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Publication numberUS20110053827 A1
Publication typeApplication
Application numberUS 12/303,667
Publication dateMar 3, 2011
Filing dateJun 8, 2007
Priority dateJun 8, 2006
Also published asWO2007141541A1
Publication number12303667, 303667, US 2011/0053827 A1, US 2011/053827 A1, US 20110053827 A1, US 20110053827A1, US 2011053827 A1, US 2011053827A1, US-A1-20110053827, US-A1-2011053827, US2011/0053827A1, US2011/053827A1, US20110053827 A1, US20110053827A1, US2011053827 A1, US2011053827A1
InventorsRoderick Peter Hafner
Original AssigneeOptinose As
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Intranasal administration
US 20110053827 A1
Abstract
Intranasal administration of proteins, such as insulin and insulin analogues, in particular immunogenic proteins to the upper posterior region of a nasal cavity of a subject, and in particular the olfactory bulb region.
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Claims(12)
1. A delivery device for delivering a protein formulation to the upper posterior region of a nasal cavity of a subject for uptake into the CNS of the subject, the delivery device comprising a nosepiece unit including a nosepiece for fitting to a nostril of a subject and a nozzle through which the formulation is in use delivered to the respective nasal cavity, and a delivery unit for delivering formulation through the nozzle of the nosepiece, wherein the delivery of the formulation is such as to provide for uptake of the protein to the CNS without triggering a significant immune response.
2-55. (canceled)
56. A method of delivering a protein formulation to the upper posterior region of a nasal cavity of a subject for uptake into the CNS of the subject, the method comprising the step of delivering the formulation through a nozzle of a nosepiece of a delivery device into the nasal cavity of the subject, such as to provide for uptake of the protein to the CNS without triggering a significant immune response.
57-110. (canceled)
111. A protein formulation for delivery to a nasal cavity of a subject for uptake into the CNS of the subject, the formulation being such as to provide for uptake of the protein to the CNS without triggering a significant immune response.
112-158. (canceled)
159. A delivery device for delivering a substance to the nasal airway of a subject, the delivery device including a nosepiece having a replaceable outer sleeve.
160. The delivery device of claim 159, wherein the sleeve includes an indicator material which provides an indication of exposure to one or more of moisture and biomaterials, such as endotoxins.
161. A delivery device for delivering a substance to the nasal airway of a subject, the delivery device including a nosepiece having a plurality of removable sleeves which are removable successively to allow for exposure of a fresh sleeve.
162. The delivery device of claim 161, wherein the sleeves are individually peelable films.
163. The delivery device of claim 161, wherein one or more of the innermost sleeves are marked to indicate that a predeterminable number of the sleeves remain.
164. The delivery device of claim 161, wherein the sleeves include an indicator material which provides an indication of exposure to one or more of moisture and biomaterials, such as endotoxins.
Description

The present invention relates to intranasal administration of proteins, such as insulin and insulin analogues, in particular immunogenic proteins to the upper posterior region of a nasal cavity of a subject, and in particular the olfactory bulb region.

Recent studies have demonstrated that the intranasal administration of insulin acts to improve memory and has an effect on obesity [1-8].

However, other studies have shown that intranasal administration of insulin over an extended period, typically six months, results in antibodies being raised to insulin [9].

Whilst the authors of this publication argue that the raising of antibodies to insulin could be beneficial in terms of being protective of loss of beta cell function in individuals at risk of Type I diabetes, there is no recognition that raising a neutralising antibody response to insulin would be of particular concern in patients with obesity who may be at risk of developing Type II diabetes and where there is limited additional capacity for the pancreas further to increase insulin production. It would also be inappropriate to increase neutralising antibody levels to insulin in patients who already have insulin loss as this may worsen the condition.

It is an aim of the present invention to provide for the intranasal administration of proteins, such as insulin and insulin analogues, and in particular by the applicant's bi-directional methodology, as disclosed in the applicant's earlier WO-A-2000/051672, the content of which is incorporated herein by reference.

Delivery of vaccine antigens by the bi-directional methodology has been shown to date to provide an increase in the circulating antibodies when compared to intranasal administration by conventional nasal spray technologies, in particular nasal spray pumps. As such, a person skilled in the art would have contemplated that intranasal administration of insulin using bi-directional delivery technology should increase the immune response to insulin and other immunogenic proteins, which is contrary to the requirement for delivery of proteins and peptides to the CNS.

