Abstract
A system for delivering a therapeutic agent to nasopharyngeal mucosa tissue has a shaft, a porous pad of compliant material coupled to the shaft near the distal end, and a drug reservoir. The porous pad is configured to expand from a contracted configuration to an expanded configuration. The expanded configuration is adapted to engage and conform to the mucosa tissue in a nasal cavity, and the contracted configuration has a size suitable for introduction into the nasal cavity. The drug reservoir holds a therapeutic agent and is at least partially covered by the porous pad. The drug reservoir is configured to release a fixed volume of the therapeutic agent into the porous pad within a period of less than about 120 minutes, and has a wall with a plurality of channels fluidly coupled with the porous pad.
Claims
1. A system for delivering a therapeutic agent to nasopharyngeal mucosa tissue, said system comprising: a shaft having a proximal end and a distal end; a porous pad of compliant material coupled to the shaft near the distal end, wherein the porous pad is configured to expand from a contracted configuration to an expanded configuration, the expanded configuration being adapted to engage and conform to the mucosa tissue in a nasal cavity, and the contracted configuration having a size suitable for introduction into the nasal cavity; and a drug reservoir holding a therapeutic agent, the drug reservoir being at least partially covered by the porous pad, the drug reservoir having a wall with a plurality of channels fluidly coupled with the porous pad.
2. The system of claim 1, wherein the drug reservoir is configured to release a fixed volume of the therapeutic agent into the porous pad within a period of less than about 120 minutes.
3. The system of claim 1, wherein the elongate central member comprises an elongate shaft.
4. The system of claim 3, wherein the elongate shaft comprises a central lumen extending therethrough.
5. The system of claim 3, wherein the elongate shaft has a lumen extending between the proximal and distal ends, the lumen fluidly coupled to the drug reservoir.
6. The system of claim 5, wherein control of fluid pressure applied to the lumen controls the flow of the therapeutic agent out of the drug reservoir.
7. The system of claim 1, further comprising a sheath slidably disposed over the porous pad, the sheath constraining the porous pad in the contracted configuration, and wherein removal of the sheath from the porous pad allows expansion thereof into the expanded configuration when the therapeutic agent wets the porous pad.
8. The system of claim 1, wherein the porous pad expands from the contracted configuration to the expanded configuration when wetted by the therapeutic agent.
9. The system of claim 7, wherein the porous pad in the expanded configuration exerts a force against the mucosa tissue.
10. The system of claim 1, further comprising a stiffening element extending at least partially from the proximal end to the distal end of the elongate central member, the stiffening element providing a desired rigidity and stiffness to the elongate central member so that the elongate central member may be delivered to a desired location.
11. The system of claim 1, wherein the porous pad comprises a sponge.
12. The system of claim 1, wherein the porous pad comprises a foamed polymer.
13. The system of claim 1, wherein the porous pad comprises a plurality of channels extending radially outward therefrom, the channels configured to direct the therapeutic agent toward an external surface of the porous pad.
14. The system of claim 1, wherein the porous pad comprises a plurality of fingers extending outward therefrom.
15. The system of claim 1, wherein the porous pad comprises a looped section.
16. The system of claim 1, wherein the porous pad comprises a plurality of protuberances spaced axially apart from one another and separated by a gap therebetween.
17. The system of claim 1, wherein the porous pad comprises a plurality of axial elements extending distally of the elongate central member, each axially extending element having a portion of the porous pad disposed thereover, and each axially extending element in fluid communication with the drug reservoir.
18. The system of claim 1, wherein the porous pad comprises a plurality of radial elements extending laterally from the elongate central member, each radial element having a portion of the porous pad disposed thereover, and each radial element in fluid communication with the drug reservoir.
19. The system of claim 1, wherein the porous pad comprises a sheet of porous material wrapped around the elongate central member.
20. The system of claim 19, wherein the sheet of porous material is helically wrapped around the elongate central member.
21. The system of claim 1, wherein the porous pad comprises a support member disposed therein, the support member configured to provide support to the porous pad in the expanded configuration.
22. The system of claim 1, wherein the porous pad comprises a plurality of fibers extending radially outward from the central member, the fibers configured to be loaded into a syringe in the contracted configuration, and wherein the fibers expand into engagement with the mucosa tissue when discharged from the syringe and in the expanded configuration.
23. The system of claim 1, further comprising a hydrophobic layer of material disposed between the drug reservoir and the porous pad, the hydrophobic layer of materials having a plurality of channels disposed therein, the channels configured to direct the therapeutic agent from the drug reservoir to the porous pad.
24. The system of claim 1, wherein the drug reservoir comprises a plurality of pores, the pores configured to allow the therapeutic agent to flow from the drug reservoir toward the porous pad.
25. The system of claim 24, further comprising a plurality of valves fluidly coupled with the plurality of pores, the valves configured to control flow through the pores.
26. The system of claim 1, further comprising a hydrophilic cover surrounding at least a portion of the drug reservoir, the hydrophilic cover configured to facilitate transport of the therapeutic agent from the drug reservoir toward an external surface of the porous pad.
