effect between 10 and 20% of the population, with nasal congestion of the erectile tissues of the nasal concha, lacrimation, secretion of watery mucus, sneezing and itching being the most common symptoms. As will be understood, nasal congestion impedes nasal breathing and promotes oral breathing, leading to snoring and sleep disturbance. Other nasal conditions include nasal polyps which arise from the paranasal sinuses, hypertrophic adenoids, secretory otitis media, sinus disease and reduced olfaction.
- In the treatment of certain nasal conditions, the topical administration of medicaments is preferable, particularly where the nasal mucosa is the prime pathological pathway, such as in treating or relieving nasal congestion. Medicaments that are commonly topically delivered include decongestants, anti-histamines, cromoglycates, steroids and antibiotics. At present, among the known anti-inflammatory pharmaceuticals, topical steroids have been shown to have an effect on nasal congestion. Topical decongestants have also been suggested for use in relieving nasal congestion. The treatment of hypertrophic adenoids and chronic secretory otitis media using topical decongestants, steroids and anti-microbial agents, although somewhat controversial, has also been proposed. Further, the topical administration of pharmaceuticals has been used to treat or at least relieve symptoms of inflammation in the anterior region of the nasopharynx, the paranasal sinuses and the auditory tubes.
- Medicaments can also be systemically delivered through the nasal pathway, the nasal pathway offering a good administration route for the systemic delivery of pharmaceuticals, such as hormones, for example, oxytocin and calcitonin, and analgetics, such as anti-migraine compositions, as the high blood flow and large surface area of the nasal mucosa advantageously provides for rapid systemic uptake.
- Nasal delivery is also expected to be advantageous for the administration of medicaments requiring a rapid onset of action, for example, analgetics, anti-emetics, insulin, anti-epileptics, sedatives and hypnotica, and also other pharmaceuticals, for example, cardio-vascular drugs. It is envisaged that nasal administration will provide for a fast onset of action, at a rate similar to that of injection and at a rate much faster than that of oral administration. Indeed, for the treatment of many acute conditions, nasal administration is advantageous over oral administration, since gastric stasis can further slow the onset of action following oral administration.
- It is also expected that nasal delivery could provide an effective delivery route for the administration of proteins and peptides as produced by modern biotechnological techniques. For such substances, the metabolism in the intestines and the first-pass-effect in the liver represent significant obstacles for reliable and cost-efficient delivery.
- Furthermore, it is expected that nasal delivery using the nasal delivery technique of the present invention will prove effective in the treatment of many common neurological diseases, such as Alzheimer'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 the nasal delivery technique of the present invention will allow for the effective delivery of vaccines.
- Aside from the delivery of medicaments, the irrigation of the nasal mucosa with liquids, in particular saline solutions, is commonly practised to remove particles and secretions, as well as to improve the mucociliary activity of the nasal mucosa. These solutions can be used in combination with active pharmaceuticals.
- For any kind of drug delivery, accurate and reliable dosing is essential, but it is of particular importance in relation to the administration of potent drugs which have a narrow therapeutic window, drugs with potentially serious adverse effects and drugs for the treatment of serious and life-threatening conditions. For some conditions, it is essential to individualize the dosage to the particular situation, for example, in the case of diabetes mellitus. For diabetes, and, indeed, for many other conditions, the dosage of the pharmaceutical is preferably based on actual real-time measurements. Currently, blood samples are most frequently used, but the analysis of molecules in the exhalation breath of subjects has been proposed as an alternative to blood analysis for several conditions. Breath analysis is currently used for the diagnosis of conditions such as helicobacter pylori infections which cause gastric ulcers.
- WO-A-00/51672 discloses a delivery device for delivering a substance, in particular a medicament, in a bi-directional flow through the nasal cavities, that is, an air flow which passes into one nostril, around the posterior margin of the nasal septum and in the opposite direction out of the other nostril. This bi-directional air flow advantageously acts to stimulate the sensory nerves in the nasal mucosa, thereby conditioning the subject for the delivery and providing a more comfortable delivery situation.
- It is an aim of the present invention to provide nasal delivery devices and nasal delivery methods for providing for the improved delivery of substance to a nasal cavity of subject.
- One particular aim of the present invention is to optimize the shape, direction and particle distribution of the plume of a delivered dose, in order to reach targeted regions and reduce deposition outside these regions.
- Another particular aim of the present invention is to provide for improved targeting of specific regions of the nasal airway and improved reproducibility and consistency of dosing.
- The present inventors have recognized that an increased delivery of substance to the posterior region of the nasal airway, and in particular the upper posterior region of the nasal airway, as illustrated in
FIG. 1( b), relative to the anterior region of the nasal airway, surprisingly provides for a disproportionately greater CNS effect, which is suggestive of a greater uptake of substance into the CNS than would be predicted from the blood plasma concentration of the substance. - The posterior region of the nasal airway is that region which is posterior of the nasal valve NV, as illustrated in
FIG. 1( b). - The nasal valve NV comprises the anterior bony cavum which contains inferior turbinate erectile tissue and septal erectile tissue, which are supported respectively by compliant ala tissue and the rigid cartilaginous septum (Cole). These elements combine to form a dynamic valve, which extends over several millimetres, that adjusts nasal airflow, and is stabilized by cartilage and bone, modulated by voluntary muscle and regulated by erectile tissue. The lumen of the nasal valve NV is the section of narrowest cross-sectional area between the posterior and anterior regions of the nasal airway, and is much longer and narrower dorsally than ventrally, and this lumen defines a triangular entrance which extends to the piriform region of the bony cavum. The nasal valve NV is lined in its anterior part with transitional epithelium, with a gradual transition posterior to respiratory epithelium. The nasal valve NV and anterior vestibule define roughly the anterior one-third of the nose.
- In human subjects, the upper lateral wall of the nasal valve NV collapses to form a collapsed region, as illustrated in
FIG. 1( b), which significantly narrows the upper part of the nasal valve NV and obstructs access to the upper posterior region of the nasal cavity, and in particular the olfactory region. This collapsed region, in combination with the upper lateral wall of the nasal valve NV having a curved shape, makes the insertion of a rigid structure into the lumen of the nasal valve NV particularly difficult and uncomfortable. - The posterior region of the nasal airway is that region which is lined with respiratory epithelium, which is ciliated, and olfactory epithelium, which comprises nerves which extend downwards through the cribiform plate CP from the olfactory bulb, whereas the anterior region of the nasal airway is that region which is lined with squamous epithelium, which is not ciliated, and transitional epithelium. The olfactory epithelium extends on both the lateral and medial sides of the nasal airway, and typically extends downwards about 1.5 to 2.5 cm.
- The upper posterior region is the region above the inferior meatus IM, as illustrated in
FIG. 1( b), and encompasses the middle turbinate, the sinus ostia in infundibulum (ostia to maxillary, frontal and ethmoidal sinuses), the olfactory region, and the upper branches of the trigeminal nerve, and is that region which includes veins which drain to the venous sinuses that surround the brain. - As illustrated in
FIG. 1( b), the posterior region of the nasal airway is the nasal region posterior of an imaginary vertical plane VERT which is located at a position corresponding to the lower angle of the anterior nasal aperture (aperture piriformis), which corresponds substantially to one-quarter of the distance between the anterior nasal spine AnS, which is a pointed projection at the anterior extremity of the intermaxillary suture, and the posterior nasal spine PnS, which is the sharp posterior extremity of the nasal crest of the hard palate and represents the transition between the nose and the nasopharynx, which corresponds to a distance posterior of the anterior nasal spine AnS of between about 13 mm and about 14 mm (Rosenberger defines the distance between the anterior nasal spine AnS and the posterior nasal spine PnS as being 56 mm in eighteen year old boys and 53.3 mm in eighteen year old girls). - As further illustrated in
FIG. 1( b), the upper region of the nasal airway is an upper segment of the nasal airway which is bounded by the cribiform plate CP and a horizontal plane HORIZ which is located at a position corresponding to one-third of the distance between the nasal floor NF of the nasal airway and the cribiform plate CP, which corresponds to a height of typically between about 13 and about 19 mm above the nasal floor NF (Zacharek et al define the distance from the nasal floor NF to the cribiform plate CP as 46+/−4 mm). - The upper posterior region is thus that upper posterior region which is bounded by the above-defined vertical and horizontal planes VERT, HORIZ.
- The present inventors have postulated that this increased concentration within the CNS arises as a result of the veins in the upper posterior region of the nasal airway draining backwards to the venous sinuses that surround the brain, which leads to a higher local concentration in the cerebrovasculature. Although the sinus cavernous is outside the blood-to-brain barrier, animal models have shown that substances can be transported by a counter-current mechanism from the veins therein to the carotid artery which passes through the sinus cavernous. Other mechanisms have been proposed which include extra axonal transport along the surface of the olfactory and trigeminal nerves. This mode of transport is apparently quite rapid as compared to intra axonal transport.
- The improved efficacy as achieved by the present invention as compared to existing nasal spray administration systems can apparently be explained in that such nasal spray administration systems have been determined initially to deliver largely to the anterior one-third of the nasal airway, that is, the nasal region anterior of the nasal valve, from which region drainage is mainly along the floor of the nose and in which region the veins drain to the external facial vein, which in turn drains to the external carotid and in turn to the peripheral circulation.
- In one aspect the present invention provides a nosepiece which provides for expansion in the sagittal plane, opening the connection of the mucosal surfaces of the nasal valve and isthmus, in particular by expansion of the collapsed region at the upper lateral wall of the nasal valve.
- In another aspect the present invention provides a nosepiece which includes a flexible tip to fit the cross-sectional shape of a nasal cavity. In a preferred embodiment the nosepiece has an internal configuration, at least at the tip, which acts to prevent collapse and maintain a stable cross-sectional area and a relatively-stable resistance.
- In a further aspect the present invention provides a spray nozzle which provides an asymmetrical spray plume, where either a powder or a liquid.
- The present invention is particularly advantageous when used in combination with bi-directional nasal delivery, but is not restricted to such delivery.
- The present invention can be combined with delivery concepts which generate a mist, an aerosol, an aerosol spray of particles, either liquid or powder, drops, droplets, or a liquid jet or jets of liquid.
- An entraining flow can be provided by the exhalation breath of the subject or from an external flow source, such as from an air chamber or a compressed air supply.
- The delivery device can be triggered, such that one or both of the dose and gas flow are triggered by an intraoral pressure which is such as to close the oropharyngeal velum or by another event, which may or may not secure velum closure.
- The present invention also finds application in delivery systems which do not utilize an auxiliary gas flow and even with inhalation environments which provide for nasal inhalation or a sniffing manoeuvre through one or both of the nostrils.
- The devices can be a multi-dose or single-dose.
- Preliminary results in models and gamma-scintigraphic pilot studies show that it is possible to improve the access to and deposition in the narrow passages of the upper region of the nasal airway including the olfactory region, the regions with veins draining to the sinus cavernous and innervated by the trigeminal nerve.
- Furthermore, experiments in models and humans show that modification of the plume geometry and positioning of the nozzle provides for optimal delivery.
