Extracellular vesicle-mediated delivery of a therapeutic agent to the brain

Abstract

Described herein are shockwave catheters for delivering active agents of a drug to the CNS via a body lumen or cavity, such as a sinus cavity, that can bypass the blood-brain barrier (BBB), and methods of use thereof. The catheters described herein can be advanced through an intranasal passageway to the nasal cavity such that at least a portion of the housing is disposed in the nasal cavity. The housing can be coated with a drug coating. Methods can include filling the housing with a conductive fluid. At least one shockwave can be generated at a shockwave emitter of the catheter disposed within the housing. The at least one shockwave can cause a therapeutically effective amount of an active agent of the drug coating to be delivered to the CNS via tissue of the nasal cavity, in turn treating a central nervous system disease.

Description

Cross-reference to related applications

[0001] This application claims priority and benefit to U.S. non-provisional patent application No. 18 / 620,248, filed March 28, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure generally relates to the field of medical devices and methods, and more specifically to the use of intravascular lithotripsy devices and methods for extravascular drug delivery. Background Technology

[0003] Recently, techniques and treatments for intravascular lithotripsy (IVL) have been developed, which is an interventional procedure used to improve calcified plaques in diseased arteries. The mechanism of plaque improvement is achieved through the use of a catheter with one or more acoustic shock wave generating sources located within a fluid to generate acoustic shock waves that improve calcified plaques. IVL devices vary in design regarding the energy source used to generate the acoustic shock waves, with two exemplary energy sources being electrohydraulic generation and laser generation.

[0004] For electrohydraulic generation of acoustic shock waves, a conductive solution (e.g., physiological saline) can be contained within a housing surrounding the electrodes or flushed through a tube surrounding the electrodes. Improvement of calcified plaques is achieved by generating acoustic shock waves within the catheter through transelectrode discharge. The energy from this discharge enters the surrounding fluid faster than the speed of sound, thus generating acoustic shock waves. Furthermore, the energy generates one or more rapidly expanding and collapsing vapor bubbles, which generate secondary shock waves. These shock waves propagate radially outward and improve calcified plaques within the blood vessel. For laser-generated acoustic shock waves, a laser pulse is transmitted into the fluid within the catheter and absorbed by the fluid. This absorption process rapidly heats the fluid and causes it to evaporate, thereby generating rapidly expanding and collapsing vapor bubbles and acoustic shock waves that propagate outward and improve calcified plaques. If a fluid exhibiting strong absorption at the laser wavelength employed is selected, the intensity of the acoustic shock waves is higher. These examples of IVL devices are not intended to comprehensively list all potential energy sources for generating IVL shock waves.

[0005] More specifically, catheters for delivering IVL therapy have been developed that include electrode pairs for electrohydraulically generating shock waves within an angioplasty balloon. In these devices, the catheter is advanced via a guidewire through the patient's vascular system until it is positioned proximal to and / or aligned with a calcified plaque lesion in a body cavity. The balloon is then inflated using a conductive fluid (using a relatively low pressure of 2 atm to 4 atm), causing the balloon to expand to contact the lesion, but the inflation pressure is insufficient to substantially displace the lesion. Voltage pulses can then be applied across the electrodes in the electrode pair to generate an acoustic shock wave that propagates through the wall of the angioplasty balloon into the lesion. Alternative devices for delivering IVL therapy can be housed within a closed volume other than the angioplasty balloon, such as a cap, a variable compliance balloon, or other housing.

[0006] Treatment of central nervous system disorders (CNSDs), such as Parkinson's disease, Alzheimer's disease, epilepsy, and psychiatric disorders, remains an unresolved challenge across various fields due to several confounding factors that limit drug uptake in the central nervous system (CNS). Notably, several commonly used drugs exhibit difficulty in bypassing the blood-brain barrier (BBB), and existing therapeutic strategies designed to enhance BBB delivery cause adverse peripheral toxicities at the drug delivery site. Other factors limiting drug uptake in the CNS include first-pass metabolism, slow absorption, rapid elimination, and plasma protein binding. Non-invasive therapies, including deep brain stimulation (DBS), spinal cord stimulation (SNS), and oral medications, have been investigated in an attempt to bypass the BBB and increase drug uptake in the CNS, but with limited success. Furthermore, surgical treatment for CNSD is often intolerable for patients exhibiting comorbidities and limited life expectancy.