27. The system of claim 1, wherein the drug reservoir comprises a plurality of loops extending distally from the elongate central member, the loops having a central reservoir extending therethrough.
28. The system of claim 27, wherein at least some of the loops comprise a stiffening member extending therethrough, the stiffening member configured to maintain patency of the central reservoirs.
29. The system of claim 1, wherein the drug reservoir comprises an expandable member, and wherein expansion of the expandable member advances the porous pad toward the mucosa tissue.
30. The system of claim 1, wherein the drug reservoir comprises an expandable member, and wherein expansion of the expandable member forces the therapeutic agent out of the drug reservoir.
31. The system of claim 1, wherein the therapeutic agent comprises a toxin configured to inhibit mucus secretions.
32. The system of claim 31, wherein the toxin comprises botulinum toxin.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
[0039] FIG. 1 illustrates basic anatomy of the nasal cavity.
[0040] FIGS. 2A-2B illustrate an exemplary delivery device having a covered porous reservoir.
[0041] FIGS. 3A-3E illustrate other exemplary delivery devices of a covered porous reservoir with cover configurations.
[0042] FIG. 4 illustrates still another exemplary embodiment of a delivery device with a porous reservoir and an alternative cover configuration.
[0043] FIGS. 5A-5F illustrate use of a single sheet of material to form a portion of a drug delivery device.
[0044] FIG. 6 illustrates an alternative embodiment of a foam contact element.
[0045] FIGS. 7A-7B illustrate an exemplary method of delivering a therapeutic agent to a nasal cavity.
[0046] FIGS. 8A-8B illustrate another exemplary method of delivering a therapeutic agent to a nasal cavity.
[0047] FIGS. 9A-9B illustrate still another exemplary method of delivering a therapeutic agent to a nasal cavity.
[0048] FIG. 10 illustrates an exemplary embodiment of a device for delivering a therapeutic agent to a nasal cavity.
[0049] FIG. 11 illustrates an exemplary embodiment of a pressurized drug reservoir.
[0050] FIGS. 12A-12B illustrate an exemplary method of delivering a therapeutic agent to the nasal cavity.
[0051] FIGS. 13A-13C illustrate a porous balloon for delivery of a therapeutic agent to the nasal cavity.
[0052] FIG. 13D illustrates another balloon embodiment for delivery of a therapeutic agent.
[0053] FIGS. 14A-14C illustrate an embodiment of a delivery device having a tissue penetrating needle.
[0054] FIGS. 15A-15B illustrate use of the device in FIGS. 14A-14C to deliver a therapeutic agent to the nasal cavity.
[0055] FIGS. 16A-16C illustrate use of a nasal patch to deliver a therapeutic agent to the nasal cavity.
[0056] FIG. 17 illustrates a paint on device for delivering a therapeutic agent.
[0057] FIG. 18 illustrates cilial transport of a therapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION
[0058] The present invention is preferably directed to methods and systems for delivering one or more therapeutic agents including toxins or non-toxins to target cells within a patient's nasal cavity. The toxins may be intact toxins, such as botulinum toxin, ricin, exotoxin A, diphtheria toxin, cholera toxin, tetanus toxin, other neurotoxins, and active fragments thereof. Each of these toxins comprises a heavy chain responsible for cell binding and a light chain having enzyme activity responsible for cell toxicity.
[0059] Botulinum toxin blocks acetylcholine release from cells, such as the epithelial or goblet cells in the nasal membranes responsible for mucus hypersecretion, and can thus be effective in accordance with the principles of the present invention. The use of energy to permeablize or porate the cell membranes of the epithelial or goblet cells or other mucus-secreting cells of the nasal lining, may facilitate botulinum and other toxins to be preferentially delivered to the targeted epithelial or goblet and other mucus-producing cells. Additionally, energy-mediation allows use of the active or light chains of these toxins (having the heavy chains removed or inactivated) for treatments. Normally, the light chains when separated from the cell-binding heavy chains of botulinum and the other toxins are incapable of entering the cells and thus will be free from significant cell toxicity. By using energy-mediated protocols the toxin light chains may be locally and specifically introduced into the target cells located within defined regions of the nasal membrane. Thus, even if the toxin fragments are accidentally dispersed beyond the desired target regions, the fragments will not generally enter cells without the additional application of cell permeablizing or porating energy. For that reason, toxin delivery methods are particularly safe when performed with toxin fragments, such as the light chain of botulinum and other toxins.
[0060] While the remaining portion of this disclosure will be presented with specific reference to the botulinum toxin, one of skill in the art will appreciate that other toxins may also be used, including the active fragment of the toxin in combination with energy-mediated delivery protocols such as those disclosed in U.S. Patent Applications previously incorporated by reference above.