- U.S. Pat. No. 6,647,980 discloses a device which utilizes a modified plume in order to attempt to decrease lateral deposition, and thereby increase the amount of the dose which reaches the upper region of the nasal airway. Although this device may provide for reduced deposition in the anterior part of the nasal cavity which is lined by squamous epithelium, owing to the narrower cone angle, only a moderate increase in deposition in the upper region of the nose is expected to be achieved, owing to the difficult and protected access to this region. Furthermore, narrowing of the nose during inhalation, as caused by the Bernoulli effect, will further narrow the nasal cavity to increase the fraction deposited in valve region.
- In its preferred embodiment the present invention provides for a bi-directional air flow in the nasal passages in which optimally-sized particles are entrained and subsequently delivered to appropriate target sites in the nasal airway.
- The present invention aims further to improve upon the devices as disclosed in the applicant's earlier WO-A-03/000310, the content of which is herein incorporated by reference.
- In one embodiment the present invention provides for optimisation of the delivery to upper parts of the nasal airway, including the olfactory region, by configuring the nosepiece, in particular the shape and position thereof, and the emitted plume of particles or liquid jet or jets in conjunction.
- In one embodiment the present invention provides for significantly enhanced access and deposition in the upper region of the nasal airway, and thereby improved dose-to-dose consistency and repeatability of drug delivery to this region of the nasal airway.
- In one embodiment the present invention provides for expansion of the nasal airway in the vertical or sagittal plane and the delivery of an asymmetric plume which has the greater spray angle in the vertical plane, and this particular mode of expansion of the nasal airway in combination with the particular geometrical arrangement of the spray plume has been found to be particularly advantageous in achieving targeted delivery to posterior regions, in particular the olfactory region, of the nasal airway.
- The delivery device of the present invention provides both for positioning of the outlet nozzle and the expansion of the upper lateral and medial surfaces of the valve region of a nasal cavity.
- By configuring the external and internal shape of the nosepiece, the nosepiece both ensures the correct positioning of the outlet nozzle and optimizes the vertical expansion of the nasal cavity.
- The operative function of the nosepiece of the present invention, in vertically expanding the nasal cavity, can be contrasted to that of a conventional, frusto-conical nosepiece, which, during insertion into a nasal cavity, has been found by the present inventor to push the soft, nasal tissue rearwardly, which is particularly disadvantageous where attempting delivery to posterior regions of the nasal airway. One such nosepiece is disclosed in WO-A-1999/049984.
- Various other nosepiece geometries are known for nasal delivery devices, such as disclosed in US-A-2003/0101992, U.S. Pat. No. 6,561,193 and WO-A-2004/108197, but none of these nosepieces are configured to provide for vertical or sagittal expansion of the nasal cavity, in particular at the nasal valve.
- In its preferred embodiment the present invention provides a narrow nosepiece which can be easily slid into a nasal cavity beyond the nasal valve to the required depth, before expansion in the vertical or sagittal plane.
- This expanding movement of the nosepiece can either be to the upper part, the lower part or both the upper and lower parts.
- In one embodiment the nosepiece comprises two members, that is, an upper and a lower member, where one or both of the members are movable relative to the supporting body. Such members are exemplified by a pair of scissors, a pair of pliers and expansion screws.
- In another embodiment the nosepiece could comprise an expanding cuff-like member, which comprises one or both of upper and lower cuff members which expand in the vertical plane.
- In one embodiment the nosepiece can comprise a moderately-flexible anterior part such as to allow the nosepiece to adapt to the curved shape of a nasal passage, and thereby facilitate deeper insertion into the nasal slit, and even into the bony part thereof.
- In a preferred embodiment the nosepiece includes internal features, such as ribs, which prevent collapse of the flow path and prevents substantial reduction in the internal cross-sectional area, which would otherwise lead to an increase in flow resistance.
- This flexibility enables the nosepiece to conform, at least in part, to the different shapes and directions of the nasal passage in this region, but at the same time assists in expanding the isthmus. Though the shape of the anterior part of the nasal passage normally varies within a pre-defined range, pathological deviations may cause more pronounced changes which otherwise may create problems for insertion and positioning of the nosepiece, and hence efficient delivery.
- Furthermore, this adaptation of the anterior shape of the nosepiece to conform to the nasal passage provides for reduced turbulence, which would otherwise lead to unwanted deposition in the zone of turbulence.
- The present invention also provides for a nozzle, such as the swirl chamber of a spray pump or a pMDI or a nebulizer, which delivers a modified, asymmetric plume of particles.
- In its preferred embodiment the plume is an asymmetric plume which is relatively flat, with a small dimension in one axis and much greater in the other axis.
- Such a shaped plume reduces deposition in the anterior part of the valve region and increases the fraction of the dose entering into the upper, more posterior region of the nasal passage including the olfactory region and the sinus ostia, which is located below the middle meatus.
- The present invention also extends to means for securing a correct and reproducible positioning of nosepiece.
- Positioning of the delivery device can be achieved by the function of the mouthpiece or an exit resistor in the exit nostril of a bi-directional device, or as a separate feature with the main function of assisting positioning of the nosepiece. Triangular-shaped nose pieces assist in achieving the correct positioning. The mouthpiece of a device intended for bi-directional delivery also assists in achieving a reproducible positioning of the nosepiece. The provision of a nosepiece in the contralateral nostril also assists in achieving a reproducible positioning of the nosepiece. The provision of a special cap or the like as applied to the exterior of the exterior nose also assists in achieving a reproducible positioning of the nosepiece. Also, tape or vacuum can be used to assist in positioning of the nosepiece and potentially in addition helps expanding the valve region by external action, such as an external dilator used to open the nose (“Breath-Right” nasal strip).
- The present invention extends to devices which are adapted to bi-directional delivery where driven by the exhalation breath of the subject or an auxiliary gas source, and conventional nasal delivery devices which do not utilize an auxiliary gas flow.
- Furthermore, the present invention can be adapted to any traditional delivery modality, including but not restricted to a spray pump, a pMDI, a nebulizer or any other means of delivering liquid jets, particles or drops, either in powder or liquid form.
- In its preferred embodiment the present invention provides for expansion in the vertical or sagittal plane, but the expansion is not restricted to this plane. The expansion can be a combination of movement in different planes.
- The expansion can be only or predominantly to the upper part or the lower part of a nasal cavity, or the upper and lower parts in combination.
- The expansion can be achieved by any possible movement, such as pushing, pulling, lifting, pressing, rotating, expanding, flexing, suction (vacuum) and even by secondary chemical reactions initiated by, for example, pressure, moisture and temperature which create the desired movement of retraction of a mass or volume.
- In one embodiment, where the nosepiece comprises two movable members in the form of a speculum, one of the members can provide a delivery channel through which substance is delivered into the nasal airway, and the other member can include a pressure-sensitive release valve or an open channel which allows for the venting of particles from the nasal airway. Such a configuration has particular application in relation to a completely obstructed nose, where the delivered flow would otherwise have no means of escape.
- Where the substance includes relatively-large particles, those particles will due to their momentum travel forward and deposit on an opposing surface, whereas the air flow will deviate and flow towards the exit valve.
- In having an on/off valve which opens at a predetermined pressure which is just above the pressure where bi-directional flow is expected to occur in a moderately-blocked nose, an air flow will occur suddenly and carry the particles forward, and this will entrain the particles or at least a large fraction of the particles into the blocked nose and onto an opposing surface before the airflow turns around and exits in the opposite direction through the valve.
- The valve can have a filter to prevent the particles from escaping to the atmosphere. Using large particles, such as from about 100 μm to about 200 μm, will also avoid or at least reduce this problem.
- By providing a relatively-large distance between the point of emission, which is preferably in the upper member, and the point of exit, which is preferably in the lower arm, increased deposition can be achieved.
- In a preferred embodiment the positioning of the nosepiece should preferably occur prior to release of substance, but could also occur in sequence immediately prior to or simultaneously with the releasing action.
- The preferred action is as follows. The positioning and expansion of the specialized nozzle can be achieved by a finger action. When complete, this action will also open the flow path permitting delivery of substance into the nasal airway, preferably by bi-directional delivery, but alternatively also even in the absence of bi-directional delivery. Alternatively, a pre-charged spring or similar can be released when the nosepiece is inserted into a nostril to the correct position. When this positioning action is complete, a valve is opened, making it possible to blow through the device or alternatively release the force from a gas chamber or another stored force, or alternatively allowing a mechanical action by hand compression, similar to actuation of a spray pump. In an alternative configuration, which can be utilized with or without bi-directional flow, for example, when used in infants and unconscious subjects, the two actions of expansion and release of substance from, for example, a spray pump can be integrated. The first part of the mechanical action/compression of a lever by the finger will secure the expansion of the lever and positioning of the nosepiece. Then, when a certain trigger point or resistance is reached the finger force will result in the generation of a spray or release of a compressed gas by exhalation against a resistor or from a pressurized compartment or the combination thereof.
- The following represent potential areas of application. Delivery to the olfactory epithelium for transport into or along nerve paths or by diffusion across the cribiform plate. Delivery to the upper part of the nasal passage including the olfactory region which drains via veins to the sinus cavernous to achieve higher concentrations of drugs, with the potential of diffusing into the carotid artery passing through the sinus cavernous, where diffusing through the rete mirabile. Delivery to the branches of the trigeminal nerve for potential peripheral action on the nerves (anagetic), uptake and transport along the nerves to the central ganglion and potentially into the CNS or with reflectory actions in other parts of the face or CNS. Deposition of drugs in the middle meatus and infundibulum which includes the sinus ostia. This region plays a key role in ventilation of the sinuses and in the development of sinus pathology and consequently for the treatment of pathology in this region. Delivery of topically-acting substances, such as decongestants, steroids and antihistamines, which can reduce the mucosal swelling in the entrances to and in the narrow slit like passages of the upper part of the nose in order to improve olfaction or reverse anosmia.