[0007] A potential alternative CNS pathway has been identified in the sinus cavities. The sinus cavities (including the sinuses, nasal cavity, and passageways between them) contain accessible nerves (e.g., olfactory nerves) within the vascular system connecting to the brain, thus presenting a promising pathway for drug molecules to be absorbed into the brain without crossing the BBB. Gel-based drug delivery systems and nasal sprays have been investigated as potential drug delivery routes that deliver drugs to the brain via intranasal delivery. Gel-based drug delivery systems are highly compatible with a range of drugs, exhibit good solubility, and can be used at high drug concentrations at the desired delivery site, while having reduced systemic side effects. Gels also exhibit ideal biocompatibility, are biodegradable, and demonstrate sustained drug release over extended periods, thereby enhancing patient compliance. However, the degradation of gels is often too rapid (e.g., uncrosslinked gels) or too slow (e.g., crosslinked gels), thus making these systems currently unsuitable for nasal drug delivery. Furthermore, for nasal spray systems, anatomical differences in patients' olfactory regions have been shown to be a significant obstacle to the local delivery of drugs using these mechanisms. Therefore, intranasal drug delivery for the treatment of CNSD is clearly promising, but a robust and efficient drug delivery system that can overcome the aforementioned existing problems for extra-blood-brain barrier drug delivery is still needed. Summary of the Invention

[0008] This document discloses systems, methods, and apparatus for using shockwaves to bypass the blood-brain barrier (BBB) ​​and deliver drugs to the central nervous system (CNS) for the treatment of central nervous system disorders (CNSD). The sinus cavities (containing nerves closely connected to the brain) are an example of anatomical regions through which the BBB can be bypassed for drug delivery to the CNS. A catheter configured to generate shockwaves can be inserted into a sinus cavity (such as the nasal cavity) and controlled to generate shockwaves that deliver a therapeutically effective amount of drug to the CNS via the tissues of the nasal cavity without damaging the tissues of the nasal cavity. The drug can be coated on the outer surface of a conduit housing surrounding one or more shockwave emitters of the catheter. The shockwaves generated by the one or more shockwave emitters impinge on the inner surface of the conduit housing, causing the drug coated on the outer surface of the conduit to be ejected from the outer surface and delivered to the tissues of the nasal cavity. Because drugs delivered to nasal tissues bypass the blood-brain barrier (BBB), and the use of shockwaves enhances drug delivery, drug uptake in the CNS is improved compared to existing drug delivery methods such as oral medications and nasal sprays. Therefore, systems, devices, and methods based on the principles described herein can improve the treatment of CNSD diseases such as Parkinson's disease, Alzheimer's disease, and epilepsy.

[0009] In some aspects, a method for treating a central nervous system disease via the nasal cavity is provided, the method comprising: advancing a distal portion of a catheter through an intranasal passage to the nasal cavity, such that the housing of the catheter is at least partially positioned within the nasal cavity, the distal portion of the catheter including at least one shock wave emitter surrounded by the housing, at least a portion of the surface of the housing being coated with a drug coating; filling the housing to inflate the housing within the nasal cavity; and generating at least one shock wave via the at least one shock wave emitter, the at least one shock wave causing a therapeutically effective amount of active agent of the drug coating to be delivered via nasal tissue from the surface of the housing to the central nervous system (CNS).

[0010] In some aspects, the method includes generating a series of shock waves at frequencies between 1 Hz and 5 Hz. In some aspects, generating at least one shock wave includes generating at least one bubble within a housing, the at least one bubble impinging on an inner surface of the housing to eject at least a portion of a drug coating from the surface of the housing. In some aspects, the method includes delivering one or more voltage pulses to at least one shock wave emitter to generate at least one shock wave. In some aspects, the one or more voltage pulses include voltages between 1 kV and 10 kV. In some aspects, the method includes delivering one or more laser pulses to at least one shock wave emitter to generate at least one shock wave. In some aspects, filling the housing includes pressurizing the housing to a pressure less than 10 atm. In some aspects, prior to generating at least one shock wave, the method includes delivering an irrigation solution into at least one of an intranasal passage and a nasal cavity to clean the intranasal passage and at least one of the nasal cavity. In some aspects, the irrigation solution includes saline and / or a drug. In some aspects, the intranasal passage includes the frontal sinus ostium, and the nasal cavity includes the frontal sinus. In some aspects, generating at least one shock wave causes the active agent of the drug coating to be delivered to the CNS via the olfactory nerve. In some aspects, advancing the distal portion of the catheter through an intranasal passage includes advancing the catheter via a guidewire. In some aspects, at least a portion of the shell contacts the tissue of the nasal cavity when at least one shock wave is generated. In some aspects, at least a portion of the shell is spaced apart from the tissue of the nasal cavity when at least one shock wave is generated. In some aspects, the drug coating comprises a crystalline form, an amorphous form, or a combination thereof. In some aspects, the drug coating comprises a plurality of microcapsules containing an active agent. In some aspects, the plurality of microcapsules comprises a plurality of microspheres and / or a plurality of microcapsules having a diameter between 0.5 micrometers and 500 micrometers.