It is a particular aim of the present invention to provide for the intranasal administration of proteins, such as insulin and insulin analogues, in therapeutically-significant amounts to the olfactory bulb region in the upper posterior region of the nasal cavity, such that the proteins access the CNS and avoid being presented to the nasal associated lymphatic tissue (HALT) which includes M-cells, as encompassed by Waldeyer's ring, and in particular in the adenoids, and antigen presenting cells (APCs) which are widely distributed throughout the nasal mucosa, which would cause a neutralising antibody response.

The posterior region of the nasal airway is that region which is posterior of the nasal valve NV, as illustrated in FIG. 1. The nasal valve 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 [10]. 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 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 is lined In its anterior part with transitional epithelium, with a gradual transition posterior to respiratory epithelium. The nasal valve and anterior vestibule define roughly the anterior one-third of the nose.

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 OB and defines the olfactory bulb region, 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 which defines the olfactory cleft, 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, and encompasses the middle turbinate, the middle meatus, 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, 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 [11] 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, 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 [12] 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.

It is a further aim of the present invention to provide for the intranasal administration of proteins, such as insulin and insulin analogues, such that the proteins which are not absorbed into the CNS remain in solution and are not phagocytosed by immunogenic cells, such as the antigen presenting cells.

It is a still further aim of the present invention to provide for the intranasal administration of proteins, such as insulin and insulin analogues, and in particular where delivered as a powdered formulation, such that a minimal amount of associated endotoxin is delivered therewith, so as to avoid triggering the maturation of immature antigen presenting cells.

It is a yet further aim of the present invention to provide that the intranasal administration of insulin, in particular in the treatment of Alzheimer's disease and obesity, does not result in the exacerbation or precipitation of type II diabetes.

In one aspect the present invention provides for selective delivery of immunogenic proteins to the upper posterior region of the nasal cavity, and in particular the olfactory bulb region, such as to provide for uptake of an immunogenic protein to the CNS without triggering a significant immune response.

In another aspect the present invention provides for an administration methodology which minimizes the delivery of endotoxins.

In one embodiment the nosepiece of the delivery device is configured to prevent the accumulation of endotoxins thereon, such as by way of an agent, for example, as a coating, which degrades polysaccharides, which represent the immunogenic component of endotoxins, for example, by way of binding to the polysaccharide. In one embodiment a cap for the nosepiece could similarly include such an agent.

In another embodiment the nosepiece of the delivery device is replaceable. With this methodology, the accumulation of endotoxins on the nosepiece, as would occur through repeated use, is prevented.

In another aspect the present invention provides a solubilized protein formulation which is formulated, such as by including one or more solubilizing agents, to provide for the protein to remain in solution following intranasal administration.

In this way, the one or more proteins do not precipitate out of solution following administration, for example, owing to a shift in pH, ionic balance or osmolarity, which would result in undesirable phagocytosation of the protein by the antigen presenting cells.

In a further aspect the present invention provides for a powdered protein formulation which provides for the rapid and complete dissolution of the protein following administration.

Powdered protein formulations may have advantages in terms of stability, but are likely to result in insoluble particles being phagocytosed by the antigen presenting cells. The present inventors have recognized that this can be overcome by ensuring that the powder particles are rapidly hydrated following administration.

In a still further aspect the present invention provides for a protein formulation which includes an immunomodulator, which acts to prevent an immune response to the administered protein.

In a yet still further aspect the present invention provides for a protein formulation which is formulated to degrade any of the protein which remains to be absorbed within 15 minutes, and preferably 10 minutes, following administration.

With this formulation, any of the protein which is transported by the mucociliary clearance mechanisms to the nasal associated lymphatic tissue and the antigen presenting cells is degraded such that no immune response is raised to the protein.

In yet another aspect the present invention provides a protein formulation which is formulated to ensure uptake from the olfactory bulb region within 10 minutes following administration.

In one embodiment the formulation includes an uptake agent, such as a cyclodextrin, for providing for rapid uptake of the protein in the olfactory bulb region.

In another embodiment, where the formulation is delivered by the bi-directional methodology, the particle sizes of the delivered formulation and the flow rate of the entraining gas flow are such as to provide for targeted delivery to and efficient transfer across the olfactory bulb region, such as to provide for a much reduced antibody response as compared to delivery by conventional nasal spray technology, in particular nasal spray pumps.

With this formulation, none of the protein remains to be transported by the mucociliary clearance mechanisms to the nasal associated lymphatic tissue, including the specialized M-cells, and the antigen presenting cells.

In yet another aspect the present invention provides a delivery device for delivering a substance to the nasal airway of a subject, the delivery device including a nosepiece having a replaceable outer sleeve, with the sleeve preferably including an indicator material which provides an indication of exposure to one or more of moisture and biomaterials, such as endotoxins.