- Preferred embodiments of the present invention will now be described hereinbelow by way of example only with reference to the accompanying drawings, in which:
-
FIG. 1( a) schematically illustrates the anatomy of the upper respiratory tract of a human subject; -
FIG. 1( b) illustrates the segmentation of a nasal cavity in accordance with a preferred embodiment of the present invention; -
FIG. 2 illustrates a nasal delivery device in accordance with a first embodiment of the present invention; -
FIG. 3 illustrates the delivery device ofFIG. 2 prior to insertion into a nasal cavity of a subject; -
FIG. 4 illustrates the delivery device ofFIG. 2 inserted into a nasal cavity of the subject prior to operation; -
FIG. 5 illustrates the delivery device ofFIG. 2 following operation of the actuating members of the nosepiece assembly to expand the upper and lower walls of the nasal cavity of the subject; -
FIG. 6 illustrates the delivery device ofFIG. 2 following actuation of the substance supply unit; -
FIGS. 7( a) and (b) illustrate the tip of a delivery element as one modified embodiment of the delivery device ofFIG. 2 , where illustrated in respective ones of the rest or uncompressed state and the operative or compressed state; -
FIG. 8 illustrates a nasal delivery device in accordance with a second embodiment of the present invention; -
FIG. 9 illustrates a cross sectional view (along section I-I inFIG. 8 ) of the nosepiece assembly of the delivery device ofFIG. 8 ; -
FIG. 10 illustrates the delivery device ofFIG. 8 prior to insertion into a nasal cavity of a subject; -
FIG. 11 illustrates the delivery device ofFIG. 8 inserted into a nasal cavity of a subject prior to operation; -
FIG. 12 illustrates a cross sectional view (along section II-II inFIG. 11 ) of the nosepiece assembly of the delivery device ofFIG. 8 inserted into the nasal cavity of the subject for operation; -
FIG. 13 illustrates the delivery device ofFIG. 8 following actuation of the substance supply unit; -
FIG. 14 illustrates a nasal delivery device in accordance with a third embodiment of the present invention; -
FIG. 15 illustrates a fragmentary perspective view of the nosepiece of the delivery device ofFIG. 14 (other side symmetrical); -
FIG. 16 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device ofFIG. 14 (other side symmetrical); -
FIG. 17 illustrates a fragmentary plan view of the nosepiece of the delivery device ofFIG. 14 (other side symmetrical); -
FIG. 18 illustrates the delivery device ofFIG. 14 prior to insertion into a nasal cavity of a subject; -
FIG. 19 illustrates the delivery device ofFIG. 14 inserted into a nasal cavity of the subject prior to operation; -
FIG. 20 illustrates the delivery device ofFIG. 14 following actuation of the substance supply unit; -
FIG. 21 illustrates a nasal delivery device in accordance with a fourth embodiment of the present invention; -
FIG. 22 illustrates a fragmentary perspective view of the nosepiece of the delivery device ofFIG. 21 (other side symmetrical); -
FIG. 23 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device ofFIG. 21 (other side symmetrical); -
FIG. 24 illustrates a fragmentary plan view of the nosepiece of the delivery device ofFIG. 21 (other side symmetrical); -
FIG. 25 illustrates the delivery device ofFIG. 21 prior to insertion into a nasal cavity of a subject; -
FIG. 26 illustrates the delivery device ofFIG. 21 inserted into a nasal cavity of the subject prior to operation; -
FIG. 27 illustrates the delivery device ofFIG. 21 following actuation of the substance supply unit; -
FIG. 28 illustrates a nasal delivery device in accordance with a fifth embodiment of the present invention; -
FIG. 29 illustrates a fragmentary perspective view of the nosepiece of the delivery device ofFIG. 28 (other side symmetrical); -
FIG. 30 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device ofFIG. 28 (other side symmetrical); -
FIG. 31 illustrates a fragmentary plan view of the nosepiece of the delivery device ofFIG. 28 (other side symmetrical); -
FIG. 32 illustrates the delivery device ofFIG. 28 prior to insertion into a nasal cavity of a subject; -
FIG. 33 illustrates the delivery device ofFIG. 28 inserted into a nasal cavity of the subject prior to operation; -
FIG. 34 illustrates the delivery device ofFIG. 28 following actuation of the substance supply unit; -
FIG. 35 illustrates a nasal delivery device in accordance with a sixth embodiment of the present invention; -
FIG. 36 illustrates a fragmentary perspective view of the nosepiece of the delivery device ofFIG. 35 (other side symmetrical); -
FIG. 37 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device ofFIG. 35 (other side symmetrical); -
FIG. 38 illustrates a fragmentary plan view of the nosepiece of the delivery device ofFIG. 35 (other side symmetrical); -
FIG. 39 illustrates the delivery device ofFIG. 35 prior to insertion into a nasal cavity of a subject; -
FIG. 40 illustrates the delivery device ofFIG. 35 inserted into a nasal cavity of the subject prior to operation; -
FIG. 41 illustrates the delivery device ofFIG. 35 following actuation of the substance supply unit; -
FIG. 42 illustrates a nasal delivery device in accordance with a seventh embodiment of the present invention; -
FIG. 43 illustrates a fragmentary perspective view of the nosepiece of the delivery device ofFIG. 42 (other side symmetrical); -
FIG. 44 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device ofFIG. 42 (other side symmetrical); -
FIG. 45 illustrates a fragmentary plan view of the nosepiece of the delivery device ofFIG. 42 (other side symmetrical); -
FIG. 46 illustrates the delivery device ofFIG. 42 prior to insertion into a nasal cavity of a subject; -
FIG. 47 illustrates the delivery device ofFIG. 42 inserted into a nasal cavity of the subject prior to operation; -
FIG. 48 illustrates the delivery device ofFIG. 42 following actuation of the substance supply unit; -
FIG. 49 illustrates a nasal delivery device in accordance with an eighth embodiment of the present invention; -
FIG. 50 illustrates a fragmentary perspective view of the nosepiece of the delivery device ofFIG. 49 (other side symmetrical); -
FIG. 51 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device ofFIG. 49 (other side symmetrical); -
FIG. 52 illustrates a fragmentary plan view of the nosepiece of the delivery device ofFIG. 49 (other side symmetrical); -
FIG. 53 illustrates a fragmentary perspective view of the nozzle of the outlet unit of the delivery device ofFIG. 49 ; -
FIG. 54 illustrates a vertical sectional view (along section III-III inFIG. 53 ) of the nozzle ofFIG. 53 ; -
FIG. 55 illustrates an enlarged view of detail A inFIG. 54 ; -
FIG. 56 illustrates the delivery device ofFIG. 49 prior to insertion into a nasal cavity of a subject; -
FIG. 57 illustrates the delivery device ofFIG. 49 inserted into a nasal cavity of the subject prior to operation; -
FIG. 58 illustrates the delivery device ofFIG. 49 following actuation of the substance supply unit; -
FIG. 59 illustrates a nasal delivery device in accordance with a ninth embodiment of the present invention; -
FIG. 60 illustrates a fragmentary perspective view of the nosepiece of the delivery device ofFIG. 59 (other side symmetrical); -
FIG. 61 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device ofFIG. 59 (other side symmetrical); -
FIG. 62 illustrates a fragmentary plan view of the nosepiece of the delivery device ofFIG. 59 (other side symmetrical); -
FIG. 63 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device ofFIG. 59 where twisted about the longitudinal axis of the nosepiece; -
FIG. 64 illustrates a fragmentary, sectional perspective view of the nosepiece of the delivery device ofFIG. 59 where bent about an axis orthogonal to the longitudinal axis of the nosepiece and extending in the plane of the support member of the nosepiece; -
FIG. 65 illustrates the delivery device ofFIG. 59 prior to insertion into a nasal cavity of a subject; -
FIG. 66 illustrates the delivery device ofFIG. 59 inserted into a nasal cavity of the subject prior to operation; -
FIG. 67 illustrates the delivery device ofFIG. 59 following actuation of the substance supply unit; -
FIG. 68 illustrates a fragmentary perspective view of a nosepiece as one modification of the nosepiece of the delivery device ofFIG. 42 (other side symmetrical); -
FIG. 69 illustrates a fragmentary, sectional perspective view of the nosepiece ofFIG. 68 (other side symmetrical); and -
FIG. 70 illustrates a fragmentary plan view of the nosepiece ofFIG. 68 (other side symmetrical). -
FIGS. 2 to 6 illustrate a nasal delivery device in accordance with a first embodiment of the present invention. - The delivery device comprises a
housing 15, anosepiece assembly 17 for fitting in a nasal cavity of a subject, and amouthpiece unit 19 through which the subject exhales to actuate the delivery device. - The
nosepiece assembly 17 comprises first andsecond nosepiece units housing 15 and are operable by the subject, in this embodiment by gripping the same between one of the fingers and the thumb, to expand the nasal cavity of the subject in the vertical or sagittal plane. - In this embodiment the
first nosepiece unit 20 comprises a lower,guide element 26 which acts to guide thenosepiece assembly 17 when fitted in the nasal cavity of the subject, and anactuating arm 28 which extends rearwardly of theguide element 26 and is operated by the subject, in this embodiment by gripping the same, to position theguide element 26. - In this embodiment the
second nosepiece unit 24 comprises an upper,delivery element 32 which acts to guide thenosepiece assembly 17 when fitted in the nasal cavity of the subject, anoutlet unit 34 which is disposed within thedelivery element 32 for delivering substance into the nasal airway of the subject, and anactuating arm 36 which extends rearwardly of the delivery element and is operated by the subject, in this embodiment by gripping the same, to position thedelivery element 32. - In this embodiment the
delivery element 32 has a relatively-narrow section in the horizontal plane so as to facilitate insertion beyond the narrow nasal valve of the nasal cavity of the subject and a tapering section in the vertical plane which narrows to the distal end thereof. - In this embodiment the
outlet unit 34 comprises adelivery channel 43 which is in fluid communication with themouthpiece unit 19 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through themouthpiece unit 19, and anozzle 45 for delivering substance to the nasal airway of the subject. - In this embodiment the
nozzle 45 is disposed in thedelivery channel 43 co-axially with the same. - In this embodiment the
nozzle 45 is configured to provide an aerosol spray. - In an alternative embodiment, for the delivery of a liquid, the
nozzle 45 could be configured to deliver a liquid jet as a column of liquid. - In this embodiment the
outlet unit 34 is coupled to thehousing 15 by a flexible coupling, such as to allow for the positioning of thedelivery element 32 in the nasal cavity of the subject, as will be described in more detail hereinbelow. - In an alternative embodiment the
delivery element 32 could be fixed to thehousing 15, and themouthpiece unit 19 instead movably coupled to thehousing 15, typically by a flexible coupling, such as to allow for the positioning of thedelivery element 32 in the nasal cavity of the subject. - In one embodiment, as illustrated in
FIGS. 7( a) and (b), at least the tip of thedelivery element 32 can comprise a tubular section of a flexible, preferably resilient, material, which is such as to expand in the vertical axis when compressed in the horizontal axis. In a preferred embodiment the material is a semi-soft plastics material, such as silicone rubber. - In this embodiment the tip of the
delivery element 32 is configured such that the lateral sections thereof preferentially flex when compressed in the horizontal axis, but yet exhibit sufficient rigidity as to drive the upper and lower sections thereof to expand in the vertical axis. - In this embodiment the tip of the
delivery element 32 includes supportingelements delivery element 32, and act to prevent compression of the lateral sections of the tip of thedelivery element 32 beyond a predetermined separation, which is that required to achieve an optimal flow profile through thenosepiece 120. - With this configuration, as will be described in more detail hereinbelow, operation of the actuating
arms second nosepiece units guide element 26 of thefirst nosepiece unit 20 relative to thedelivery element 32 of thesecond nosepiece unit 24 to an expanded state. - This expansion acts to engage the lower and upper walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure as compared to the lower wall of the nasal cavity of the subject, which is a relatively-firm structure, and also position the
delivery element 32 of thesecond nosepiece unit 24 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion. - This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the
delivery element 32 of thesecond nosepiece unit 24. - In this embodiment the
nozzle 45 of theoutlet unit 34 is configured to deliver an asymmetric aerosol spray, with the aerosol spray having a significantly greater spray angle in the vertical plane α than in the horizontal plane β. Such an aerosol spray has been found to be particularly advantageous in the delivery of substance to posterior regions of the nasal cavities, in particular the olfactory region. In a preferred embodiment the spray angle in the vertical plane α is greater than 35°, and more preferably greater than 40°. - In this embodiment the aerosol spray presents an elliptical spray zone.