[0011] In some aspects, an apparatus for intranasal drug delivery is provided, the apparatus comprising: an elongated tube; at least one shock wave emitter configured to generate at least one shock wave; and a housing sealed to a distal portion of the elongated tube and surrounding the at least one shock wave emitter, the housing being capable of being filled with a conductive fluid, and at least a portion of the surface of the housing being coated with a drug coating, wherein the at least one shock wave is configured to deliver a therapeutically effective amount of active agent of the drug coating from the surface of the housing to the central nervous system (CNS) via nasal tissue.

[0012] In some aspects, at least one shock wave emitter is configured to generate at least one shock wave, the at least one shock wave being configured to deliver the active agent of the drug coating to the CNS via the olfactory nerve. In some aspects, at least one shock wave emitter is configured to generate at least one bubble within the housing, the at least one bubble impinging on the inner surface of the housing to spray at least a portion of the drug coating from the surface of the housing. In some aspects, at least one shock wave emitter is configured to generate a series of shock waves at frequencies between 1 Hz and 5 Hz. In some aspects, the housing is configured to be pressurized to a pressure of less than 10 atm. In some aspects, the elongated tube is configured to deliver an irrigation solution to at least one of the intranasal passage and the nasal cavity to clean at least one of the intranasal passage and the nasal cavity. In some aspects, the device includes a guidewire lumen disposed within the elongated tube and configured to receive a guidewire to guide the housing through the intranasal passage and to the nasal cavity. In some aspects, the elongated tube includes a guidewire lumen configured to receive a guidewire and an irrigation lumen configured to deliver an irrigation solution to at least one of the intranasal passage and the nasal cavity. In some aspects, the guidewire lumen is disposed within a flushing lumen in an elongated tube. In some aspects, the flushing lumen extends through the length of the housing to a fluid outlet at the distal end of the housing. In some aspects, the elongated tube is configured to be coupled to a syringe to fill the housing with a conductive fluid. In some aspects, the housing is capable of being filled with an X-ray contrast agent for observation of the housing. In some aspects, the housing comprises at least one of an elliptical balloon, a spherical balloon, and a hemispherical balloon. In some aspects, at least 20% of the surface of the housing is coated with a drug coating. In some aspects, the entire surface of the housing is coated with a drug coating. In some aspects, the drug coating comprises a crystalline form, an amorphous form, or a combination thereof. In some aspects, the drug coating comprises a plurality of microcapsules containing an active agent. In some aspects, the plurality of microcapsules comprises a plurality of microspheres and / or a plurality of microcapsules having a diameter between 0.5 micrometers and 500 micrometers.

[0013] In some aspects, a system for intranasal drug delivery is provided, the system comprising: an apparatus according to any of the foregoing examples; and a pulse generator coupled to at least one shock wave emitter and configured to generate energy pulses such that the at least one shock wave emitter generates at least one shock wave. In some aspects, the pulse generator is configured to generate energy pulses such that the at least one shock wave emitter generates a series of shock waves at a frequency between 1 Hz and 5 Hz. In some aspects, the pulse generator is configured to generate one or more voltage pulses such that the at least one shock wave emitter generates a series of shock waves. In some aspects, the one or more voltage pulses comprise voltages between 1 kV and 10 kV. In some aspects, the pulse generator is configured to generate one or more laser pulses such that the at least one shock wave emitter generates at least one shock wave. In some aspects, the system includes an endoscope disposed adjacent to the apparatus and including an imaging sensor located at a distal portion of the endoscope, the imaging sensor being configured to capture images of at least one of the intranasal passage and the nasal cavity. Attached Figure Description

[0014] The invention will now be described by way of example only with reference to the accompanying drawings, in which:

[0015] Figure 1A An exemplary shock wave duct distal portion is illustrated according to one or more aspects of this disclosure.

