CIRCUMFERENTIAL AEROSOL DEVICE
The present application discloses devices and methods for delivering a therapeutic compound to the olfactory epithelium of an animal or human. The device having one or more channels for imparting a circumferential and axial velocity to the discharged fluid, and an outlet that discharges an aerosol spray having a circumferential and axial velocity as it enters the nasal cavity of a user. The device is designed to displace the air in the upper nasal cavity in order to specifically deposit a therapeutic agent on the olfactory epithelium while minimizing pressure and discomfort experienced by the user.
Latest University of Washington through its Center for Commercialization Patents:
This application is a continuation of U.S. patent application Ser. No. 14/292,481, filed May 30, 2014, which is a division of U.S. patent application Ser. No. 12/866,448, filed Oct. 22, 2010, now U.S. Pat. No. 8,757,146, which is the national stage of International Application No. PCT/US2009/033468, filed Feb. 6, 2009, which claims the benefit of U.S. Provisional Patent Application No. 61/027,002, filed Feb. 7, 2008; each application is incorporated herein by reference in its entirety.
STATEMENT OF GOVERNMENT LICENSE RIGHTSThis invention was made with U.S. Government support under Grant Nos. AI052663 and 5R01A177390-04 awarded by the National Institutes of Health (NIH). The U.S. Government has certain rights in the invention.
BACKGROUNDDepositing therapeutic drugs on the olfactory epithelium has been shown to lead to rapid and direct uptake into the brain. This direct nose-to-brain delivery route bypasses the blood-brain-barrier, which keeps a majority of drugs or drug candidates from reaching the brain in any significant concentrations. Many studies, including those of the present inventors, have shown that depositing a drug on the olfactory epithelium, while minimizing drug absorption on the respiratory epithelium, is key to maximizing the fraction of drug that bypasses the blood-brain-barrier and reaches the brain.
Currently there are no suitable nasal delivery devices that sufficiently target the olfactory region of the nasal cavity while avoiding the lungs and respiratory area of the nasal cavity. The olfactory region is a narrow space at the top of the nasal cavity taking up about 10% of the total surface area of the nasal cavity. In addition, when a subject breaths in through the nose, the inhaled air travels primarily along the lower part of the nasal cavity into the trachea and lung, thus, leaving the air in the olfactory region mainly undisturbed and stagnant in the olfactory region (and hence leading to a low fraction of olfactory drug exposure for drugs carried along the breath path).
The present disclosure overcomes the disadvantages associated with the anatomical impediments described above by providing pressurized olfactory drug delivery devices and methods for delivering pharmaceutical compounds to the olfactory epithelium.
SUMMARYThe present application discloses a pressurized olfactory drug delivery device for producing an aerosol nasal spray having a narrow spray plume with circumferential velocity. The device disclosed herein is designed to displace the residual olfactory air volume to deliver therapeutic compound to the olfactory region of the nasal cavity. In one aspect, the pressurized olfactory drug delivery device comprises a container having a mixture of a pressurized fluid and a therapeutic compound, a delivery device defining a longitudinal axis connected to the container and having an exit opening at the nasal-proximal end, a cylindrical channel connected to the outlet of the container and extending to the exit opening, and a plurality of discharge outlets radially disposed around the longitudinal axis, wherein each discharge outlet is oriented to discharge the pressurized fluid mixture in an axial and circumferential direction. The device further comprises a metering device for selectively discharging the pressurized fluid through the outlets, such that the outlets produce a plurality of aerosol spray discharges comprising the therapeutic compound that converge into a single spray plume having a circumferential helical velocity.
In a second aspect, the pressurized olfactory drug delivery device includes a container containing a mixture of a pressurized fluid and a therapeutic compound; a delivery device in communication with the container, the delivery device having a plurality of longitudinal helical channels, each helical channel comprising an inlet and an outlet disposed at the nasal proximal-most end of the device; and a metering device for selectively discharging the pressurized fluid mixture through the helical channels. The outlets are configured to discharge a plurality of aerosol spray jets comprising the pressurized fluid mixture that converge into a single spray plume having a circumferential helical velocity as the spray exits the device.
The present application also discloses a method for depositing a therapeutic compound on the olfactory epithelium in the nasal cavity of a human or animal subject, the method comprising administering a pressurized fluid comprising the therapeutic compound from a pressurized olfactory drug delivery device into the nasal cavity, wherein the device discharges a pressurized aerosol spray comprising the therapeutic compound, the pressurized aerosol spray having a circumferential velocity after exiting the device.
This summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This summary is not intended to identify key features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same become better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein:
The present application discloses a pressurized olfactory drug delivery (PODD) device that produces an aerosol nasal spray having a narrow spray plume with circumferential velocity. The device disclosed herein is designed to displace the residual olfactory air volume under low pressure to increase the efficiency and consistency with which pharmaceutical compounds are delivered to olfactory epithelium, and further to enhance patient tolerability.
A pressurized olfactory drug delivery device (PODD) 10 according to one embodiment of the present disclosure is best seen by referring to
Referring to
The housing 142 further comprises a spin chamber 160 defined by the space between the interior surface 146 of the housing and the exterior surface 158 of the fluid reservoir. The housing further comprises a compressed gas inlet 148 that is in communication with the spin chamber 160 and fluidically connected to the pneumatic solenoid 30. The spin chamber further comprises a coiled wire 162 that is wrapped around the exterior 158 of the fluid chamber, the coiled wire 162 having a helical or corkscrew shape and extending from the gas inlet 148 to the proximal orifice 154.
Referring now to
Referring now to
The nasal delivery device can be used to deposit numerous types of therapeutic compounds and compositions on the olfactory epithelium, including neurological, analgesic, anti-viral and cancer treatment compounds. Compounds that can be delivered include, but are not limited to, compounds comprising small molecular weight synthetic organic pharmaceuticals, peptide and protein therapeutic compounds, antibodies and antibody fragments, aptamer compounds, and DNA and RNA compounds. The compounds can be delivered as part of a composition or formulation to aid in stability or penetration of the olfactory epithelium. The composition may further comprise stabilizers, preservatives, or additives mixed with the therapeutic compound.
Referring to
The device 200 further comprises a cylindrical fluid reservoir 230 that is radially disposed about the longitudinal axis and enclosed by the housing 210. The fluid reservoir 230 has an exterior surface 232 and an interior surface 234 and a second orifice 236 at the proximal end disposed near the first orifice 216 of the housing, the second orifice 236 having a diameter smaller than that of the first orifice 216 and being generally radially aligned about the longitudinal axis of the housing 210. The fluid reservoir 230 has a diameter narrower than the diameter of the housing 210. The proximal end of the fluid reservoir 230 is conically shaped adjacent to and surrounding the second orifice 236. The fluid reservoir 230 preferably is provided with a vent (not shown) to prevent a vacuum that would increase the pressure required to remove fluid from the second orifice 236.
The distal end of the housing 210 comprises one or more nozzles 220 that are fluidically connected to a compressed fluid container 222. The compressed fluid may be compressed air, compressed nitrogen, or a compressed propellant such as CFC or HFA, or any other suitable propellant recognized in the art. The compressed fluid container preferably has a metering device (not shown) to deliver a predetermined amount of fluid, gas or propellant when activated. In some embodiments, the compressed fluid container is a MDI. The proximal end of the nozzles 220 have openings 224 that open into a spin chamber 240 defined by the space between the exterior surface 232 of the fluid reservoir 230 and the interior surface 214 of the housing 210. The nozzles 220 are configured such that the openings 224 discharge the compressed fluid in a circumferential and axial direction, thereby establishing a circumferential velocity to the pressurized fluid.
With continued reference to
Referring now to
The housing 310 further comprises an inner wall 320 defining an axially aligned inner cylinder 322 open at both ends and connected to the proximal end 318 of the housing 310 at the orifice 316 and having a distal open end 324 disposed near the interior surface 315 of the distal wall of the housing, thereby defining a sufficient gap for receiving a fluid between the distal open end 324 and the interior surface 315 of the wall.
The inner cylinder 322 has a diameter less than the diameter of the outer wall 311, thereby defining a space between the exterior surface 326 of the cylinder 322 and the interior surface 314 of the outer wall 311 of the housing 310 that serves as a fluid reservoir 330 suitable for storing a liquid pharmaceutical composition.
Referring still to
With continued reference to
Referring now to
Referring now to
Referring now to
The circumferential velocity created by the plurality of vents has the added advantage that the spray plume is able to penetrate the upper regions of the nasal cavity compared to a spray plume produced without circumferential velocity, and be much more narrow than the wide spray plume produced by a device having a single aerosol source with vortical flow, which further helps the spray to penetrate the upper nasal cavity and contact the olfactory epithelium.