- In another embodiment the aerosol spray could present a substantially rectangular spray zone.
- The
nosepiece assembly 17 further comprises a sealingmember 48, in this embodiment a tapered, annular ring of a resilient material, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of theoutlet unit 34 of thesecond nosepiece unit 24 of thenosepiece assembly 17 into the nasal cavity of the subject. In a preferred embodiment the distal end of theoutlet unit 34 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably at least about 4 cm, and preferably from about 2 cm to about 4 cm, into the nasal cavity of the subject. - The delivery device further comprises a
substance supply unit 49 for delivering metered doses of a substance, in this embodiment an aerosol canister for delivering metered volumes of a propellant, preferably a hydrofluoroalkane (HFA) propellant or the like, containing medicament, either as a suspension or solution, which is fluidly connected to thenozzle 45 of theoutlet unit 34 to deliver substance from thenosepiece assembly 17, in this embodiment as an aerosol spray. - In this embodiment the
substance supply unit 49 is a multi-dose unit for delivering a plurality of metered doses of substance. In another embodiment thesubstance supply unit 49 could be a single-dose unit for delivering a single metered dose of substance. - The
substance supply unit 49 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuatedrelease mechanism 51 which, when triggered, releases the resilient element and actuates thesubstance supply unit 49 to deliver a metered dose of substance through thenozzle 45 of theoutlet unit 34. - In this embodiment the
release mechanism 51 is configured to cause actuation of thesubstance supply unit 49 on generation of a predetermined flow rate through thedelivery channel 43 of thedelivery element 32. - In another embodiment the
release mechanism 51 could be configured to cause actuation of thesubstance supply unit 49 on generation of a predetermined pressure within thedelivery channel 43 of thedelivery element 32. - In a further embodiment the
release mechanism 51 could be configured to cause actuation of thesubstance supply unit 49 on generation of either one of a predetermined flow rate through thedelivery channel 43 of thedelivery element 32 or a predetermined pressure within thedelivery channel 43 of thedelivery element 32. - In an alternative embodiment the
substance supply unit 49 could comprise a mechanical delivery pump, in particular a liquid delivery pump or a powder delivery pump, which delivers metered doses of a substance on actuation thereof. - In another alternative embodiment the
substance supply unit 49 could comprise a dry powder delivery unit which delivers metered doses of a substance, as a dry powder, on actuation thereof. - In yet another alternative embodiment the
substance supply unit 49 could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof. - Operation of the delivery device will now be described hereinbelow with reference to
FIGS. 3 to 6 of the accompanying drawings. - Referring to
FIGS. 3 and 4 , thenosepiece assembly 17 is first inserted into one of the nasal cavities of a subject until the sealingmember 48 abuts the nares of the nostril of the subject, at which point the distal end of theoutlet unit 34 typically extends from about 2 cm to about 4 cm into the nasal cavity of the subject, and themouthpiece unit 19 is then gripped in the lips of the subject. - Referring to
FIG. 5 , the subject then operates the actuatingarms second nosepiece units guide element 26 of thefirst nosepiece unit 20 relative to thedelivery element 32 of thesecond nosepiece unit 24 to an expanded state. This expansion acts to engage the lower and upper walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and position thedelivery element 32 of thesecond nosepiece unit 24 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject being a relatively-hard structure, which acts as a reference for the expansion. This expansion also acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls to be urged into sealing contact with thedelivery element 32 of thesecond nosepiece unit 24. - Referring to
FIG. 6 , the subject then begins to exhale through themouthpiece unit 19, which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through thedelivery channel 43 of theoutlet unit 34, with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject. - In this embodiment, when the flow rate developed through the
delivery channel 43 of thedelivery element 32 reaches a predetermined value, therelease mechanism 51 is triggered to actuate thesubstance supply unit 49 to deliver a metered dose of a substance to thenozzle 45 of theoutlet unit 34 and into the nasal cavity of the subject, in this embodiment as an asymmetric aerosol spray. In the alternative embodiment therelease mechanism 51 could be triggered on the generation of a predetermined pressure in thedelivery channel 43 of thedelivery element 32. - Following exhalation, the subject then releases the actuating
arms second nosepiece units guide element 26 of thefirst nosepiece unit 20 and thedelivery element 32 of thesecond nosepiece unit 24 to return to the contracted state, at which point themouthpiece unit 19 is released and thenosepiece assembly 17 is withdrawn from the nasal cavity of the subject. - In one embodiment, where the delivery device is a single-dose device, the device can be discarded.
- In another embodiment, where the delivery device is a multi-dose device, the device is ready for further use following priming of the
substance supply unit 49. -
FIGS. 8 to 13 illustrate a nasal delivery device in accordance with a second embodiment of the present invention. - The delivery device comprises a
housing 115, anosepiece assembly 117 for fitting in a nasal cavity of a subject, and amouthpiece unit 119 through which the subject exhales to actuate the delivery device. - The
nosepiece assembly 117 comprises anosepiece 120 which is attached to thehousing 115 and defines adelivery channel 123 which is in fluid communication with themouthpiece unit 119 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through themouthpiece unit 119, and anoutlet unit 124 which is disposed within thenosepiece 120 for delivering substance into the nasal airway of the subject. - In this embodiment the
nosepiece 120 is frusto-conical in shape and semi-flexible, here formed of a semi-soft plastics material, such as to expand in the vertical axis when compressed in the horizontal axis. - In this embodiment the
nosepiece 120 is configured such that the lateral sections thereof preferentially flex when compressed in the horizontal axis, but yet exhibit sufficient rigidity as to drive the upper and lower sections thereof to expand in the vertical axis. - In this embodiment the
nosepiece 120 includes upper and lowerre-inforcing elements nosepiece 120, and provide for the application of the expansion force to upper and lower regions of the nasal cavity of the subject. - In this embodiment the
nosepiece 120 includes supportingelements nosepiece 120, and act to prevent compression of the lateral sections of thenosepiece 120 beyond a predetermined separation, which is that required to achieve an optimal flow profile through thenosepiece 120. - In this embodiment the
outlet unit 124 comprises anozzle 145 for delivering substance to the nasal airway of the subject. In this embodiment thenozzle 145 is disposed to the upperre-inforcing element 127. In this embodiment thenozzle 145 is configured to provide an aerosol spray. In an alternative embodiment, for the delivery of a liquid, thenozzle 145 could be configured to deliver a liquid jet as a column of liquid. - In this embodiment the
outlet unit 124 is coupled to thehousing 115 by a flexible coupling, such as to allow for the positioning of thenosepiece 120 in the nasal cavity of the subject, as will be described in more detail hereinbelow. - With this configuration, as will be described in more detail hereinbelow, insertion of the
nosepiece 120 into the nasal cavity of the subject acts to compress the lateral sections of thenosepiece 120 by engagement with the relatively-narrow passage as presented at the nasal valve, which in turn acts to cause the expansion of the upper and lower sections of thenosepiece 120 in the vertical axis. - This expansion acts to engage upper and lower walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position the
nosepiece 120 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion. - This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the
nosepiece 120. - In this embodiment the
nozzle 145 of theoutlet unit 124 is configured to deliver an asymmetric aerosol spray, with the aerosol spray having a significantly greater spray angle in the vertical plane α than in the horizontal plane β. Such an aerosol spray has been found to be particularly advantageous in the delivery of substance to posterior regions of the nasal cavities, in particular the olfactory region. In a preferred embodiment the spray angle in the vertical plane α is greater than 35°, and more preferably greater than 40°. - In this embodiment the aerosol spray presents an elliptical spray zone.
- In another embodiment the aerosol spray could present a substantially rectangular spray zone.
- The
nosepiece assembly 117 further comprises a sealingmember 148, in this embodiment a tapered, annular ring of a resilient material, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of theoutlet unit 124 of thenosepiece assembly 117 into the nasal cavity of the subject. In a preferred embodiment the distal end of theoutlet unit 124 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably at least about 4 cm, and preferably from about 2 cm to about 4 cm, into the nasal cavity of the subject. - The delivery device further comprises a
substance supply unit 149 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 thenozzle 145 of theoutlet unit 124 to deliver substance from thenosepiece assembly 117, in this embodiment as an aerosol spray. - In this embodiment the
substance supply unit 149 is a multi-dose unit for delivering a plurality of metered doses of substance. In another embodiment thesubstance supply unit 149 could be a single-dose unit for delivering a single metered dose of substance. - The
substance supply unit 149 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuatedrelease mechanism 151 which, when triggered, releases the resilient element and actuates thesubstance supply unit 149 to deliver a metered dose of substance through thenozzle 145 of theoutlet unit 124. - In this embodiment the
release mechanism 151 is configured to cause actuation of thesubstance supply unit 149 on generation of a predetermined flow rate through thedelivery channel 123 of thenosepiece 120. - In another embodiment the
release mechanism 151 could be configured to cause actuation of thesubstance supply unit 149 on generation of a predetermined pressure within thedelivery channel 123 of thenosepiece 120. - In a further embodiment the
release mechanism 151 could be configured to cause actuation of thesubstance supply unit 149 on generation of either one of a predetermined flow rate through thedelivery channel 123 of thenosepiece 120 or a predetermined pressure within thedelivery channel 123 of thenosepiece 120. - In an alternative embodiment the
substance supply unit 149 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 149 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 149 could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof. - Operation of the delivery device will now be described hereinbelow with reference to
FIGS. 10 to 13 of the accompanying drawings. - Referring to
FIGS. 10 and 11 , thenosepiece assembly 117 is first inserted into one of the nasal cavities of a subject until the sealingmember 148 abuts the nares of the nostril of the subject, at which point the distal end of theoutlet unit 124 typically extends from about 2 cm to about 4 cm into the nasal cavity of the subject, and themouthpiece unit 119 is then gripped in the lips of the subject. - As illustrated in
FIG. 12 , insertion of thenosepiece 120 into the nasal cavity of the subject acts to compress the lateral sections of thenosepiece 120 by engagement with the relatively-narrow passage as presented at the nasal valve, which in turn acts to cause the expansion of the upper and lower sections of thenosepiece 120 in the vertical axis, with the extent of the compression being determined by the supportingelements nosepiece 120 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion. This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with thenosepiece 120. - Referring to
FIG. 13 , the subject then begins to exhale through themouthpiece unit 119, which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through thedelivery channel 123 of thenosepiece 120, with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject. - In this embodiment, when the flow rate developed through the
delivery channel 123 of thenosepiece 120 reaches a predetermined value, therelease mechanism 151 is triggered to actuate thesubstance supply unit 149 to deliver a metered dose of a substance to thenozzle 145 of theoutlet unit 124 and into the nasal cavity of the subject, in this embodiment as an asymmetric aerosol spray. In the alternative embodiment therelease mechanism 151 could be triggered on the generation of a predetermined pressure in thedelivery channel 123 of thenosepiece 120. - Following exhalation, the subject then releases the
mouthpiece unit 119 and thenosepiece assembly 117 is 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 149. -
FIGS. 14 to 20 illustrate a nasal delivery device in accordance with a third embodiment of the present invention. - The delivery device comprises a
housing 215, anosepiece assembly 217 for fitting in a nasal cavity of a subject, and amouthpiece unit 219 through which the subject exhales to actuate the delivery device. - The
nosepiece assembly 217 comprises anosepiece 220 which is attached to thehousing 115 and defines adelivery channel 223 which is in fluid communication with themouthpiece unit 219 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through themouthpiece unit 219, and anoutlet unit 224 which is disposed within thenosepiece 220 for delivering substance into the nasal airway of the subject. - In this embodiment, as particularly illustrated in
FIGS. 15 to 17 , thenosepiece 220 is generally frusto-conical in shape and includes atip element 225 of asymmetric, elongate section, in having a dimension d1 in a first, sagittal direction which is substantially greater than a dimension d2 in a second, lateral direction which is orthogonal to the first, sagittal direction. In this embodiment the dimension d1 in the sagittal direction is at least twice that of the dimension d2 in the lateral direction. In one embodiment the dimension d2 in the lateral direction is not more than 6 mm and more preferably not more than 4 mm. - In this embodiment the
tip element 225 extends substantially axially to the longitudinal axis of thenosepiece 220. - In this embodiment the
nosepiece 220 further comprises a sealingelement 248, in this embodiment a tapered, annular section, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of theoutlet unit 224 of thenosepiece assembly 217 into the nasal cavity of the subject. In a preferred embodiment the distal end of theoutlet unit 224 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably at least about 4 cm, and preferably from about 2 cm to about 4 cm, into the nasal cavity of the subject. - In this embodiment the
nosepiece 220 is formed as a substantially rigid structure, here formed of a plastics material. - In this embodiment the
outlet unit 224 comprises anozzle 245 for delivering substance to the nasal airway of the subject. - In this embodiment the
nozzle 245 is configured to provide an aerosol spray, either as a liquid or powder aerosol. - In an alternative embodiment the
nozzle 245 could be configured to deliver a jet as a column of substance, either as a liquid or powder jet. - With this configuration, as will be described in more detail hereinbelow, on insertion of the
nosepiece 220 into the nasal cavity of the subject, the longer, sagittal section of thetip element 225 of thenosepiece 220 becomes aligned in the sagittal plane and acts to engage upper and lower walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position thenosepiece 220 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion. - This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the
nosepiece 220. - In this embodiment the
nozzle 245 of theoutlet unit 224 is configured to deliver an asymmetric aerosol spray, with the aerosol spray having a significantly greater spray angle in the vertical, sagittal plane α than in the horizontal plane β. Such an aerosol spray has been found to be particularly advantageous in the delivery of substance to posterior regions of the nasal cavities, in particular the olfactory region. - In a preferred embodiment the spray angle in the vertical, sagittal plane α is greater than about 35°, more preferably greater than about 40°, still more preferably greater than about 45° and yet more preferably greater than about 50°.