[0016] Figure 1B An exemplary shock wave duct proximal portion according to one or more aspects of this disclosure is illustrated.

[0017] Figure 2A A side view of the distal portion of an exemplary shock waveguide in a deflated state, according to one or more aspects of this disclosure, is illustrated.

[0018] Figure 2B A side view of the distal portion of an exemplary shock wave duct in an inflated state, which emits shock waves by a shock wave emitter according to one or more aspects of this disclosure, is illustrated.

[0019] Figure 2C A side view of the distal portion of an exemplary shock waveguide, in an inflated state and spraying a drug from the surface of a housing, is illustrated according to one or more aspects of this disclosure.

[0020] Figure 3 A cross-sectional view of an exemplary shock wave duct according to one or more aspects of this disclosure is illustrated.

[0021] Figure 4 Exemplary endoscopic devices for use with the shock wave catheter described herein, according to one or more aspects of this disclosure, are illustrated.

[0022] Figure 5A A sagittal section of a sinus cavity according to one or more aspects of this disclosure is illustrated, wherein a shock wave catheter is disposed in the nasal cavity.

[0023] Figure 5B Another sagittal section of a sinus cavity according to one or more aspects of this disclosure is illustrated, wherein a shock wave catheter is disposed in the sinus cavity.

[0024] Figure 6 Exemplary methods for treating central nervous system disorders (CNSD) via the nasal cavity are illustrated according to one or more aspects of this disclosure.

[0025] Figure 7A An exemplary shockwave catheter according to one or more aspects of this disclosure is illustrated for delivering saline solution to a vascular access to clear the vascular access.

[0026] Figure 7B An exemplary shock wave duct according to one or more aspects of this disclosure is illustrated, wherein the shock wave radiator emits a shock wave when the shock wave duct is not in contact with tissue to enable drug delivery through tissue.

[0027] Figure 7C An exemplary shock wave duct according to one or more aspects of this disclosure is illustrated, wherein the shock wave emitter emits a shock wave when the shock wave duct comes into contact with tissue to deliver a drug through the tissue. Detailed Implementation

[0028] The following description is intended to enable those skilled in the art to make and use the various embodiments and aspects disclosed herein. Descriptions of specific devices, components, techniques, and applications are provided by way of example only. Various modifications to the examples described herein will be apparent to those skilled in the art, and the general principles described herein can be applied to other examples and applications without departing from the spirit and scope of its various embodiments and aspects. Therefore, its various embodiments and aspects are not intended to be limited to the examples described and illustrated herein, but are consistent with the scope of the claims.

[0029] This document describes systems, methods, and apparatus for treating central nervous system disorders (CNSDs) by delivering medication to an anatomical region using shockwaves, the anatomical region enabling access to the central nervous system (CNS) by bypassing the blood-brain barrier (BBB). An exemplary anatomical region for bypassing the BBB is the sinus cavity, the tissue of which includes nerves enabling access to the CNS. A shockwave conduit for delivering medication to the CNS may include at least one shockwave emitter configured to generate a shockwave. A housing encloses the shockwave emitter and is coated with medication. The shockwave conduit may be advanced through an intranasal passage to the sinus cavity (e.g., nasal cavity, sinus cavity) to at least partially position the housing and shockwave emitter within the desired sinus cavity. The housing may be filled with a conductive fluid, and one or more voltage pulses may be applied to at least one shockwave emitter to generate a shockwave within the conductive fluid. The shockwave may propagate outward from at least one shockwave emitter, causing the medication coated on the housing to be removed from the surface of the housing and directed onto the tissue of the sinus cavity. A therapeutically effective amount of the active agent of a drug can be transported throughout the body to the nerves of the central nervous system (CNS), through which the active agent bypasses the body's blood-brain barrier (BBB) ​​and enters the CNS. Compared to alternative drug delivery mechanisms (e.g., oral medications, nasal sprays), shockwaves can deliver drugs at precisely targeted locations and allow the drug to penetrate deeper into the tissues of the sinuses, which can increase drug uptake in the CNS.