In yet still another aspect the present invention provides a delivery device for delivering a substance to the nasal airway of a subject, the delivery device including a nosepiece having a plurality of removable sleeves which are removable successively to allow for exposure of a fresh sleeve, with the sleeves preferably including an indicator material which provides an indication of exposure to one or more of moisture and biomaterials, such as endotoxins.

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 illustrates the segmentation of a nasal cavity in accordance with a preferred embodiment of the present invention;

FIG. 2 schematically illustrates a nasal delivery device for delivering a protein formulation to a nasal airway of a subject in accordance with one embodiment of the present invention;

FIG. 3 illustrates the delivery device of FIG. 2 where operative to deliver a dose of the embodied protein formulation into the nasal airway of the subject;

FIG. 4 illustrates a nasal delivery device as one modification of the first-described embodiment, with an outer sleeve of the nosepiece fitted;

FIG. 5 illustrates the delivery device of FIG. 4, with the outer sleeve of the nosepiece removed;

FIG. 6 illustrates a nasal delivery device as another modification of the first-described embodiment; and

FIG. 7 illustrates the delivery device of FIG. 6, with a sleeve of the nosepiece removed.

The delivery device comprises a housing 15, a nosepiece unit 17 for fitting in a nasal cavity of a subject, and a mouthpiece 19 through which the subject exhales to actuate the delivery device.

The nosepiece unit 17 comprises a nosepiece 20, in this embodiment a frusto-conical element, for guiding the nosepiece unit 17 into a nasal passage of the subject and being configured both to provide a fluid-tight seal with the nares of the nostril and obstruct, in this embodiment close, the nasal passage at a position therealong, in this embodiment at a position corresponding substantially to the nasal valve, thereby obstructing the anterior one-third of the nasal passage and leaving open the posterior two-thirds of the nasal passage, as illustrated in FIG. 3, and an outlet unit 21 for delivering substance, in this embodiment a protein formulation containing insulin, to an upper posterior region of the nasal passage of the subject, in this embodiment an upper posterior region as bounded by a vertical plane which is located posterior of the anterior nasal spine AnS at a position corresponding to one-quarter of the distance between the anterior and posterior nasal spines AnS, PnS and a horizontal plane which is located above the nasal floor at a height one-third of the distance between the nasal floor and the cribiform plate, which encompasses the olfactory bulb region from which the substance is uptaken into the CNS of the subject.

In this embodiment the delivery device is re-usable, and the nosepiece 20 is replaceable, such as to prevent the accumulation of endotoxins thereon, which could be transferred to the nasal cavity of the subject.

In an alternative embodiment the nosepiece 20 could be configured to prevent accumulation of endotoxins thereon, such as by including an anti-bacterial.

In this embodiment the outlet unit 21 comprises a delivery channel 23 which is in fluid communication with the mouthpiece 19 such that an air flow is delivered into and through the nasal airway of the subject on exhalation by the subject through the mouthpiece 19, and a nozzle 25 for delivering the nasal formulation to the nasal airway of the subject.

In this embodiment the nozzle 25 is configured to deliver an aerosol spray, either as a liquid or a powder aerosol spray, but in an alternative embodiment the nozzle could be configured to deliver a jet, that is, as a column of the formulation, either as a liquid or powder jet.

The delivery device further comprises a substance supply unit 29 for delivering metered doses of the formulation, which is fluidly connected to the nozzle 25 to deliver the nasal formulation from the nosepiece 17, in this embodiment as an aerosol spray.

In this embodiment the substance supply unit 29 comprises a mechanical delivery pump, in particular a liquid delivery pump or a powder delivery pump, which delivers metered doses of substance, on actuation thereof.

In another alternative embodiment the substance supply unit 29 could comprise a dry powder delivery unit which delivers metered doses of substance, as a dry powder, on actuation thereof. In one embodiment the substance supply unit 29 could provide for delivery of substance from a capsule.

In yet another alternative embodiment the substance supply unit 29 could comprise an aerosol canister which delivers metered volumes of a propellant, preferably a hydrofluoroalkane (HFA) propellant or the like, containing substance, either as a suspension or solution.

In this embodiment the substance supply unit 29 is a multi-dose unit for delivering a plurality of metered doses of the nasal formulation. In another embodiment the substance supply unit 29 could be a single-dose unit for delivering a single metered dose of the nasal formulation.

The substance supply unit 29 is pre-primeable, in this embodiment by loading a resilient element, and includes a breath-actuated release mechanism 31 which, when triggered, releases the resilient element and actuates the substance supply unit 29 to deliver a metered dose of the nasal formulation through the nozzle 25.