- In a preferred embodiment the spray angle in the horizontal plane β is not more than about 35°, more preferably not more than about 30°, still more preferably not more than about 25°, yet more preferably not more than about 20°, and still yet more preferably not more than about 15°.
- In this embodiment the aerosol spray presents an elliptical spray zone.
- In another embodiment the aerosol spray could present a substantially rectangular spray zone.
- The delivery device further comprises a
substance supply unit 249 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 thenozzle 245 of theoutlet unit 224 to deliver substance from thenosepiece assembly 217, in this embodiment as an aerosol spray. - In this embodiment the
substance supply unit 249 is a multi-dose unit for delivering a plurality of metered doses of substance. In another embodiment thesubstance supply unit 249 could be a single-dose unit for delivering a single metered dose of substance. - The
substance supply unit 249 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuatedrelease mechanism 251 which, when triggered, releases the resilient element and actuates thesubstance supply unit 249 to deliver a metered dose of substance through thenozzle 245 of theoutlet unit 224. - In this embodiment the
release mechanism 251 is configured to cause actuation of thesubstance supply unit 249 on generation of a predetermined flow rate through thedelivery channel 223 of thenosepiece 220. - In another embodiment the
release mechanism 251 could be configured to cause actuation of thesubstance supply unit 249 on generation of a predetermined pressure within thedelivery channel 223 of thenosepiece 220. - In a further embodiment the
release mechanism 251 could be configured to cause actuation of thesubstance supply unit 249 on generation of either one of a predetermined flow rate through thedelivery channel 223 of thenosepiece 220 or a predetermined pressure within thedelivery channel 223 of thenosepiece 220. - In an alternative embodiment the
substance supply unit 249 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 249 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 249 could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof. - Operation of the delivery device will now be described hereinbelow with reference to
FIGS. 18 to 20 of the accompanying drawings. - Referring to
FIGS. 18 and 19 , thenosepiece assembly 217 is first inserted into one of the nasal cavities of a subject until the sealingmember 248 abuts the nares of the nostril of the subject, at which point the distal end of theoutlet unit 224 typically extends from about 2 cm to about 4 cm into the nasal cavity of the subject, and themouthpiece unit 219 is then gripped in the lips of the subject. - As illustrated, insertion of the
nosepiece 220 into the nasal cavity of the subject acts to cause the longer, sagittal section of thetip element 225 of thenosepiece 220 to become aligned in the sagittal plane and engage upper and lower walls of the nasal cavity of the subject, which engagement causes the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position thenosepiece 220 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion. This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with thenosepiece 220. - Referring to
FIG. 20 , the subject then begins to exhale through themouthpiece unit 219, which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through thedelivery channel 223 of thenosepiece 220, with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject. - In this embodiment, when the flow rate developed through the
delivery channel 223 of thenosepiece 220 reaches a predetermined value, therelease mechanism 251 is triggered to actuate thesubstance supply unit 249 to deliver a metered dose of a substance to thenozzle 245 of theoutlet unit 224 and into the nasal cavity of the subject, in this embodiment as an asymmetric aerosol spray. In an alternative embodiment therelease mechanism 251 could be triggered on the generation of a predetermined pressure in thedelivery channel 223 of thenosepiece 220. - Following exhalation, the subject then releases the
mouthpiece unit 219 and thenosepiece assembly 217 is 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 249. -
FIGS. 21 to 27 illustrate a nasal delivery device in accordance with a fourth embodiment of the present invention. - The delivery device of this embodiment is quite similar to the delivery device of the above-described third embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts.
- The delivery device of this embodiment differs from that of the above-described third embodiment in the
release mechanism 251 being a manually-actuated unit and themouthpiece unit 219 being omitted. With this configuration, a gas flow is not delivered into the nasal cavity of the subject, but the device still advantageously provides for delivery to the olfactory region by virtue of the operation of thenosepiece 220 of thenosepiece unit 217. - Operation of the delivery device is the same as for the above-described third embodiment, except that a gas flow is not delivered into the nasal cavity.
-
FIGS. 28 to 34 illustrate a nasal delivery device in accordance with a fifth embodiment of the present invention. - The delivery device of this embodiment is very similar to the delivery device of the above-described third embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts.
- The delivery device of this embodiment differs from that of the above-described third embodiment in further comprising an oral exhalation breath-actuatable
gas supply unit 257 for delivering a gas flow through thedelivery channel 223 of the outlet unit 221 in response to exhalation by a subject, and in that themouthpiece unit 219 is not in fluid communication with thedelivery channel 223 of the outlet unit 221, whereby a gas flow, separate to the exhalation breath of the subject, is delivered to thedelivery channel 223 of the outlet unit 221, and hence the nasal airway of the subject, in response to exhalation through themouthpiece unit 219. - Operation of the delivery device is the same as for the above-described third embodiment, with a gas flow, separate to the exhalation breath of the subject, being delivered to the
delivery channel 223 of the outlet unit 221 in response to exhalation through themouthpiece unit 219. - In one alternative embodiment the
release mechanism 251 could be a manually-actuated unit and themouthpiece unit 219 omitted. -
FIGS. 35 to 41 illustrate a nasal delivery device in accordance with a sixth embodiment of the present invention. - The delivery device of this embodiment is very similar to the delivery device of the above-described third embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts.
- The delivery device of this embodiment differs from that of the above-described third embodiment in the configuration of the
nosepiece 220 of thenosepiece unit 217. - In this embodiment the
tip element 225 of thenosepiece 220 is inclined, in this embodiment upwardly, in the vertical, sagittal plane relative to the longitudinal axis of thenosepiece 220. As illustrated inFIGS. 40 and 41 , this configuration is such as to provide for greater deflection of the upper surface of the nasal cavity relative to the bony and substantially rigid structure at the lower surface of the nasal cavity. With this configuration, thetip element 225 of thenosepiece 220 is inserted generally more caudally into the nasal opening, and subsequently rotated to the correct position by rotation. - Operation of the delivery device is the same as for the above-described third embodiment.
-
FIGS. 42 to 48 illustrate a nasal delivery device in accordance with a seventh embodiment of the present invention. - The delivery device of this embodiment is very similar to the delivery device of the above-described third embodiment, and thus, in order to avoid unnecessary duplication of description, only the differences will be described in detail, with like reference signs designating like parts.
- The delivery device of this embodiment differs from that of the above-described third embodiment in the configuration of the
nosepiece 220 of thenosepiece unit 217. - In this embodiment the
nosepiece 220 is attached to thehousing 215 by aflexible coupling 259, in this embodiment a resilient coupling, which allows for limited movement of thenosepiece 220 relative to thehousing 215, which facilitates the fitting of thenosepiece 220 in a nasal cavity of the subject. - Also, in this embodiment the
nosepiece 220 includes a lateralgas flow outlet 261, which is in fluid communication with thedelivery channel 223 and disposed rearwardly of the distal end thereof, such as to allow for a gas flow through thedelivery channel 223 in the event that the distal end of thedelivery channel 223 becomes obstructed. - Operation of the delivery device is the same as for the above-described third embodiment.