Referring now to
In the embodiments illustrated in
Referring now to
Still referring to the embodiment illustrated in
With continued reference to
The nozzle 700 may be constructed by machining threads or grooves in the exterior surface 714 of the inner cylinder portion 710 to produce the corkscrew shaped axial members 760 thereof. Alternatively, the nozzle 700 may be constructed by machining threads or grooves in the interior surface 722 of the outer cylinder portion 720 to produce the corkscrew shaped axial members 760 thereof. It is understood that the nozzle is not limited by the method of producing or manufacturing the nozzle.
In a preferred embodiment, the cross-sectional area of the channel decreases from distal to proximal, such that the outlets 730 are smaller than the inlets 740, thereby providing acceleration to a pressurized fluid entering the channel. It will be understood that the channels may be round, square, rectangular, ovoid, or any other suitable shape in cross section. The outlets 730 are configured such that a pressurized fluid discharged from the outlet has an axial velocity and a circumferential velocity. The outlets 730 are further configured to atomize the pressurized fluid into an aerosol spray as the pressurized fluid exits the outlets 730. Further, in some embodiments, the outlets 730 are configured such that the aerosol spray discharged from the outlet is further directed radially inwardly at an oblique angle toward the longitudinal axis of the nozzle.
Referring again to
The circumferential velocity created by the plurality of outlets 730 has the added advantages that the spray plume is able to penetrate the upper regions of the nasal cavity compared to a spray plume produced without circumferential velocity, and is much narrower than the wide spray plume produced by a device having a single aerosol source with vortical flow. The narrow spray plume, in combination with the circumferential velocity provided by the nozzle 700, allows the aerosolized spray to penetrate the upper nasal cavity and deposit therapeutic compounds on the olfactory epithelium. Representative methods for measuring the diameter of the spray plume are described in Example 1.
In some embodiments, the device of the disclosure discharges a plurality of particles having an average or mean diameter in the range selected from the group consisting of about 1 to about 100 micrometers, about 5 to about 50 micrometers, about 5 to about 30 micrometers, about 5 to about 25 micrometers, about 5 to about 20 micrometers, about 5 to about 15 micrometers, and about 10 to about 15 micrometers. In some embodiments, at least 70%, at least 80%, at least 90% and at least 95% of the particles produced by the device have a diameter between about 5 and 25 micrometers. In one embodiment, the majority of the particles discharged by the device are in the range of about 5 to 20 micrometers. Aerosol discharge outlet diameters for producing the desired particle sizes are typically in the range of 0.1 to 0.5 mm.
The disclosure further provides a method for depositing a therapeutic compound on the olfactory epithelium in the nasal cavity of a human or animal subject. In one embodiment, the method comprises administering the therapeutic compound from a pressurized nasal spray device into the nasal cavity, wherein the pressurized nasal spray device comprises an aerosol outlet that discharges a pressurized spray comprising the therapeutic compound, the pressurized spray having a circumferential velocity as it exits the outlet and enters the nasal cavity.
In another embodiment the method comprises administering a pressurized fluid comprising the therapeutic compound from a pressurized olfactory drug delivery device into the nasal cavity, wherein the device comprises a plurality of outlets that discharge a plurality of pressurized aerosol sprays comprising the therapeutic compound, the plurality of pressurized aerosol sprays converging into a single spray plume having a circumferential velocity after exiting the device. In one embodiment, each outlet of the device is located at the nasal-proximal most end of the device and discharges the aerosol spray having a circumferential velocity directly into the nasal cavity.
In some embodiments, the method administers a plurality of particles to the nasal cavity, the plurality of particles having an average or mean diameter in the range selected from the group consisting of about 1 to about 100 micrometers, about 5 to about 50 micrometers, about 5 to about 30 micrometers, about 5 to about 25 micrometers, about 5 to about 20 micrometers, about 5 to about 15 micrometers, and about 10 to about 15 micrometers. In other embodiments, at least 70%, at least 80%, at least 90% and at least 95% of the particles administered by the method have a diameter between about 5 and 25 micrometers. In one embodiment, the majority of the particles administered by the method are in the range of about 5 to 20 micrometers.