[0030] The blood-brain barrier (BBB) ​​is the protective barrier that separates the blood from structures of the central nervous system, including the brain, spinal cord, and eyes. While the description provided herein pertains to bypassing the BBB for drug delivery to the CNS primarily via the sinuses, alternative anatomical regions exist where the BBB is present and can be bypassed for drug delivery to the CNS. Although the barriers (such as the blood-spinal barrier and blood-eye barrier) vary at different anatomical locations, the term blood-brain barrier is used herein to refer collectively to these protective barriers within the central nervous system.

[0031] As used herein, the term "electrode" refers to a conductive element (typically made of metal) that receives current and subsequently releases it to another conductive element. In the context of this disclosure, electrodes are typically positioned relative to each other, such as in an arrangement of inner and outer electrodes. Thus, as used herein, the term "electrode pair" refers to two electrodes positioned adjacent to each other such that applying a sufficiently high voltage to the electrode pair will cause current to be transmitted across the gap between the two electrodes (also known as a "spark gap") (e.g., from the inner electrode to the outer electrode and vice versa; optionally, the power is transmitted through a conductive fluid or gas between them). Further information regarding the physical properties of shock wave generation and its control can be found in U.S. Patents 8,956,371, 8,728,091, 9,522,012, and 10,226,265, each of which is incorporated herein by reference in its entirety. In some contexts, one or more electrode pairs may also be referred to as an electrode assembly. In the context of this disclosure, the term "emitter" broadly refers to the region of the electrode assembly in which current is transmitted across the electrode pair, thereby generating a shock wave. The term "emitter strip" refers to a continuous or discontinuous strip of conductive material that can form one or more electrodes in one or more electrode pairs, thereby forming the location of one or more emitters.

[0032] In some embodiments, the shockwave catheter is a so-called "rapid-exchange" (Rx) catheter with an opening through which a guidewire is guided (e.g., through the middle portion of the central tube in the longitudinal direction). In other embodiments, the shockwave catheter may be an "integral guidewire" ("OTW") catheter, wherein a guidewire lumen is formed throughout the entire length of the catheter, and the guidewire is guided through the proximal end of the hub.

[0033] Although this article describes a shock wave device based on a high voltage applied to electrodes to generate shock waves, it should be understood that the shock wave device may additionally or alternatively include a laser and an optical fiber as a shock wave transmitter system, whereby the laser source delivers energy through the optical fiber and enters the fluid to form shock waves and / or cavitation bubbles.

[0034] In the following description of various implementation schemes, reference is made to the accompanying drawings, which illustrate specific implementation schemes that can be practiced. It should be understood that other implementation schemes and examples, and modifications, may be made without departing from the scope of this disclosure.

[0035] Furthermore, in the following description, it should be understood that, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the / described” used in the following description are intended to also include the plural forms. It should also be understood that, as used herein, the term “and / or” refers to and covers any and all possible combinations of one or more of the associated listed items. It should also be understood that, when used herein, the terms “comprising” and / or “including” specify the presence of the stated feature, integer, step, operation, element, component, and / or unit, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, units, and / or groups thereof. As provided herein, it should be understood that any disclosure describing a range of values ​​for dimensions or measurements (such as thickness, length, weight, time, frequency, temperature, voltage, current, angle, etc.) includes any numerical increments or gradients relative to the range stated for a given dimension or measurement.

[0036] Exemplary shockwave catheters that can be used for drug delivery, such as by configuring a drug coating on the housing (e.g., a balloon), are described in U.S. Patent Nos. 10,441,300, 11,517,338, and 9,180,280, each of which is incorporated herein by reference in its entirety. Shockwave catheters for treating sinusitis (such as those described in U.S. Provisional Patent Application No. 63 / 456,272, which is incorporated herein by reference in its entirety) can be configured for drug delivery, such as by a suitable drug coating. Shockwave catheters for drug delivery can be configured to direct shock waves in different directions. For example, a forward-biased shock wave catheter (such as the shock wave catheter described in U.S. Patent No. 10,966,737 and U.S. Publication No. 2019 / 0388110, both of which are incorporated herein by reference) guides a shock wave in a generally forward direction (e.g., from the distal end of the catheter toward the distal end) and can be configured for drug delivery according to the principles described herein, such as by coating the forward portion of the shock wave with a suitable drug coating. A shock wave catheter configured to generate constructive interference shock waves emitted from multiple locations (such as the shock wave catheter depicted in U.S. Publication No. 2023 / 0123003, the entire disclosure of which is incorporated herein by reference) can be configured for drug delivery, such as by a suitable drug coating. Shockwave catheters (such as those described in U.S. Patent Application No. 18 / 595,148, the entire contents of which are incorporated herein by reference) configured to deliver several high-pressure pulses in short bursts (i.e., operable in “burst mode”) can be configured for drug delivery, such as by means of a suitable drug coating. Shockwave catheters (such as those described in U.S. Patents Nos. 8,888,788 and 10,709,462 and U.S. Publication No. 2021 / 0085347, the entire contents of which are incorporated herein by reference) configured to include a low-profile array of electrode assemblies that reduces the catheter’s cross-section and allows for easier navigation of the catheter into narrow body cavities can be configured for drug delivery, such as by means of a suitable drug coating.