-
FIGS. 49 to 58 illustrate a nasal delivery device in accordance with an eighth embodiment of the present invention. - The delivery device comprises a
housing 315, anosepiece assembly 317 for fitting in a nasal cavity of a subject, and amouthpiece unit 319 through which the subject exhales to actuate the delivery device. - The
nosepiece assembly 317 comprises anosepiece 320 which is attached to thehousing 315 and defines adelivery channel 323 which is in fluid communication with themouthpiece unit 319 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through themouthpiece unit 319, and anoutlet unit 324 which is disposed within thenosepiece 320 for delivering substance into the nasal airway of the subject. - In this embodiment, as particularly illustrated in
FIGS. 50 to 52 , thenosepiece 320 is generally frusto-conical in shape and includes atip element 325 of asymmetric, elongate section, in having a dimension d1 in a first, sagittal direction which is substantially greater than a dimension d2 in a second, lateral direction which is orthogonal to the first, sagittal direction. In this embodiment the dimension d1 in the sagittal direction is at least twice that of the dimension d2 in the lateral direction. In one embodiment the dimension d2 in the lateral direction is not more than 6 mm and more preferably not more than 4 mm. - In this embodiment the
tip element 325 extends substantially axially to the longitudinal axis of thenosepiece 320. - In this embodiment the
nosepiece 320 further comprises a sealing element 326, in this embodiment a tapered, annular section, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of theoutlet unit 324 of thenosepiece assembly 317 into the nasal cavity of the subject. In a preferred embodiment the distal end of theoutlet unit 324 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably at least about 4 cm, and preferably from about 2 cm to about 4 cm, into the nasal cavity of the subject. - In this embodiment the
nosepiece 320 is formed as a substantially rigid structure, here formed of a plastics material. - With this configuration, as will be described in more detail hereinbelow, on insertion of the
nosepiece 320 into the nasal cavity of the subject, the longer, sagittal section of thetip element 325 of thenosepiece 320 becomes aligned in the sagittal plane and acts to engage upper and lower walls of the nasal cavity of the subject and cause the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position thenosepiece 320 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion. - This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the
nosepiece 320. - In this embodiment the
outlet unit 324 comprises anozzle 345 for delivering substance to the nasal airway of the subject. - In this embodiment, as illustrated in
FIGS. 53 to 55 , thenozzle 345 includes a plurality ofnozzle outlets 347 which provide a plurality of jets as columns of substance, either as a liquid or powder jet. - In this embodiment the
nozzle 345 of theoutlet unit 324 is configured to deliver an asymmetric profile, with the jet spray having a significantly greater spray angle in the vertical, sagittal plane α than in the horizontal plane β. Such jets have been found to be particularly advantageous in the delivery of substance to posterior regions of the nasal cavities, in particular the olfactory region. - In a preferred embodiment the jet spray angle in the vertical, sagittal plane α is greater than about 35°, more preferably greater than about 40°, still more preferably greater than about 45° and yet more preferably greater than about 50°.
- In this embodiment the nozzle outlets are aligned in the vertical, sagittal direction and thus the jet angle in the horizontal plane β approaches 0°. In other embodiments the jet angle in the horizontal plane β is not more than about 35°, more preferably not more than about 30°, still more preferably not more than about 25°, yet more preferably not more than about 20°, still yet more preferably not more than about 15°, yet further more preferably not more than about 10° and still yet further more preferably not more than about 5°.
- In this embodiment the jet spray presents a substantially rectangular spray zone.
- The delivery device further comprises a
substance supply unit 349 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 thenozzle 345 of theoutlet unit 324 to deliver substance from thenosepiece assembly 317, in this embodiment as a plurality of liquid jets. - In this embodiment the
substance supply unit 349 is a multi-dose unit for delivering a plurality of metered doses of substance. In another embodiment thesubstance supply unit 349 could be a single-dose unit for delivering a single metered dose of substance. - The
substance supply unit 349 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuatedrelease mechanism 351 which, when triggered, releases the resilient element and actuates thesubstance supply unit 349 to deliver a metered dose of substance through thenozzle 345 of theoutlet unit 324. - In this embodiment the
release mechanism 351 is configured to cause actuation of thesubstance supply unit 349 on generation of a predetermined flow rate through thedelivery channel 323 of thenosepiece 320. - In another embodiment the
release mechanism 351 could be configured to cause actuation of thesubstance supply unit 349 on generation of a predetermined pressure within thedelivery channel 323 of thenosepiece 320. - In a further embodiment the
release mechanism 351 could be configured to cause actuation of thesubstance supply unit 349 on generation of either one of a predetermined flow rate through thedelivery channel 323 of thenosepiece 320 or a predetermined pressure within thedelivery channel 323 of thenosepiece 320. - In an alternative embodiment the
substance supply unit 349 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 239 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 349 could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof. - Operation of the delivery device will now be described hereinbelow with reference to
FIGS. 56 to 58 of the accompanying drawings. - Referring to
FIGS. 56 and 57 , thenosepiece assembly 317 is first inserted into one of the nasal cavities of a subject until the sealingmember 327 abuts the nares of the nostril of the subject, at which point the distal end of theoutlet unit 324 typically extends from about 2 cm to about 4 cm into the nasal cavity of the subject, and themouthpiece unit 319 is then gripped in the lips of the subject. - As illustrated, insertion of the
nosepiece 320 into the nasal cavity of the subject acts to cause the longer, sagittal section of thetip element 325 of thenosepiece 320 to become aligned in the sagittal plane and engage upper and lower walls of the nasal cavity of the subject, which engagement causes the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position thenosepiece 320 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion. This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with thenosepiece 320. - Referring to
FIG. 58 , the subject then begins to exhale through themouthpiece unit 319, which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through thedelivery channel 323 of thenosepiece 320, with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject. - In this embodiment, when the flow rate developed through the
delivery channel 323 of thenosepiece 320 reaches a predetermined value, therelease mechanism 351 is triggered to actuate thesubstance supply unit 349 to deliver a metered dose of a substance to thenozzle 345 of theoutlet unit 324 and into the nasal cavity of the subject, in this embodiment as an asymmetric jet spray comprising a plurality of liquid jets. In an alternative embodiment therelease mechanism 351 could be triggered on the generation of a predetermined pressure in thedelivery channel 323 of thenosepiece 320. - Following exhalation, the subject then releases the
mouthpiece unit 319 and thenosepiece assembly 317 is 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 349. -
FIGS. 59 to 67 illustrate a nasal delivery device in accordance with a ninth embodiment of the present invention. - The delivery device comprises a
housing 415, anosepiece assembly 417 for fitting in a nasal cavity of a subject, and amouthpiece unit 419 through which the subject exhales to actuate the delivery device. - The
nosepiece assembly 417 comprises anosepiece 420 which is attached to thehousing 415 and defines adelivery channel 423 which is in fluid communication with themouthpiece unit 419 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through themouthpiece unit 419, and anoutlet unit 424 which is disposed within thenosepiece 420 for delivering substance into the nasal airway of the subject. - In this embodiment, as particularly illustrated in
FIGS. 60 to 62 , thenosepiece 420 comprises anosepiece member 425 which acts to engage the nasal cavity of the subject and asupport member 426 which acts structurally to support thenosepiece member 425, such as to confer a required rigidity in the sagittal plane, as will be described in more detail hereinbelow. - In this embodiment the
nosepiece member 425 is generally frusto-conical in shape and includes atip element 427 of asymmetric, elongate section, in having a dimension d1 in a first, sagittal direction which is substantially greater than a dimension d2 in a second, lateral direction which is orthogonal to the first, sagittal direction. In this embodiment the dimension d1 in the sagittal direction is at least twice that of the dimension d2 in the lateral direction. In one embodiment the dimension d2 in the lateral direction is not more than 6 mm and more preferably not more than 4 mm. - In this embodiment the
tip element 427 extends substantially axially to the longitudinal axis of thenosepiece 420. - In this embodiment the
nosepiece member 425 further includes a sealingelement 428, in this embodiment a tapered, annular section, which acts both to provide a seal with the nares of the nostril of the nasal cavity of the subject and determine the extent of the insertion of theoutlet unit 424 of thenosepiece assembly 417 into the nasal cavity of the subject. In a preferred embodiment the distal end of theoutlet unit 424 is configured to extend at least about 2 cm, preferably at least about 3 cm, more preferably at least about 4 cm, and preferably from about 2 cm to about 4 cm, into the nasal cavity of the subject. In a preferred embodiment the distal end of theoutlet unit 424 extends into the bony part of the nasal valve, or at least as far into the nasal cavity as possible with theoutlet unit 424 aligned with the nasal slit, such that theoutlet unit 424 targets substance at the upper posterior region of the nasal cavity, and in particular the olfactory region. - In this embodiment the
nosepiece member 425 is formed as a flexible or semi-rigid structure, here formed of a plastics material, which allows thenosepiece 420 to conform to the nasal cavity of the subject, where the nasal cavities of different subjects can differ quite markedly. - In this embodiment the
support member 426 confers rigidity to thenosepiece member 425 in both the axial direction, such as to prevent the collapse of thenosepiece 420 on insertion into the nasal cavity, and the vertical, sagittal plane along the elongate, sagittal direction of thetip element 427 of thenosepiece member 425, such as to enable expansion of the nasal cavity in the vertical, sagittal plane, as will be described in more detail hereinbelow. - In this embodiment the
support member 426 comprises an elongate plate, here a plastics plate, which extends along a length of thenosepiece member 425 in the elongate, sagittal direction of thetip element 427 of thenosepiece member 425. This plate is flexible in allowing for torsional flexing, as illustrated inFIG. 63 , and flexing over the major surface thereof, as illustrated inFIG. 64 , but presents a substantially rigid structure in the plane of the plate, such as not to allow for flexing in the plane of the plate. - In an alternative embodiment the
support member 426 could take the form of a living hinge, which comprises a plurality of rigid elements interconnected by flexible elements, which allow for torsional and bending moments. - In this embodiment the
outlet unit 424 comprises anozzle 445 for delivering substance to the nasal airway of the subject. - In this embodiment the
nozzle 445 is attached to thesupport member 426, and can be integrally formed therewith in one embodiment. - In this embodiment the
nozzle 445 is configured to provide an aerosol spray, either as a liquid or powder aerosol. - In an alternative embodiment the
nozzle 445 could be configured to deliver a jet as a column of substance, either as a liquid or powder jet. - With this configuration, as will be described in more detail hereinbelow, on insertion of the
nosepiece 420 into the nasal cavity of the subject, the flexibility of thenosepiece 420 facilitates the longer, sagittal section of thetip element 427 of thenosepiece member 425 in becoming aligned in the sagittal plane and acts to engage upper and lower walls of the nasal cavity of the subject and, by virtue of the rigidity of thenosepiece 420 in the sagittal plane, cause the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position thenosepiece 420 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion. - This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with the
nosepiece 420. - In this embodiment the
nozzle 445 of theoutlet unit 424 is configured to deliver an asymmetric aerosol spray, with the aerosol spray having a significantly greater spray angle in the vertical, sagittal plane α than in the horizontal plane β. Such an aerosol spray has been found to be particularly advantageous in the delivery of substance to posterior regions of the nasal cavities, in particular the olfactory region. - In a preferred embodiment the spray angle in the vertical, sagittal plane α is greater than about 35°, more preferably greater than about 40°, still more preferably greater than about 45° and yet more preferably greater than about 50°.
- In a preferred embodiment the spray angle in the horizontal plane β is not more than about 35°, more preferably not more than about 30°, still more preferably not more than about 25°, yet more preferably not more than about 20°, and still yet more preferably not more than about 15°.
- In this embodiment the aerosol spray presents an elliptical spray zone.
- In another embodiment the aerosol spray could present a substantially rectangular spray zone.