In one embodiment, the device used in the method comprises a metered dose device that releases a predetermined amount of the pressurized fluid comprising a predetermined dose of the therapeutic compound when the device is activated. In this embodiment, the method delivers about 40% of the predetermined amount of the pressurized fluid that enters the nasal cavity as an aerosol spray to the olfactory epithelium. In other embodiments, the method delivers at least about 40% of the predetermined dose of the therapeutic compound to the olfactory epithelium. In one embodiment, the method results in higher concentrations of a therapeutic compound in the brain than in the blood.
In some embodiments, the therapeutic compound of the method is provided as part of a composition or formulation containing stabilizers, preservatives, or additives that are well known in the art. Further, in some embodiments, the therapeutic compound may be formulated with colloids, nanoparticles, liposomes, micelles, or another type of suspension.
While not wishing to be bound by theory, the devices and methods described in the above embodiments are believed to improve the penetration of an aerosol spray into the upper nasal cavity by displacing the resident or residual air volume present in the upper naval cavity. This allows a larger fraction of the therapeutic compound to be deposited directly on the olfactory epithelium while at the same time reducing the amount of the therapeutic compound that is deposited on the respiratory epithelium, esophagus, stomach and lungs. A further advantage of the devices described in the present disclosure is a reduction in the back pressure required to deliver drugs to the olfactory epithelium when compared to devices that deliver a narrow spray plume without a corresponding centrifugal velocity component.
Example 1This example describes various functional parameters of the device illustrated in
The spray rate was tested by varying the driving pressure from 1 to 6 pounds per square inch and the diameter of the orifice 154. The spray rates were reproducible and within the desired range for human application, namely less than 50 microliters per second.
Table 1 shows the delivery of the antiviral drug nelfinavir to different brain regions in rats using nose drops (which approximates nasal distribution with a standard nasal spray) or the PODD device illustrated in
The results presented in this Example show that the device and methods disclosed in the application are useful for delivering therapeutic compounds to the olfactory epithelium and brain regions, and that a large fraction of the dose present in nasal spray having a circumferential velocity is deposited on the olfactory epithelium. The results also show that the device delivers a high fraction of drug to the olfactory epithelium, which leads to higher drug concentrations in the brain and lower drug concentrations in the systemic circulation.
Example 2This example demonstrates the improved penetration of a simulated nose cone using a device comprising a plurality of outlets in comparison to a device having a single outlet with and without circumferential flow.
Methods:
Flow simulations were carried out using the Star-CCM+ computational fluid dynamics simulation software package (CD-adapco), version 3.06.006. In the simulation, a cone was used with similar geometry to a nasal cavity for the sake of simplicity. The cone was designed to be narrow towards the top with the only outlet for residual air located at the bottom of the cone. Thus, the air in the top of the cone was stagnant and had to be displaced in order for the nozzle flow to penetrate the top of the cone, much like the upper nasal cavity of a human. The dimensions of the cone were 7.5 cm from top to bottom, in order to realistically simulate nasal delivery to the olfactory epithelium of a human.
The Following Nozzle Structures were Tested:
(1) a nozzle without circumferential flow and a single outlet;
(2) a nozzle with circumferential flow and a single outlet; and
(3) a nozzle with circumferential flow and a plurality of outlets, in accordance with an embodiment of a device of the present disclosure as illustrated in
The various nozzle structures were place in the bottom of the cone with the outlets pointed upward towards the top of the cone. The area of flow for each of the nozzles was kept at 3.54 mm2 and the air velocity coming from the outlets was kept constant at 60 m/s. The simulation was performed under a steady time condition with k-epsilon turbulence. The simulations were run between 115 to 370 iterations until the momentum residuals remained constant between iterations.
Results:
The results of the flow simulations are shown in
The flow simulation comparison using the various nozzle structures described in this example demonstrates the advantages of using a nozzle having a plurality of outlets which generates a narrow spray pattern having circumferential velocity to penetrate a narrow area, such as the upper nasal cavity of a human, where the air must be displaced to allow for penetration of the spray in order to deposit a large fraction of drug on the olfactory epithelium.
While illustrative embodiments have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.
Claims
1. An olfactory drug delivery device comprising:
- a reservoir containing a therapeutic compound;
- a container containing a pressurized propellant fluid;
- a delivery device comprising: an opening at a proximal end of the delivery device; a first channel having a proximal end coupled to the reservoir and a distal end in fluid communication with the opening; a second channel having a proximal end coupled to the container and a distal end in fluid communication with the opening; and
- wherein the pressurized propellant fluid exiting the container travels through the second channel and comes into contact near the opening with the therapeutic compound exiting the reservoir through the first channel, the propellant and the therapeutic compound creating a plume,
- wherein at least 15% of the plume is delivered to the olfactory region.