[0061] FIG. 1 illustrates the basic anatomy of the nasal cavity. The entrance to the nasal cavity is via the external naris. The anterior-most portion of the nasal cavity is referred to as the nasal vestibule and is enclosed by cartilage and lined by epithelium. Small hairs in the vestibule help filter dust and other contaminants in the air that is breathed in. Long, narrow, and curled bone shelves line a portion of the nasal cavity. These bones are referred to as nasal concha or turbinates. An upper or superior turbinate, a middle turbinate, and an inferior turbinate divide the nasal airway into four channel-like air passages which direct inhaled air to flow in a steady, regular pattern around the largest possible surface of cilia and climate controlling tissue. Various sinus cavities are also disposed within the bones of the face and skull adjacent the nasal cavity. These sinuses, such as the frontal sinus and the sphenoid sinus are mucosa lined airspaces that produce mucus. The nasal cavity communicates with the throat via the nasopharynx.
[0062] Foam Covered Reservoir Embodiments
[0063] FIGS. 2A-2B illustrate an exemplary embodiment of a delivery device having a porous reservoir with a soft covered tip. The delivery device 22 includes an elongate catheter shaft 24 having a lumen 25 therethrough. The proximal end of the delivery device 22 includes a standard connector 26 such as a Luer connector for fluidly coupling the delivery device 22 with a source of the toxin, or other therapeutic agent to be delivered therefrom. In preferred embodiments, the connector 26 also has a one-way valve to prevent the therapeutic agent, here a toxin such as botulinum toxin from leaking out of the proximal end of the shaft 24. The distal portion of the delivery device 22 includes a soft covered portion, here a resilient foam contact element 30 that is disposed around the shaft 24. A wire support 28 extends through the lumen 25 of elongate shaft 24 and provides stiffness to the shaft to facilitate advancement into the nasal cavity, and prevent kinking or unwanted bending. Other support members including wires, plastic members, nitinol components, sutures, foam elements, etc. may also be coupled to various portion of the delivery system in order to help provide support.
[0064] FIG. 2B is a cross-section of the resilient foam contact element 30. The elongate shaft 24 extends under the foam contact element 30, and support wire 28 preferably extends through lumen 25 of the elongate shaft 24 under foam contact element 30. One or more pores 38 extend laterally through the sidewall of shaft 24 so that they are in fluid communication with lumen 25 which serves as a reservoir 34 for the toxin or therapeutic agent to be delivered. The reservoir 34 may also be a pressure filled bladder. The reservoir 34 may extend only under the foam contact element 30, or it may extend proximally beyond the foam contact element 30 into shaft 24. Foam contact element 30 may be a hydrophilic material to help hold and distribute the therapeutic agent. The foam contact element 32 also may include channels 36, perforations, or slits which help direct the therapeutic agent to flow 40 from the lumen 25 which acts as reservoir 34, through the pores 38 in the shaft sidewall, through the foam contact element 30 to a surface of the foam contact element for delivery to the target tissue which in this embodiment is preferably nasopharyngeal mucosa tissue. Thus, in this embodiment, a syringe or other device may be coupled to the connector 26 and the lumen may be filled with a therapeutic agent. Thus the lumen 25 acts as a reservoir for the therapeutic agent. The therapeutic agent will be absorbed by the foam contact element for delivery to the tissue. Additional actuation of the syringe may be used to pressurize the therapeutic agent within the reservoir to help it flow outward into the foam contact element. Thus, the foam contact element acts as an absorbent and porous pad. Additionally, the foam contact element, which may be made from any number of polymeric foam materials or woven or nonwoven materials including fabrics or synthetics, is preferably resilient so that it may have a collapsed low profile configuration suitable for delivery through the confined space of the nostrils and nasal cavity, and also have an expanded larger profile for maximum tissue contact. The foam contact element may be constrained in the low profile collapsed configuration with a sheath, cannula, or other constraining element (not illustrated), and it may expand once the sheath or constraining element is removed. In preferred embodiments, the foam contact element in the collapsed configuration has a cross-section less than or equal to a 6 mm diameter cylindrical shaft. Additionally, wetting of the foam contact element with the therapeutic agent may further facilitate expansion thereof
[0065] The embodiment of FIGS. 2A-2B has a cylindrical shaped body with a tapered nosecone. Any number of other geometries for the foam contact element are also possible. For example, FIGS. 3A-3E illustrate other exemplary embodiments of foam contact elements that can be used as a porous pad to deliver a therapeutic agent to the target tissue. Other aspects of the delivery device may generally take the same form as device 22 previously described above.
[0066] FIG. 3A illustrates a delivery device having an elongate shaft 24 with a foam contact element 30a adjacent a distal portion of the elongate shaft 24. The foam contact element 30a has a plurality of wings 42 extending therefrom. The wings 42 may be sized and shaped in order to accommodate various sizes and anatomies in the nasal cavity. The wings 42 may be fabricated from any of the materials previously discussed with reference to device 22 in FIGS. 2A-2B. A porous reservoir 34a similar to reservoir 34 in FIG. 2B may extend under each wing 42 in order to ensure even distribution of therapeutic agent to each wing 42. The wings 42 may also be collapsed for delivery, and expanded into engagement with target tissue.