[0037] The following description, with reference to several accompanying figures, illustrates an exemplary shockwave catheter for treating central nervous system disorders (CNSDs) and its method of use. For example, throughout the text, references... Figures 1A to 1B , Figures 2A to 2C , Figure 3 and Figures 5A to 5B To describe an exemplary shock wave duct. About Figure 4 An exemplary endoscope that can be used with the shock wave catheter described herein is described. About Figure 6 The methods shown and Figures 7A to 7CThe figures provided illustrate an exemplary method for treating CNSD using the shockwave catheter provided herein.

[0038] Shockwave catheter for drug delivery to CNS

[0039] Figures 1A to 1B An exemplary shockwave catheter 100 is illustrated, which can be used to deliver drugs to the central nervous system (CNS) by bypassing the blood-brain barrier (BBB). For example, catheter 100 can be inserted into a sinus cavity for drug delivery to tissues within the sinus cavity, including a vascular system for access to the CNS. In some examples, in addition to or instead of delivering drugs to the CNS, catheter 100 can be used to deliver shockwaves to a target area of ​​the CNS for focused ultrasound therapy of that area. For example, catheter 100 can be used to deliver shockwaves to the brain, such as for focused ultrasound therapy of the cortical and / or subcortical regions of the brain. Figure 1A As shown, the distal portion 100a of the catheter 100 may include an elongated tube 102, at least one shock wave emitter 104, and a housing 106, the at least one shock wave emitter being configured to generate at least one shock wave, the housing being sealed to the distal portion of the elongated tube 102 and surrounding the at least one shock wave emitter 104. At least a portion of the outer surface of the housing 106 may be coated with a drug coating 110.

[0040] In the example shown, the conduit 100 includes two shock wave emitters 104. However, the conduit 100 may include any number of shock wave emitters, including a single shock wave emitter, more than two shock wave emitters, at least four shock wave emitters, etc. The conduit 100 may include at least two shock wave emitters 104 positioned close enough to each other that the shock waves generated by the shock wave emitters 104 constructively interfere with each other. In some embodiments, adjacent shock wave emitters may be spaced 4.0 mm or less apart.

[0041] At least one shock wave emitter 104 can be configured to generate a series of shock waves. For example, at least one shock wave emitter 104 can generate a series of shock waves based on a frequency or duty cycle (e.g., a frequency between about 1 Hz and 5 Hz). In some examples, at least one shock wave emitter 104 can be configured to generate one or more micro-pulse bursts that are generated rapidly and continuously (e.g., at frequencies between about 100 Hz and 10 kHz). A series of micro-pulse bursts can be generated based on the aforementioned frequency between about 1 Hz and 5 Hz. As described in more detail below, the frequency of the shock waves generated by at least one shock wave emitter 104 can be determined by a pulse generator 140 coupled to the shock wave emitter 104 (…). Figure 1B (As shown in the diagram) control. In some examples, at least one shock wave transmitter 104 can generate a series of shock waves at frequencies greater than or equal to about 1 Hz, 2 Hz, 3 Hz, or 4 Hz. In some examples, at least one shock wave transmitter 104 can generate a series of shock waves at frequencies less than or equal to about 2 Hz, 3 Hz, 4 Hz, or 5 Hz.

[0042] Advantageously, in some embodiments, the characteristics of the shock wave generated by at least one shock wave transmitter 104 are set or modulated (e.g., by controlling the pulse or micropulse algorithm, pulse width, and / or pulse amplitude) to ensure that the shock wave does not damage any adjacent cartilage or bone structures. For example, in the case of treatment within the sinus cavity, the maximum power delivered to at least one shock wave transmitter can be set to ensure that any pressure waves generated do not damage the bone of the nasal septum.