- The delivery device further comprises a
substance supply unit 449 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 thenozzle 445 of theoutlet unit 424 to deliver substance from thenosepiece assembly 417, in this embodiment as an aerosol spray. - In this embodiment the
substance supply unit 449 is a multi-dose unit for delivering a plurality of metered doses of substance. In another embodiment thesubstance supply unit 449 could be a single-dose unit for delivering a single metered dose of substance. - The
substance supply unit 449 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuatedrelease mechanism 451 which, when triggered, releases the resilient element and actuates thesubstance supply unit 449 to deliver a metered dose of substance through thenozzle 445 of theoutlet unit 424. - In this embodiment the
release mechanism 451 is configured to cause actuation of thesubstance supply unit 449 on generation of a predetermined flow rate through thedelivery channel 423 of thenosepiece 420. - In another embodiment the
release mechanism 451 could be configured to cause actuation of thesubstance supply unit 449 on generation of a predetermined pressure within thedelivery channel 423 of thenosepiece 420. - In a further embodiment the
release mechanism 451 could be configured to cause actuation of thesubstance supply unit 449 on generation of either one of a predetermined flow rate through thedelivery channel 423 of thenosepiece 420 or a predetermined pressure within thedelivery channel 423 of thenosepiece 420. - In an alternative embodiment the
substance supply unit 449 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 449 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 449 could comprise a nebulizer which delivers metered doses of a substance, as an aerosol spray, on actuation thereof. - Operation of the delivery device will now be described hereinbelow with reference to
FIGS. 65 to 67 of the accompanying drawings. - Referring to
FIGS. 65 and 66 , thenosepiece assembly 417 is first inserted into one of the nasal cavities of a subject until the sealingelement 428 of thenosepiece member 425 abuts the nares of the nostril of the subject, at which point the distal end of theoutlet unit 424 typically extends from about 2 cm to about 4 cm into the nasal cavity of the subject, and themouthpiece unit 419 is then gripped in the lips of the subject. - As illustrated, insertion of the
nosepiece 420 into the nasal cavity of the subject acts to cause the longer, sagittal section of thetip element 427 of thenosepiece member 425 to become aligned in the sagittal plane and engage upper and lower walls of the nasal cavity of the subject, which engagement causes the expansion of the nasal cavity in the vertical, sagittal plane, in particular the upper wall of the nasal cavity of the subject, which is a fleshy structure, as compared to the lower wall of the nasal cavity of the subject, which is a relatively-hard structure, and also position thenosepiece 420 in the nasal cavity of the subject, with the lower wall of the nasal cavity of the subject, in being a relatively-hard structure, acting as a reference for the expansion. This expansion further acts to tension the lateral walls of the nasal cavity of the subject which defines the nasal valve, which causes the lateral walls of the nasal cavity to be urged into sealing contact with thenosepiece 420. - Referring to
FIG. 67 , the subject then begins to exhale through themouthpiece unit 419, which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through thedelivery channel 423 of thenosepiece 420, with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject. - In this embodiment, when the flow rate developed through the
delivery channel 423 of thenosepiece 420 reaches a predetermined value, therelease mechanism 451 is triggered to actuate thesubstance supply unit 449 to deliver a metered dose of a substance to thenozzle 445 of theoutlet unit 424 and into the nasal cavity of the subject, in this embodiment as an asymmetric aerosol spray. In an alternative embodiment therelease mechanism 451 could be triggered on the generation of a predetermined pressure in thedelivery channel 423 of thenosepiece 420. - Following exhalation, the subject then releases the
mouthpiece unit 419 and thenosepiece assembly 417 is 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 449. - 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 invention as defined by the appended claims.
- For example, in one modification, the nosepieces of the above-described third to eighth embodiments could be other than elliptical in section, such as an elongate, triangular section, with the base of the triangle defining a lower edge of the nosepiece.
- In another modification the outlet units of the above-described embodiments could be configured such that the nozzles thereof are extendable in a forward direction following insertion of the nosepieces, for example, in the manner of a telescopic element, such as to extend further posterior into the nasal cavity.
- In a further modification of the delivery device of the seventh-described embodiment, the
flexible coupling 259 can be integrated with thesupport member 226 of thenosepiece 220. -
FIGS. 68 to 70 illustrate one such embodiment. In this embodiment theflexible coupling 259, thesupport member 226 and theoutlet unit 224 are formed as a single, integral unit, typically of a plastics material. In this embodiment theflexible coupling 259 allows for limited axial compression of thenosepiece 220 by compression of theflexible coupling 259 and also allows for limited bending of thesupport member 226 about theflexible coupling 259, which assist in insertion of thenosepiece 220 into the nasal cavity. In this embodiment the upper part of thesupport member 226 is still substantially rigid in the plane thereof, such as to provide for vertical, sagittal expansion of the nasal cavity, in particular the collapsed region at the upper, lateral wall of the nasal cavity. - In an alternative embodiment the
flexible coupling 259 could have a simpler geometric shape, in one example as a section of thesupport member 226 of reduced thickness, which confers the limited compressibility and flexibility to theflexible coupling 259, but yet which confers the required rigidity to thesupport member 226, in particular the upper part thereof, as to achieve the vertical, sagittal expansion of the nasal cavity. - 1. Cole, P, The Respiratory Role of the Upper Airways, a selective clinical and pathophysiological review. 1993, Mosby-Year Book Inc. ISBN1.55664-390-X.
- 2. Rosenberger, H, Growth and Development of the Naso-Respiratory Area in Childhood, PhD Thesis, Laboratory of Anatomy, School of Medicine, Western Reserve University, Presented to the Annual Meeting of the American Laryngological, Rhinological and Otological Society, Charleston, S.C., USA, 1934.
- 3. Zacharek, M A et al, Sagittal and Coronal Dimensions of the Ethmoid Roof: A Radioanatomic Study, Am J Rhinol 2005,
Vol 19, pages 348 to 352.
Claims (1)
1. A nasal delivery device for delivering substance to a nasal cavity of a subject, the delivery device comprising:
a nosepiece unit including a nosepiece for fitting to a nostril of a subject and a nozzle through which substance is in use delivered, preferably substantially axially to a longitudinal axis of the nosepiece, to the respective nasal cavity, wherein at least a tip element of the nosepiece has, at least in one configuration, an elongate lateral section which has a longer dimension in a first, sagittal direction than a second direction orthogonal to the sagittal direction, such that, when the nosepiece is inserted in the nasal cavity of the subject, the longer dimension of the nosepiece acts to engage lower and upper surfaces of the nasal cavity and expand the same in the sagittal plane; and
a delivery unit for delivering substance through the nozzle of the nosepiece.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14/047,390 US20140166008A1 (en) | 2006-03-06 | 2013-10-07 | Nasal delivery |
US15/051,622 US10124132B2 (en) | 2006-03-06 | 2016-02-23 | Nasal delivery |
US16/153,876 US20190269867A1 (en) | 2006-03-06 | 2018-10-08 | Nasal delivery |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0604444.0 | 2006-03-06 | ||
GBGB0604444.0A GB0604444D0 (en) | 2006-03-06 | 2006-03-06 | Nasal devices |
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Citations (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030101992A1 (en) * | 2000-06-26 | 2003-06-05 | Giorgio Mezzoli | Distribution valve for nasal spray |
US6715485B1 (en) * | 1999-03-03 | 2004-04-06 | Optinose As | Nasal delivery device |
US20040112379A1 (en) * | 2001-02-26 | 2004-06-17 | Djupesland Per Gisle | Nasal devices |
US20040238574A1 (en) * | 2003-05-06 | 2004-12-02 | Hans Merk | Discharge device for at least one medium |
US20070039614A1 (en) * | 2003-05-20 | 2007-02-22 | Djupesland Per G | Delivery device and method |
US7204246B1 (en) * | 2004-07-08 | 2007-04-17 | Joseph Berinato | Air self-contained oxygen inhaler |
US20070125371A1 (en) * | 2003-08-28 | 2007-06-07 | Optinose As | Delivery devices |
US7377901B2 (en) * | 2000-06-21 | 2008-05-27 | Optinose As | Apparatus for collection of airway gases |
US20080163874A1 (en) * | 2001-09-06 | 2008-07-10 | Optinose As | Nasal delivery device |
US20080289629A1 (en) * | 2004-09-15 | 2008-11-27 | Optinose As | Nasal Delivery Devices |
US7481218B2 (en) * | 2002-07-02 | 2009-01-27 | Optinose As | Nasal devices |
US7784460B2 (en) * | 2003-08-14 | 2010-08-31 | Optinose As | Delivery devices |
US7854227B2 (en) * | 2002-04-25 | 2010-12-21 | Optinose As | Nasal devices |
US7934503B2 (en) * | 2002-07-09 | 2011-05-03 | Optinose As | Delivery devices |
US7975690B2 (en) * | 2001-06-12 | 2011-07-12 | Optinose As | Nasal devices |
US8136527B2 (en) * | 2003-08-18 | 2012-03-20 | Breathe Technologies, Inc. | Method and device for non-invasive ventilation with nasal interface |
US8146589B2 (en) * | 2002-03-28 | 2012-04-03 | Optinose As | Nasal devices |
US8171929B2 (en) * | 2006-02-14 | 2012-05-08 | Optinose As | Delivery device and method |
US8191552B2 (en) * | 2008-11-15 | 2012-06-05 | Cfd Research Corporation | Negative pressure, bi-directional nasal aerosol delivery |
US8231588B2 (en) * | 2008-08-01 | 2012-07-31 | Tian Xia | Methods for ameliorating pain and devices for delivering a medicament |