[0067] FIG. 3B illustrates another exemplary embodiment of a delivery device that generally takes the same form as the device in FIG. 3A, with the major difference being that the foam contact element 30b on a distal portion of the elongate shaft 24 has a plurality of fingers 34b which extend distally from elongate shaft 24. In this embodiment, three fingers 34b form a pattern similar to a bird footprint. One of skill in the art will appreciate that the length, thickness, and number of fingers may be adjusted to fit the nasal cavity being treated. A porous reservoir 34b similar to the reservoirs previously described may be disposed in each finger 34b of the foam contact element 30b.
[0068] FIG. 3C illustrates yet another exemplary embodiment of a delivery device that generally take the same form as previous delivery devices discussed above, with the major difference being that the foam contact element 30c includes a looped element 46 extending distally from the elongate shaft 24. A porous reservoir 34c similar to those described above extends through the loop 46 so that the therapeutic agent is evenly distributed along the loop. The loop 46 may be retracted into the shaft 24 for delivery, or a constraining sheath (not shown) may be passed over the loop to compress it into the collapsed configuration for delivery into the nasal cavity. Upon reaching a desired target treatment site, the sheath may be retracted, or the loop 46 may be advanced from the shaft 24 so that the loop is unconstrained and expands into its fully expanded configuration to engage the tissue. The loop 46 may be a foam, a foam-wrapped structural element, or any of the other materials previously described above with reference to device 22 in FIGS. 2A-2B.
[0069] FIG. 3D illustrates an exemplary embodiment of a delivery device having valves. Other features of the device generally take the same form as the previous delivery devices described above. Elongate shaft 24 extends under the foam contact element 30d. A lumen 25d extends through shaft 24, and a plurality of ports 38d pass through a sidewall of the shaft 24 such that they are fluidly coupled to lumen 25d which when filled with a therapeutic agent such as botulinum toxin serves as a drug reservoir 34d. Valves 48 cover each port 38d and they are resiliently biased to close and rest against ports 38d thereby fluidly closing the ports 38d. However, when the reservoir is pressurized with a therapeutic agent, the valves 48 open up allowing the therapeutic agent to flow 50 and be discharged from the reservoir into the foam contact element 30d.
[0070] In still another exemplary embodiment, the foam contact element 30e may comprise a plurality of axially spaced apart bumps 52 which form fins along the elongate shaft 24. In this embodiment, four rows of fins are evenly spaced ninety degrees apart around the circumference of shaft 24. Each row is axially staggered relative to an adjacent row. The number of fins, number of rows, axial offset, circumferential offset, as well as other aspects of the fin arrangement may be varied according to the anatomy or other relative design criteria. Other aspects of the delivery device in FIG. 3E generally take the same form as those previously described above.
[0071] FIG. 4 illustrates another exemplary embodiment of a delivery device used to deliver a therapeutic agent such as a toxin like botulinum toxin to tissue. The delivery device includes an elongate central shaft 62 and having a lumen 70 extending therethrough. A plurality of fingers 64 extend radially outward from shaft 62. Each finger has a central channel that is fluidly coupled with lumen 70, and each finger 64 has one or more ports 68 through a sidewall that allow fluid to egress from the finger into a foam contact element 66. Thus, a therapeutic agent such as botulinum toxin may be introduced into lumen 70 and the lumen acts as a drug reservoir. The drug may then be discharged from lumen 70, into the fingers and out ports 68 until the therapeutic agent wets foam contact element 66. The fingers 64 preferably extend perpendicularly from shaft 62, however, the fingers may extend at any desired angle. In this embodiment, four rows of fingers are distributed around the circumference of shaft 62, each row spaced ninety degrees apart from one another. Additionally, adjacent rows are axially offset from one another, or staggered. The distal end of shaft 62 may also include a finger with ports 68 and foam contact element 66. Thus, the delivery device in FIG. 4 may appear to be similar to the pattern used for bottle brushes. One of skill in the art will appreciate that the number of rows of fingers, axial spacing between adjacent rows, as well as circumferential spacing of rows of fingers, and other aspects of geometry may be modified depending on usage.
[0072] FIGS. 5A-5F illustrate how a single sheet of laminated material may be used to form a drug reservoir and foam contact element of a delivery device similar to those described above. In FIG. 5A, a single sheet of material, comprising a laminate of a support structure 82 such as a wire frame or other substrate material laminated to an inner liner 88a having a plurality of ports 88 extending through the liner wall, and a foam material or other porous pad 86 laminated to the liner. The laminated sheet of material may then be formed into various configurations to form the drug reservoir portion and tissue engaging portion of a drug delivery device. For example, in FIG. 5A, the laminated sheet of material may be folded over itself with the edges sealed to form a lumen 84 which holds the therapeutic agent and thus functions as a drug reservoir 89. The proximal end of the folded laminated sheet may then be coupled to an elongated shaft similar to those discussed above. Thus, in FIG. 5A, the drug is introduced via a lumen in an elongated shaft into lumen 84 where it is stored in reservoir 89. The device may be advanced through a nostril into the nasal cavity, and the drug flows 90 through ports 88 into foam contact element 86. The drug wets the foam contact element 86, and then the drug is delivered to the nasopharyngeal mucosa tissue.