[0043] The housing 106 may be attached to the distal portion of the elongated tube 102 via an adhesive or other attachment means. The housing 106 may include at least one of an elliptical balloon, a spherical balloon, and a hemispherical balloon. The housing 106 may be able to be filled with a conductive fluid that enables the generation of a shock wave from an electric arc generated by the shock wave emitter 104. The conductive fluid may include water or saline solution. When a suitable voltage pulse is applied to the shock wave emitter 104, an electric arc can be formed in the conductive fluid within the housing 106. The formation of the arc can generate a shock wave propagating outward toward the housing 106. In some examples, the housing 106 may additionally or alternatively be filled with an X-ray contrast agent to facilitate observation of the housing 106.

[0044] When housing 106 is filled, housing 106 can be pressurized to a pressure less than about 10 atmospheres, such as less than about 5 atm. In some examples, housing 106 is pressurized to a pressure sufficient to ensure that at least a portion of housing 106 is juxtaposed with nearby body tissue (e.g., sinus cavities). In some examples, housing 106 is pressurized to a pressure up to the nominal pressure of the housing, which may vary based on the size of housing 106. In some examples, pressurizing housing 106 may not stretch housing 106 itself. In other examples, housing 106 will stretch when pressurized to the aforementioned sufficient pressure. A shock wave generated by at least one shock wave emitter 104 can cause a pressure spike of less than about 15 atm within housing 106.

[0045] As described above, the housing 106 may be coated with a drug coating 110. At least a portion of the drug coating 110 may be able to be released from the surface of the housing 106 via a shock wave generated by at least one shock wave emitter 104. For example, when at least one shock wave emitter 104 within the housing 106 generates at least one shock wave, the shock wave may interact with the housing 106 and / or the drug coating 110 itself, causing drug particles from the drug coating 110 to be ejected from the surface of the housing 106. In some examples, shock wave generation is accompanied by the expansion and collapse of cavitation bubbles, which generates one or more microjets. These microjets may impinge on the inner surface of the housing 106, thereby causing at least a portion of the drug coating 110 to be ejected from the surface of the housing 106.

[0046] The drug coating 110 may include multiple microcapsules containing a pharmaceutical active agent. For example, the multiple microcapsules may include multiple microspheres and / or multiple microcapsules. A shock wave generated by the shock wave emitter 104 can cause the microcapsules to break down into smaller particles and release the active agent held therein. The diameter of the microcapsules may be between about 0.5 micrometers and 500 micrometers (μm). For example, the diameter of the microcapsules may be between about 0.5 μm-100 μm, 0.5 μm-50 μm, 0.5 μm-10 μm, 5 μm-500 μm, 5 μm-100 μm, 5 μm-50 μm, 5 μm-20 μm, 10 μm-100 μm, 10 μm-50 μm, 50 μm-500 μm, 50 μm-100 μm, or 100 μm-500 μm. In some examples, the diameter of the microcapsules can be greater than or equal to about 0.5 μm, 1 μm, 2 μm, 5 μm, 10 μm, 20 μm, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, or 450 μm. In other examples, the diameter of the microcapsules can be less than or equal to about 1 μm, 2 μm, 5 μm, 10 μm, 20 μm, 50 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, or 450 μm.

[0047] Drug coating 110 may comprise nanoparticles in crystalline, amorphous, or combinations thereof. For example, drug coating 110 may comprise a gel-like structure. As described herein, gel-based drug delivery systems exhibit several desirable properties. Gel-based systems are highly compatible with a range of drugs, have good solubility, and can be used at high drug concentrations at the desired drug delivery site while reducing systemic side effects. Gels are also biocompatible, biodegradable, and exhibit sustained drug release over extended periods.

[0048] At least a portion of the outer surface of the housing 106 may be coated with a drug coating 110. For example, at least about 20% of the surface of the housing 106 may be coated with the drug coating 110. In some examples, about 20%-100%, 20%-80%, 20%-60%, or 20%-40% of the surface of the housing 106 may be coated with the drug coating 110. In some examples, greater than or equal to about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% of the surface of the housing 106 may be coated with the drug coating 110. In some examples, less than or equal to about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% of the housing 106 may be coated with the drug coating 110.