In this embodiment the trigger mechanism 31 is configured to cause actuation of the substance supply unit 29 on generation of a predetermined flow rate through the delivery channel 23.

In one embodiment the protein formulation comprises a solubilized protein formulation.

In one embodiment the solution comprises a viscous solution, such as a gel.

In one embodiment the protein formulation is such as to remain in solution following delivery, and preferably includes a solubilizing agent for maintaining the protein in solution following delivery.

In one embodiment the protein formulation is such that the protein does not precipitate from solution owing to one or more of a shift in pH, ionic balance or osmolarity following delivery.

In an alternative embodiment the protein formulation could be a powdered protein formulation.

In one embodiment the powdered protein formulation provides for dissolution of the protein following delivery.

Preferably, the powdered protein formulation provides for dissolution of the protein within about 5 minutes of delivery.

More preferably, the powdered protein formulation provides for dissolution of the protein within about 2 minutes of delivery.

Still more preferably, the protein formulation provides for dissolution of the protein within about 1 minute of delivery.

In one embodiment the protein formulation includes an immunomodulator, which acts to prevent an immune response to the protein.

In one embodiment the protein formulation is such as to degrade the protein which remains to be absorbed subsequent to a predeterminable period following delivery.

In one embodiment the protein formulation includes a proteolytic agent which acts to degrade the protein which remains to be absorbed subsequent to the predeterminable period following delivery.

In one embodiment the proteolytic agent can include one or more of trypsin, chymotrypsin, N terminal peptidases and C terminal peptidases.

Preferably, the protein formulation is such as to degrade the protein which remains to be absorbed within about 15 minutes following delivery.

More preferably, the protein formulation is such as to degrade the protein which remains to be absorbed within about 10 minutes following delivery.

Still more preferably, the protein formulation is such as to degrade the protein which remains to be absorbed within about 5 minutes following delivery.

In one embodiment the protein formulation provides for rapid uptake of the protein from the olfactory bulb region in the upper posterior region.

In one embodiment the protein formulation includes an uptake agent for providing for uptake of the protein from the olfactory bulb region.

In one embodiment the uptake agent is a cyclodextrin.

Preferably, the protein formulation provides for uptake of the protein from the olfactory bulb region within about 10 minutes following delivery.

More preferably, the protein formulation provides for uptake from the olfactory bulb region within about 5 minutes following delivery.

In an alternative embodiment the protein formulation comprises an antidiuretic hormone, such as argipressin, lypressin, desmopressin, felypressin, ornipressin, terlipressin and vasopressin or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises an oxytocic hormone, such as carbetocin, demoxytocin and oxytocin or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises an oxytocin antagonist, such as atosiban or its pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises a corticotrophic hormone, such as corticotrophin and tetracosactide or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises a corticotrophic releasing hormone, such as corticorelin or its pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises an omatotrophic hormone, such as mecasermin, somatrem and somatropin or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises a somatotrophic hormone receptor antagonist, such as pegvisomant or its pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises an omatotrophic releasing hormone, such as sermorelin and somatorelin or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises a somatotrophic release inhibitor, such as lanreotide, octreotide, somatostatin and vapreotide or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises a gonadotrophic hormone, such as choriogonadotrophin alfa, chorionic gonadotrophin, a follicle stimulating hormone, follitropin alfa, follitropin beta, a luteinising hormone, lutropin alfa, menotrophin and urofollitropin or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises a gonadotrophic releasing hormone, such as buserelin, deslorelin, gonadorelin, goserelin, histrelin, leuprorelin, naferlin and triptorelin or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises an onadotrophic releasing hormone antagonist, such as abarelix, cetorelix and ganirelix or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises a thyrotrophic hormone, such as thyrotrophin and thyrotrophin alfa or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises a thyrotrophic releasing hormone, such as posatirelin, protirelin and taltirelin or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises a lactotrophic hormone, such as prolactin or its pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises a metabolic peptide, such as an insulin-like growth factor, a glucagon, a growth hormone and PYY3-36 or their pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises calcitonin or pharmaceutically-acceptable derivatives or analogues thereof, such as elcatonin and salcatonin.

In an alternative embodiment the protein formulation comprises a melanocyte stimulating hormone.

In an alternative embodiment the protein formulation comprises a nerve growth factor.

In an alternative embodiment the protein formulation comprises an epidermal growth factor.

In an alternative embodiment the protein formulation comprises an epoetin or its pharmaceutically-acceptable derivatives or analogues.

In an alternative embodiment the protein formulation comprises an interleukin.

In an alternative embodiment the protein formulation comprises a protein involved in one or both of blood coagulation and fibrinolysis.