[0073] FIG. 5B illustrates another exemplary embodiment where the laminated sheet 94 similar to that in FIG. 5A is rolled up on itself like a cinnamon roll and coupled to an elongate shaft 92 to form the drug delivery device. FIG. 5C illustrates the laminated sheet 96 in a flat unrolled configuration. It may include structural support features 98 such as ribs, support wires, or other structural elements that help it to form cylindrical rolls such as in FIG. 5D. FIG. 5E illustrates another possible configuration that may be formed by rolling the laminated sheet 96. It includes lower profile proximal and distal ends 106 which may be attached to an elongate shaft (not illustrated), as well as proximal and distal enlarged profile collars and a smaller middle profile region 110. Thus different portions of the length of the device can expand to different diameters based on the surrounding anatomy. This configuration may be useful for accommodating and treating various anatomical areas of the nasal cavity.
[0074] FIG. 5F illustrates still another exemplary embodiment of how the laminated sheet may be formed into a drug delivery device. An elongate shaft or push wire 110 may be used to wrap the laminated sheet 112 around the shaft to form a helix or corkscrew pattern. Rotation and/or linear advancement of the push wire relative to the laminated sheet 112 may expand or contract the helix, thereby increasing or decreasing its profile. This may be advantageous since it allows the device to be delivered into the nasal cavity in a low profile configuration, and then it may be easily expanded to engage the nasopharyngeal mucosa tissue.
[0075] FIG. 6 illustrates an alternative embodiment of a foam contact element or porous pad material that may be used with any of the foam contact element embodiments described herein. The foam contact element 212 may be coupled to an elongate shaft as previously described above, or it may be coupled to other delivery instruments, or used alone. The foam contact element 212 includes an outer foam layer 202 that surrounds the porous reservoir 208 having a central lumen 214 for holding a therapeutic agent, and pores 216 that allow the therapeutic agent to be released therefrom. A layer of hydrophobic foam 206 is disposed between the outer foam layer 202 and the porous reservoir 208. Channels 204 are disposed in the hydrophobic foam layer 206 and they help direct the therapeutic agent to the outer foam layer 202. This configuration provides a large outer surface area for contact with tissue for delivering the therapeutic agent, while minimizing the volume of therapeutic agent that is absorbed into the foam due to the hydrophobic layer.
[0076] FIGS. 7A-7B illustrate an exemplary method of delivering a therapeutic agent to the nasal cavity with a foam contact element. The delivery device 230 includes an elongate shaft 240 having a foam contact element 234 similar to those described above, adjacent a distal portion of the elongate shaft 240. Disposed under the foam contact element 240 lies a porous reservoir 236 similar to those previously described above. A connector 238 coupled to the proximal end of the elongate shaft 240 allows a syringe or other device to be fluidly coupled to the elongate shaft and the porous reservoir. An optional sheath 232 may be slidably disposed over the foam contact element 234 to constrain the foam contact element into a collapsed configuration that facilitates insertion into the nasal cavity via a nostril. In FIG. 7B, the delivery device 230 has been advanced into the nasal cavity via a nostril, and sheath 232 has been proximally retracted, thereby allowing the foam contact element to expand into engagement with nasopharyngeal mucosa tissue. The shape of the foam contact element may be varied as discussed above in order to engage specific regions of the nasal cavity. Possible targets include any of the turbinates as well as the nasal septum, uncinate process, inferior, superior, and lateral extents of the nasopharynx. The therapeutic agent, such as botulinum toxin may then be released from the reservoir 236 into the foam contact element 234 and delivered to the tissue. The reservoir may be pre-filled, or a syringe or other device may also be coupled to connector 238 to deliver the therapeutic agent to the reservoir and/or to pressurize the reservoir to facilitate its delivery. Wetting of the foam contact element may further result in expansion of the foam contact element so that it contacts an even larger surface area. The size of the foam contact element may be selected depending on the size of the nasal cavity, or the size of the target area to treat. In alternative embodiments, multiple delivery devices may be used to treat a larger area.
[0077] The delivery device in FIGS. 7A-7B may be used to treat symptoms associated with rhinitis. A toxin may be used such as botulinum toxin that reduces or inhibits mucus production. In an exemplary embodiment, 50 U of botulinum toxin A may be hydrated with saline per manufacturer's recommendations to a concentration of 25 U/ml. Each side of the nose may then be treated with 1 ml of the therapeutic agent, resulting in delivery of 25 U to the tissue. Dosage may vary, and can be as little as 10 U or as large as 200 U. Concentration can vary and may be as great as 100 U/ml. In preferred embodiments the delivery device is configured to deliver the full dosage of the therapeutic agent to the tissue within 30 minutes, however depending on concentration of the substance, it may be preferable to deliver more slowly (e.g. over 60 minutes), or more rapidly (e.g. in one to two minutes). Delivery may also occur over a time period somewhere in between these slower and faster time periods. Also, in this as well as other embodiments, the therapeutic agent may be chemically modified to help with absorption through the skin, such as by forming salts of the drug having increased solubility, or by forming esters of the drug that help increase permeability of the mucus membranes. The use of surfactants may also help modify mucosa permeability. Drugs may also be modified to have increased hydrogen bonding thereby allowing increased mucoadhesiveness to prevent the therapeutic agent from migrating to undesirable areas. Other modifications to the therapeutic agent include the use of bioadhesive polymers such as polyacrylic acid to form a gel-like layer that enhances contact between the drug and the tissue, resulting in increased residence time of the agent. Microspheres, nanoparticles, and liposomes may also be used to help with mucoadhesiveness.