2. The olfactory drug delivery device of claim 1, further comprising a metering device for selectively discharging the pressurized propellant fluid from the container into the second channel.
3. The olfactory drug delivery device of claim 1, wherein the container is a metered dose inhaler.
4. The olfactory drug delivery device of claim 1, wherein the second channel induces a circumferential helical flow in the propellant fluid when the propellant fluid exits the container into the second channel.
5. The olfactory drug delivery device of claim 4, wherein the plume has a circumferential velocity.
6. The olfactory drug delivery device of claim 1, further comprising a plurality of outlets at the distal end of the second channel for discharging the pressurized propellant fluid.
7. The olfactory drug delivery device of claim 1, wherein at least 40% of the plume are delivered to the olfactory region.
8. The olfactory drug delivery device of claim 1, wherein a pressure of the container is between 3 psi and 5 psi.
9. The olfactory drug delivery device of claim 1, wherein a portion of the first channel and a portion of the second channel are substantially parallel.
10. The olfactory drug delivery device of claim 1, further comprising a sealing mechanism configured to seal the first channel.
11. An olfactory drug delivery device comprising:
- a container comprising a mixture of a pressurized fluid and a therapeutic compound;
- a delivery device in fluid communication with the container and defining a longitudinal axis, the delivery device having a plurality of helical channels, each helical channel comprising an inlet and an outlet disposed at a nasal proximal end of the device, wherein the outlets are radially disposed around the longitudinal axis; and
- a metering device for selectively discharging the mixture of the pressurized fluid and the therapeutic compound through the helical channels, such that the outlets produce a plurality of spray discharges that converge into a single spray plume having a circumferential velocity.
12. The device of claim 11, wherein the cross-sectional area of the channel interior decreases from the inlet to the outlet.
13. The device of claim 11, wherein the outlets are symmetrically located around the longitudinal axis.
14. The device of claim 11, wherein each outlet is configured to produce an aerosol spray from the mixture of the pressurized fluid and the therapeutic compound having an axial velocity and a circumferential velocity.
15. The device of claim 11, wherein each outlet is disposed at an oblique angle relative to the longitudinal axis.
16. The device of claim 11, wherein each outlet is directed radially inwardly.
17. The device of claim 11, wherein the mixture of the pressurized fluid and the therapeutic compound becomes an aerosol spray when exiting the plurality of outlets.
18. The device of claim 11, wherein the container comprises a metered dose inhaler.
19. The device of claim 11, wherein the device produces a plurality of particles having an average diameter selected from the group consisting of about 1 to about 100 micrometers, about 5 to about 50 micrometers, about 5 to about 30 micrometers, about 5 to about 25 micrometers, about 5 to about 20 micrometers, about 5 to about 15 micrometers, and about 10 to about 15 micrometers.
20. An olfactory drug delivery device comprising:
- a container having an outlet and comprising a mixture of a pressurized fluid and a therapeutic compound;
- a delivery device defining a longitudinal axis and in fluid communication with the container, the delivery device having: an exit opening at a proximal end, a cylindrical channel connected to the outlet of the container and extending to the exit opening, and a plurality of discharge outlets radially disposed around the longitudinal axis, wherein each discharge outlet is oriented to discharge the mixture of the pressurized fluid and the therapeutic compound in an axial direction and a circumferential direction; and
- a metering device for selectively discharging the mixture of the pressurized fluid and the therapeutic compound through the plurality of discharge outlets, such that the plurality of discharge outlets produce a plurality of discharges that converge into a single spray plume having a circumferential velocity.
21. The device of claim 20, wherein the cylindrical channel defines a plurality of helical channels, wherein each helical channel has a discharge outlet oriented to discharge the pressurized fluid mixture in an axial and circumferential direction.
22. The device of claim 20, wherein the container comprises a metered dose inhaler.
Type: Application
Filed: Jun 14, 2018
Publication Date: Oct 18, 2018
Applicant: University of Washington through its Center for Commercialization (Seattle, WA)
Inventors: John D. Hoekman (Seattle, WA), Rodney J.Y. Ho (Mercer Island, WA)
Application Number: 16/008,159