In an alternative embodiment the protein formulation comprises an antibiotic.

Operation of the delivery device will now be described hereinbelow with reference to FIG. 3 of the accompanying drawings.

The nosepiece 17 is first inserted into one of the nasal cavities of a subject until the nosepiece 20 abuts the nares of the nostril, at which point the distal end of the outlet unit 21 extends about 2 cm into the nasal cavity of the subject, and the mouthpiece 19 is gripped in the lips of the subject.

The subject then begins to exhale through the mouthpiece 19, which exhalation acts to close the oropharyngeal velum of the subject and drive an air flow through the delivery channel 23 of the outlet unit 21, with the air flow passing into the one nasal cavity, around the posterior margin of the nasal septum and out of the other nasal cavity, thereby achieving a bi-directional air flow through the nasal airway of the subject.

In this embodiment, when the flow rate developed through the delivery channel 23 reaches a predetermined value, the release mechanism 31 is triggered to actuate the substance supply unit 29 to deliver a metered dose of the nasal formulation to the nozzle 25 and into the nasal cavity of the subject as an aerosol spray.

In this embodiment, where the delivery device is a multi-dose device, the device is ready for further use following priming of the substance supply unit 29.

Finally, it will be understood that the present invention has been described in its preferred embodiments and can be modified in many different ways without departing from the scope of the invention as defined by the appended claims.

In one modification of the above-described device, as illustrated in FIGS. 4 and 5, the nosepiece 20 could include a replaceable outer sleeve 35, which allows for replacement at periodic intervals, for example, after each operation. FIGS. 4 and 5 illustrate the sleeve 35 when fitted and removed, respectively.

In one embodiment the sleeve 35 can include an Indicator material which provides an indication of exposure to one or more of moisture and biomaterials, for example, endotoxins, thereby providing an indication to the user when the sleeve 35 should be replaced.

In another modification of the above-described device, as illustrated in FIGS. 6 and 7, the nosepiece 20 could include a plurality of removable sleeves 37, typically formed as thin films, which are peelable successively to allow for exposure of a fresh sleeve 37 at periodic intervals, for example, after each operation.

In one embodiment one or more of the innermost sleeves 37 can be marked, for example, colored, to indicate that a minimum number of the sleeves 37 remain.

In one embodiment the sleeves 37 can include an indicator material which provides an indication of exposure to one or more of moisture and biomaterials, for example, endotoxins, thereby providing an indication to the user when the outer sleeve 37 should be discarded.

Furthermore, in the above-described embodiment the delivery device is configured to deliver an air flow through one nostril of a subject at such a pressure as to flow around the posterior margin of the nasal septum and out of the other nostril of the subject, thereby achieving bi-directional delivery through the nasal cavities as disclosed in WO-A-2000/51672, the content of which is herein incorporated by reference, but in an alternative embodiment the delivery device could be configured to deliver an air flow which is not sufficient to achieve bi-directional delivery through the nasal cavities or utilizes no entraining gas flow. This embodiment is still advantageous as compared to known delivery devices, in providing for velum closure and being capable of achieving targeted delivery, particularly when certain regions of the nasal cavity are obstructed by cuff members.

In another alternative embodiment the above-described delivery device could be configured not to provide for any gas flow, but instead provide for targeted delivery through use of an optimized nosepiece.

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  • 14. Brandtzęg P et al, Role of secretory antibodies in the defence against infections, Int J Med Microbiol, April 2003, 293(1), pages 3-15.

For the avoidance of doubt, the contents of the above-identified references are herein incorporated by reference.

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Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US8047202Dec 19, 2008Nov 1, 2011Optinose AsNasal devices
US8511303Dec 21, 2007Aug 20, 2013Optinose AsNasal delivery devices
US8522778Apr 9, 2010Sep 3, 2013Optinose AsNasal devices
US8590530May 14, 2012Nov 26, 2013Optinose AsNasal delivery devices
Classifications
U.S. Classification514/1.1, 604/275, 530/350
International ClassificationC07K14/00, A61K38/02, A61P25/28, A61M31/00, A61P3/04, A61P3/10
Cooperative ClassificationA61M15/0098, A61M2202/064, A61M2210/0618, A61K9/0043, A61M15/08, A61M15/0091, A61M2210/0625
European ClassificationA61M15/00T, A61K9/00M14, A61M15/08
Legal Events
DateCodeEventDescription
May 21, 2009ASAssignment
Owner name: OPTINOSE AS, NORWAY
Effective date: 20090409
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:HAFNER, RODERICK PETER;REEL/FRAME:022721/0542