[0078] FIGS. 8A-8B illustrate another exemplary embodiment of delivering a therapeutic agent to the nasal cavity. The delivery device includes a plurality of flexible shafts 254, each having a foam contact element 256 disposed on a distal portion of the flexible shaft 254. A porous reservoir (not illustrated) similar to those previously described is disposed under the foam contact element. An outer sheath 252 is slidably disposed over the plurality of shafts 254, and the sheath 252 may partially cover the shafts 254 or entirely cover the shafts 254 and foam contact elements 256. Thus sheath 252 helps constrain the shafts 254 into a lower profile for ease of insertion into the nasal cavity. In FIG. 8B, the delivery device has been advanced into the nasal cavity via a nostril. The sheath 252 has been retracted relative to the plurality of flexible shafts 254 allowing the foam contact elements 256 to fan out and contact a larger area of tissue. The therapeutic agent may then be discharged from the porous reservoir into to the foam and to the tissue, as described previously. Use of multiple flexible shafts and contact elements allow the device to reach smaller, harder to reach areas within the nasal cavity, as well as to more easily navigate around obstructions or through narrow gaps. A delivery device may be used in each side of the nose, and multiple delivery devices may be used on a single side.
[0079] FIGS. 9A-9B illustrate still another exemplary embodiment of a method for delivering a therapeutic agent to the nasal cavity. A porous reservoir (not illustrated, but similar to that previously described above) may include a small diameter flexible tube covered with foam or another expandable and absorbable pad of material. Pores in the reservoir allow a therapeutic agent to be released therefrom into the foam cover for delivery to the tissue. The foam covered flexible tube 280 may be loaded into a syringe 276 for advancement through a nostril into the nasal cavity as seen in FIG. 9A. Once the syringe is advanced into the nasal cavity, the syringe plunger may be actuated and the foam covered flexible tube 280 is pushed out of the syringe into the nasal cavity as seen in FIG. 9B. Once unconstrained by the syringe, the foam expands to fill the nasal cavity. A string 278 is coupled to the foam covered flexible tube, and a free end of the string 278 remains outside of the nostril. The free end of the string may be pulled in order to remove the foam covered flexible tube. Multiple foam covered tubes may be inserted into the nasal cavity in order to deliver the therapeutic agent to a larger surface area.
[0080] Additional Delivery Device Embodiments
[0081] In addition to the embodiments previously described, other exemplary embodiments are possible. For example, the drug delivery device may include looped elements for delivering the therapeutic agent, a pressurized drug reservoir, porous balloons, retractable needles, patches, and paint brush-like embodiments.
[0082] FIG. 10 illustrates a delivery device having a plurality of looped distal elements 302 coupled to shaft 304. A connector 306 such as a Luer connector allows a syringe or other device to be fluidly coupled to the device to pre-fill the device with the therapeutic agent, or to fill and deliver the drug during use. A lumen in each loop forms a drug reservoir similar to those previously described above. Each loop may have a foam contact element disposed thereover, or as illustrated, the loops may be foamless. Each loop has a plurality of pores (not illustrated) to allow the therapeutic agent to be released therefrom. An optional stiffening member (not illustrated) such as a wire may be disposed in each loop in order to help maintain shape and patency of the loop. In alternative embodiments, the drug reservoir may include an inflatable inner chamber that can help push the outer surface of the loops against the target tissue, and that will help push the therapeutic agent out of the reservoir. FIG. 11 shows a cross-section of a porous drug reservoir 310 with an inflatable inner chamber 312 for facilitating release of the therapeutic agent 314 through the pores of the reservoir. In addition to loops, the delivery device may have a single porous balloon, an array of balloon fingers, or corkscrew-like elements for delivering drug to the target tissue.
[0083] FIGS. 12A-12B illustrate an exemplary method of advancing a drug delivery device having looped elements into the nasal cavity. The drug delivery device in FIGS. 12A-12B only has a single looped element, but one of skill in the art will appreciate that it may also have multiple looped elements, similar to the embodiment in FIG. 10. The loop element 344 having the porous drug reservoir is retracted into and constrained by sheath 342 for minimum profile that can be advanced into the nasal cavity via a nostril. Once the device has been introduced into the nasal cavity, the sheath may be retracted (or the loop may be advanced) so that the loop becomes unconstrained and it expands into its full shape as seen in FIG. 12B. The therapeutic agent may then be delivered from the loop into the target tissue. Once the drug has been delivered, the loop may be resheathed, and the device removed from the patient's nose.