Family Cites Families (47)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US605436A (en) | 1898-06-07 | Inhaler | ||
US642748A (en) | 1899-02-23 | 1900-02-06 | Arthur Manners | Inhaler. |
US746749A (en) | 1903-03-18 | 1903-12-15 | George E Seidel | Nasal medicator. |
US4227522A (en) * | 1978-09-05 | 1980-10-14 | Syntex Puerto Rico, Inc. | Inhalation device |
US4513891A (en) | 1982-04-15 | 1985-04-30 | Sterling Drug Inc. | Spray dispensing container and valve therefor |
US4648398A (en) * | 1984-10-31 | 1987-03-10 | Sherwood Medical Company | Nasal cannula |
SE9201718D0 (en) | 1992-06-03 | 1992-06-03 | Astra Ab | NASAL SPRAY DEVICE |
HU221840B1 (en) | 1995-01-23 | 2003-02-28 | Direct-Haler A/S | Inhaler for dosing into airstrom of powdered material |
US5797392C1 (en) | 1996-01-22 | 2001-01-09 | Direct Haler As | Inhaler |
US5797390A (en) | 1996-03-06 | 1998-08-25 | Mcsoley; Thomas E. | Nasal inhaler having a directed spray pattern |
US6648848B1 (en) | 1997-05-27 | 2003-11-18 | Direct-Haler A/S | Inhaler for powdered medicaments |
IS4516A (en) | 1997-07-01 | 1999-01-02 | Gizurarson Sveinbjörn | New pharmaceutical form |
GB9806937D0 (en) * | 1998-03-31 | 1998-05-27 | Procter & Gamble | A spray device |
US6561193B1 (en) | 1998-10-30 | 2003-05-13 | Linda J. Noble | Nasal gas delivery apparatus and a nasal vestibular airway |
MXPA04004631A (en) | 2001-11-14 | 2004-08-12 | Nektar Therapeutics Al Corp | Aerosolization apparatus comprising connectable body and endpiece. |
GB0207817D0 (en) | 2002-04-04 | 2002-05-15 | Optinose As | Nasal devices |
GB0300008D0 (en) | 2003-01-02 | 2003-02-05 | Optinose As | Delivery devices |
GB0313355D0 (en) | 2003-06-10 | 2003-07-16 | Glaxo Group Ltd | Nozzle |
US20070199568A1 (en) | 2003-12-15 | 2007-08-30 | Bespak Plc (Incorporated In The United Kingdom) | Nasal drug delivery |
USD530815S1 (en) | 2004-03-19 | 2006-10-24 | Optinose As | Nasal delivery device |
GB0503738D0 (en) | 2005-02-23 | 2005-03-30 | Optinose As | Powder delivery devices |
EP1792660A1 (en) | 2005-12-02 | 2007-06-06 | Boehringer Ingelheim Pharma GmbH & Co. KG | Dispensing device |
US10478574B2 (en) | 2006-01-19 | 2019-11-19 | Optinose As | Nasal administration |
GB0602980D0 (en) | 2006-02-14 | 2006-03-29 | Optinose As | Delivery device and method |
GB0604319D0 (en) | 2006-03-03 | 2006-04-12 | Optinose As | Nasal delivery |
GB0604444D0 (en) | 2006-03-06 | 2006-04-12 | Optinose As | Nasal devices |
GB0605799D0 (en) | 2006-03-23 | 2006-05-03 | Optinose As | Nasal delivery devices |
GB2437488A (en) | 2006-04-25 | 2007-10-31 | Optinose As | Pharmaceutical oily formulation for nasal or buccal administration |
GB2438834A (en) | 2006-06-08 | 2007-12-12 | Optinose As | Intranasal protein administration |
GB2440316A (en) | 2006-07-25 | 2008-01-30 | Optinose As | Nasal inhaler with scrubber |
GB0623731D0 (en) | 2006-11-28 | 2007-01-10 | Optinose As | Delivery device |
GB0623728D0 (en) | 2006-11-28 | 2007-01-10 | Optinose As | Delivery devices |
GB0623732D0 (en) | 2006-11-28 | 2007-01-10 | Optinose As | Powder delivery devices |
GB2448193A (en) * | 2007-04-05 | 2008-10-08 | Optinose As | Nasal delivery device |
GB2448183A (en) | 2007-04-05 | 2008-10-08 | Optinose As | Nasal powder delivery device |
GB0719299D0 (en) | 2007-10-03 | 2007-11-14 | Optinose As | Nasal delivery devices |
WO2010029441A2 (en) | 2008-09-15 | 2010-03-18 | Optinose As | Nasal delivery |
GB201015371D0 (en) | 2010-09-14 | 2010-10-27 | Optinose As | Nasal delivery |
US9949923B2 (en) | 2011-03-15 | 2018-04-24 | Optinose As | Nasal delivery |
IN2014DN07610A (en) | 2012-02-24 | 2015-05-15 | Optinose As | |
MY170349A (en) | 2012-02-24 | 2019-07-22 | Optinose As | Nasal delivery devices |
WO2013124491A1 (en) | 2012-02-24 | 2013-08-29 | Optinose As | Nasal delivery devices |
ES2920802T3 (en) | 2013-03-26 | 2022-08-09 | Optinose As | nasal administration |
US11554229B2 (en) | 2013-03-26 | 2023-01-17 | OptiNose Inc. | Nasal administration |
USD725769S1 (en) | 2013-05-23 | 2015-03-31 | Optinose As | Nasal delivery device |
USD723156S1 (en) | 2013-05-23 | 2015-02-24 | Optinose As | Nasal delivery device |
AU2015348297A1 (en) * | 2014-11-19 | 2017-05-25 | Optinose As | Intranasal administration |
-
2006
- 2006-03-06 GB GBGB0604444.0A patent/GB0604444D0/en not_active Ceased
-
2007
- 2007-03-06 US US12/281,894 patent/US8550073B2/en active Active
- 2007-03-06 EP EP07734890A patent/EP1996266A2/en not_active Ceased
- 2007-03-06 WO PCT/IB2007/001709 patent/WO2007102089A2/en active Application Filing
- 2007-03-06 GB GB0704302A patent/GB2435835B/en active Active
-
2013
- 2013-10-07 US US14/047,390 patent/US20140166008A1/en not_active Abandoned
-
2016
- 2016-02-23 US US15/051,622 patent/US10124132B2/en active Active
-
2018
- 2018-10-08 US US16/153,876 patent/US20190269867A1/en not_active Abandoned
Patent Citations (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060225732A1 (en) * | 1999-03-03 | 2006-10-12 | Djupesland Per G | Nasal delivery device |
US20080223363A1 (en) * | 1999-03-03 | 2008-09-18 | Optinose As | Nasal Delivery Devices |
US20060231094A1 (en) * | 1999-03-03 | 2006-10-19 | Djupesland Per G | Nasal delivery device |
US20060219241A1 (en) * | 1999-03-03 | 2006-10-05 | Djupesland Per G | Nasal delivery device |
US6715485B1 (en) * | 1999-03-03 | 2004-04-06 | Optinose As | Nasal delivery device |
US20040182388A1 (en) * | 1999-03-03 | 2004-09-23 | Djupesland Per Gisle | Nasal delivery method |
US20060219240A1 (en) * | 1999-03-03 | 2006-10-05 | Djupesland Per G | Nasal delivery device |
US20080221471A1 (en) * | 2000-06-21 | 2008-09-11 | Per Djupesland | Apparatus for collection of airway gases |
US7377901B2 (en) * | 2000-06-21 | 2008-05-27 | Optinose As | Apparatus for collection of airway gases |
US20030101992A1 (en) * | 2000-06-26 | 2003-06-05 | Giorgio Mezzoli | Distribution valve for nasal spray |
US7841337B2 (en) * | 2000-11-15 | 2010-11-30 | Optinose As | Breath-actuated nasal delivery device |
US7347201B2 (en) * | 2001-02-26 | 2008-03-25 | Optinose As | Nasal delivery devices |
US7740014B2 (en) * | 2001-02-26 | 2010-06-22 | Optinose As | Nasal devices |
US20040112379A1 (en) * | 2001-02-26 | 2004-06-17 | Djupesland Per Gisle | Nasal devices |
US20080161771A1 (en) * | 2001-02-26 | 2008-07-03 | Optinose As | Nasal delevery devices |
US20040149289A1 (en) * | 2001-02-26 | 2004-08-05 | Djupesland Per Gisle | Nasal devices |
US7975690B2 (en) * | 2001-06-12 | 2011-07-12 | Optinose As | Nasal devices |
US20080163874A1 (en) * | 2001-09-06 | 2008-07-10 | Optinose As | Nasal delivery device |
US8146589B2 (en) * | 2002-03-28 | 2012-04-03 | Optinose As | Nasal devices |
US7854227B2 (en) * | 2002-04-25 | 2010-12-21 | Optinose As | Nasal devices |
US8047202B2 (en) * | 2002-07-02 | 2011-11-01 | Optinose As | Nasal devices |
US7481218B2 (en) * | 2002-07-02 | 2009-01-27 | Optinose As | Nasal devices |
US7934503B2 (en) * | 2002-07-09 | 2011-05-03 | Optinose As | Delivery devices |
US20040238574A1 (en) * | 2003-05-06 | 2004-12-02 | Hans Merk | Discharge device for at least one medium |
US20070039614A1 (en) * | 2003-05-20 | 2007-02-22 | Djupesland Per G | Delivery device and method |
US7784460B2 (en) * | 2003-08-14 | 2010-08-31 | Optinose As | Delivery devices |
US8136527B2 (en) * | 2003-08-18 | 2012-03-20 | Breathe Technologies, Inc. | Method and device for non-invasive ventilation with nasal interface |
US20070125371A1 (en) * | 2003-08-28 | 2007-06-07 | Optinose As | Delivery devices |
US7204246B1 (en) * | 2004-07-08 | 2007-04-17 | Joseph Berinato | Air self-contained oxygen inhaler |
US20080289629A1 (en) * | 2004-09-15 | 2008-11-27 | Optinose As | Nasal Delivery Devices |
US8171929B2 (en) * | 2006-02-14 | 2012-05-08 | Optinose As | Delivery device and method |
US8231588B2 (en) * | 2008-08-01 | 2012-07-31 | Tian Xia | Methods for ameliorating pain and devices for delivering a medicament |
US8191552B2 (en) * | 2008-11-15 | 2012-06-05 | Cfd Research Corporation | Negative pressure, bi-directional nasal aerosol delivery |
Cited By (38)
Publication number | Priority date | Publication date | Assignee | Title |
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US9522243B2 (en) | 2002-07-02 | 2016-12-20 | Optinose As | Nasal devices |
US10286164B2 (en) | 2003-05-20 | 2019-05-14 | Optinose As | Delivery device and method |
US9566402B2 (en) | 2003-05-20 | 2017-02-14 | Optinose As | Delivery Device and Method |
US9452272B2 (en) | 2003-08-14 | 2016-09-27 | Optinose As | Delivery devices |
US10737045B2 (en) | 2003-08-28 | 2020-08-11 | Optinose As | Delivery devices |
US10398859B2 (en) | 2004-09-15 | 2019-09-03 | Optinose As | Nasal delivery devices |
US11571531B2 (en) | 2005-02-23 | 2023-02-07 | OptiNose Inc. | Powder delivery devices |
US10478574B2 (en) | 2006-01-19 | 2019-11-19 | Optinose As | Nasal administration |
US10124132B2 (en) | 2006-03-06 | 2018-11-13 | Optinose As | Nasal delivery |
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US11083858B2 (en) | 2007-10-03 | 2021-08-10 | Optinose As | Nasal delivery devices |
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USD761951S1 (en) * | 2013-05-23 | 2016-07-19 | Optinose As | Nosepiece unit |
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USD773644S1 (en) | 2013-05-23 | 2016-12-06 | Optinose As | Nosepiece unit |
USD809128S1 (en) * | 2013-05-23 | 2018-01-30 | Optinose As | Nosepiece unit |
US11052204B2 (en) | 2014-11-19 | 2021-07-06 | Optinose As | Intranasal administration |
US10940277B2 (en) | 2014-11-19 | 2021-03-09 | Optinose As | Intranasal administration |
US11707586B2 (en) | 2014-11-19 | 2023-07-25 | OptiNose Inc. | Intranasal administration |
US11730904B2 (en) | 2014-11-19 | 2023-08-22 | Optinose, Inc. | Intranasal administration |
US12005185B2 (en) | 2021-12-17 | 2024-06-11 | Belhaven BioPharma Inc. | Medical counter measures including dry powder formulations and associated methods |
Also Published As
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WO2007102089A2 (en) | 2007-09-13 |
US20160367772A1 (en) | 2016-12-22 |
EP1996266A2 (en) | 2008-12-03 |
GB0604444D0 (en) | 2006-04-12 |
WO2007102089A3 (en) | 2008-07-03 |
GB2435835B (en) | 2011-04-20 |
US20190269867A1 (en) | 2019-09-05 |
GB0704302D0 (en) | 2007-04-11 |
US8550073B2 (en) | 2013-10-08 |
GB2435835A (en) | 2007-09-12 |
US20090314293A1 (en) | 2009-12-24 |
US10124132B2 (en) | 2018-11-13 |
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