[0084] FIGS. 13A-13C illustrate use of a porous balloon to deliver a therapeutic agent to the nasal cavity. A catheter 372 includes an elongate flexible shaft 374 having a porous balloon 376 disposed at the distal end of the shaft 374. The balloon 376 includes a plurality of micropores 382 in the balloon wall which allow a therapeutic agent to be delivered therefrom when the balloon is pressurized. An optional foam contact element (not illustrated) similar to those previously disclosed above may be disposed over the porous balloon 376. A connector 378, such as a Luer connector is coupled to a proximal end of the elongate shaft 374 in order to allow a syringe or other component to be fluidly coupled to the catheter 372. In FIG. 13B, the catheter 372 is advanced toward the patient's nasal cavity, and the distal tip is inserted into the nostril. An optional valve member 380 may be coupled to connector 378 to prevent backflow of the therapeutic agent. In FIG. 13C, the balloon 376 is advanced into a desired portion of the nasal cavity, and a syringe or other reservoir device (not illustrated) is coupled to valve 380, and the therapeutic agent is then transferred from the syringe or reservoir to the porous balloon 376. As the balloon inflates, the therapeutic agent passes through the micropores 382 in the balloon wall, and the therapeutic agent is then delivered to the desired target tissue. In one embodiment, the volume of the balloon is about 0.3 ml, and it is filled multiple times during placement and use in order to deliver 1 ml of drug solution (such as a toxin like botulinum toxin) to one side, or both sides of the nose. Placement of the balloon may be adjusted between fills so that the drug is delivered to different areas of the anatomy. Also, in some embodiments, multiple balloons may be inserted into the nasal cavity for simultaneous delivery of a larger quantity of drug to a larger surface area. A final filling of the balloon with water or a saline solution may be used to flush the remaining drug solution out of the balloon, and the device may be removed from the patient's nose.
[0085] In an alternative embodiment as seen in FIG. 13D, the delivery system 382 includes an elongate shaft 384 having inner balloon 386 and an outer balloon 388 or outer spongy layer 388 disposed near the distal portion of the elongate shaft 384. The outer balloon 388 may be disposed over the inner balloon 386 or the spongy outer layer 388 may be disposed on top of the inner balloon 386. In this embodiment, the inner balloon 386 does not act as the drug reservoir and is not inflated for the purpose of pushing drug out of the outer balloon or spongy layer. Instead, the space 387 of the inner balloon 386 is inflated with a fluid such as a gas (e.g. air or nitrogen) or saline in order to reduce the remaining volume of the nasal cavity. Thus, the small remaining volume of the nasal cavity can easily be filled with the inflated outer balloon or spongy layer 388. Therefore the expanded volume of the inner balloon is preferably greater than the expanded volume of the outer balloon or spongy layer. Because the volume of the nasal cavity has been reduced, the therapeutic agent may be delivered in a higher concentration and lower volume and it will be more precisely delivered to a smaller volume. Using a higher concentration achieves a better therapeutic effect with a smaller and less dangerous amount of the drug required. The therapeutic agent may be a toxin such as those described in this specification or it may be other drugs including non-toxins. The therapeutic agent may be delivered via a lumen in shaft 384 to the space 389 between the inner and outer balloons and the outer balloon may be porous to allow the drug to be delivered to the tissue, or the drug may be delivered via a lumen in the shaft 384 to exit ports (not illustrated) on the shaft 384. In other embodiments, the drug may be held in the spongy layer 388 and delivered to the tissue upon contact thereagainst.
[0086] FIGS. 14A-14C illustrate an exemplary embodiment of a drug delivery device having a tissue penetrating needle that may be used to deliver a therapeutic agent to nasal cavity. The delivery device includes an outer syringe barrel 404 and an inner syringe barrel 408. In preferred embodiments, the inner syringe barrel is a 3 ml syringe holding a 1 ml volume of therapeutic agent, and the outer syringe barrel is a 5 ml syringe, although this is not intended to be limiting. An elongate flexible sleeve 402 is coupled to the distal end of the outer syringe barrel 404, and a tissue penetrating needle 406 is coupled to the distal end of the inner syringe barrel 408. The inner syringe barrel 408 is slidably disposed in the outer syringe barrel 404. The inner syringe barrel serves as a drug reservoir 412 for holding a therapeutic agent. Actuation of plunger 410 by distal advancement forces the therapeutic agent out of the reservoir 412 and through needle 406. In preferred embodiments, the inner syringe barrel 408 is disposed in a retracted position relative to the outer syringe barrel 404 such that needle 406 remains in outer syringe barrel 404, unexposed, as illustrated in FIG. 14A. Distal advancement of the inner syringe barrel relative to the outer syringe barrel advances the needle distally through sleeve 402 until the distal tissue piercing tip of the needle 406 is exposed, as seen in FIG. 14B. An optional spring 414 may be disposed between a distal end of the inner syringe barrel and a distal portion of the outer syringe barrel. This spring 414 is biased to retract the inner syringe barrel away from the outer syringe barrel, thus the tissue piercing needle will be biased to remain unexposed in the outer syringe barrel. Once the needle is exposed, the plunger 410 may be distally advanced to force the therapeutic agent out of the reservoir 412 and out the needle 406 into the target tissue.
[0087] The device in FIGS. 14A-14C may be used to inject a therapeutic agent such as a toxin like botulinum toxin into specific regions of tissue such as the turbinates. One injection, or multiple injections may be used. Also, because the needle is covered during initial delivery, this may help reduce patient anxiety associated with seeing a needle. Also, the sleeve is flexible, and therefore can navigate the nasal anatomy easier than a more rigid needle. And once the device has been positioned in a desired area of the nasal cavity, the sleeve will act as a guide to help the needle smoothly advance through the anatomy to the target. This may help reduce patient discomfort and also reduce trauma to the tissue. Also, the amount of needle that is exposed from the sleeve may be controlled or fixed, thereby controlling the penetration depth which helps to prevent overly deep delivery of the therapeutic agent. In some embodiments, an indicator mechanism such as tactile, visual, or auditory mechanisms allow the operator to know when the needle is exposed and how far it is exposed, and how much drug is delivered. An anesthetic such as Lidocaine may also be used to help alleviate patient discomfort. The Lidocaine may be injected separately, or it may be mixed with some compatible therapeutic agents and injected simultaneously.
[0088] FIGS. 15A-15B illustrate exemplary usage of the device in FIGS. 14A-14C. The sleeve 402 is advanced through a nostril into the nasal cavity as seen in FIG. 15A. Advancement of the sleeve is performed while the needle is retracted into the outer syringe barrel 404. Once the sleeve has been delivered to the target treatment site, the needle 406 is advanced distally so that it is exposed from the sleeve 402 as illustrated in FIG. 15B. The needle may then be advanced into the tissue and the therapeutic agent delivered therefrom.
[0089] FIGS. 16A-16C illustrate the use of a patch to delivery a therapeutic agent to a nasal cavity. The patch 422 may be similar to transdermal drug delivery patches, and it may include a porous reservoir for holding and delivering the therapeutic agent 428, and that is joined to a flexible adhesive structure for temporary attachment to the target tissue, such as a nasal turbinate 420. The adhesive areas 424 of the patch 422 may be arranged to ensure that the patch will stick to the tissue (e.g. mucosa tissue) with or without requiring removal of mucosa prior to application of the patch. Additionally, the adhesive areas 424 may be arranged in order to work in concert with the cilial transport mechanism of the underlying mucosa, as indicated by arrow 426. Cilial transport will be temporarily interrupted in the adhesive locations yet continue to function in other areas. This can act to slow the cilial transport of the drug solution and increase its residence time, or steer the drug solution away to affect a broader area. The patch 430 may be flexible such that it can be folded and the adhesive side 432 affixed to the anterior surface of a turbinate 420 as seen in FIG. 16B, or the patch 430 may be folded in the opposite direction to be placed in the meatus between a turbinate 420 and the nasal septum or another turbinate as seen in FIG. 16C.
[0090] Therapeutic agents such as toxins like botulinum toxin may also be spayed on or painted on to a target tissue. Spray applicators may use pressurized gas to spray the drug onto the tissue. Droplet size, viscosity may be controlled, and a broad area may be easily treated with the therapeutic agent. High pressure spraying may also be used to help ensure that the therapeutic agent penetrates the mucus blanket covering the mucosa. In other embodiments, lower pressure may be used to spray a more viscous solution of the therapeutic agent onto the target tissue in order to increase its residence time for greater drug penetration into the tissue. While spray methods are promising, in certain situations, the sprays can be hard to control which is undesirable when delivering a toxin. Additional controls may be implemented to help ensure proper delivery of the toxin. For example, delivery may be coordinated with the patient's breathing such that drug delivery only occurs when the patient exhales. Exhalation produces a strong airflow out of the lungs and closes the soft palate to seal the nasal cavity from the mouth and inferior pharynx. This prevents toxins from entering the lungs. Additionally, multiple smaller doses may be administered in order to limit the danger of one large does. Also, viscosity and droplet size may be controlled to increase residence time and help prevent aspiration into unwanted areas.
[0091] Paint applicators may also be used to deliver a therapeutic agent. They allow control over drug application, and also allow broad coverage. FIG. 17 illustrates an exemplary embodiment of a paint on applicator. The applicator is similar to a felt tipped pen. It includes a drug reservoir 452 and a wicking tip 454. Actuation of pressure mechanism 456 moves plunger 458 thereby forcing drug out of the reservoir. The wicking tip 454 may be used to paint on the therapeutic agent to a desired target tissue. For example, in FIG. 18, three regions 462 are initially painted on the turbinate 460 using the device of FIG. 17. Cilial transport 464 causes the drug to flow thereby further spreading the drug in the nasal cavity.
[0092] While the above is a complete description of the preferred embodiments of the invention, various alternatives, modifications, and equivalents may be used. Therefore, the above description should not be taken as limiting the scope of the invention which is defined by the appended claims.