[0049] In some examples, substantially all of housing 106 may be coated with drug coating 110. In another example, at least the distal portion of housing 106 may be coated with drug coating 110. In yet another example, the central portion of housing 106 may be coated with drug coating 110. In yet another example, the proximal portion of housing 106 may be coated with drug coating 110. Any combination of the foregoing coating patterns is to be understood to be covered by the scope of this disclosure. For example, the central and distal end portions of housing 106 may be coated with drug coating 110.

[0050] The drug coating 110 can be applied to the housing 106 by coating, brushing, dipping, spraying, and / or immersing the housing 106 with a fluid containing the drug (e.g., gas or liquid). In some examples, after the drug coating 110 is applied to the housing 106, the housing 106 can be air-dried, heat-treated, or cooled to allow the drug coating 110 to fully adhere to the surface of the housing 106. In this way, the drug coating 110 can be selectively applied to only a portion of the housing 106 as needed.

[0051] The elongated tube 102 of catheter 100 may include one or more lumens 112. The one or more lumens 112 may include lumens for filling housing 106 (e.g., with a conductive fluid). The one or more lumens 112 may include lumens for delivering an irrigation solution to an anatomical region (such as a sinus cavity) into which catheter 100 is inserted. In this example, the irrigation solution may be used to clear obstructions (e.g., mucus) from the sinus cavity in preparation for drug delivery. The irrigation solution may include physiological saline. In some examples, the irrigation solution may include a drug, such as a hydrophilic drug. The irrigation lumen may extend through the length of catheter 100 to the distal end of catheter 100. During use of catheter 100, the irrigation solution may be introduced into the lumen at the proximal end of catheter 100 and may be sprayed (e.g., sprayed) into the sinus cavity from the distal end of catheter 100. Once the cavity is cleared, catheter 100 can be used for drug delivery within the sinus cavity.

[0052] The housing 106 of the catheter 100 can be positioned in the desired area of ​​the body using a guidewire. Figure 1B A guidewire 120 extending from the proximal end of catheter 100 is illustrated. When catheter 100 is used with guidewire 120, one or more lumens 112 may include lumens configured to receive guidewire (i.e., guidewire lumens).

[0053] The elongated tube 102 may be made of a compliant material and / or may be configured to have a specific geometry that allows the elongated tube 102 to be twisted, bent, and physically manipulated to guide the catheter 100 to an appropriate treatment area within the body. For example, a portion of the elongated tube 102 may include a slit, a coiled area, or other incision that allows the user to manipulate the catheter 100.

[0054] Different embodiments of the catheter 100 can be selected in terms of size (e.g., length, diameter, etc.) to target different patient anatomy. For example, the length of the slender tube 102 (i.e., the distance from the distal end of the slender tube 102 (including the length of the housing 106) to the proximal end of the slender tube 102 near the handle 114) can be between approximately 10 cm and 200 cm. In some examples, the length of the slender tube 102 can be between approximately 20 cm and 100 cm or 40 cm and 80 cm.

[0055] As described above and as Figure 1BAs shown, the catheter 100 may include a handle 114 located at the proximal end of the elongated tube 102. The handle 114 may facilitate connection between one or more fluid sources and one or more lumens 112 of the elongated tube 102 at one or more fluid ports 116. The handle 114 may facilitate connection between one or more electrical components (e.g., a pulse generator 140) and wires disposed within the elongated tube 102 via one or more electrical ports 118. In an example where the catheter 100 can be used with a guidewire 120, the handle 114 may be configured to receive and supply the guidewire 120 to a corresponding lumen of the elongated tube 102. The handle 114 may be configured such that a user can grip the handle 114 to manipulate the catheter 100. By using the handle 114, a user can operate the catheter 100 with only one hand. In some examples, the handle 114 may include one or more controls (e.g., buttons, switches, knobs, etc.) for controlling the operation of the catheter 100. For example, handle 114 may include one or more controls for controlling the inflow and / or outflow of fluid into housing 106 (e.g., via the lumen of elongated tube 102). Handle 114 may include one or more controls for controlling the delivery of energy to one or more shock wave emitters 104 (e.g., via wires contained within elongated tube 102, described in more detail below). Handle 114 may include one or more controls for controlling the delivery of flushing solution through the flushing lumen of elongated tube 102 and out of the distal end of elongated tube 102.

[0056] As described above, the handle 114 may include one or more fluid ports 116 configured to receive fluid from an external fluid source and deliver fluid to a corresponding lumen of the elongated tube 102. The one or more fluid ports 116 may be configured to be coupled to different fluid sources. For example, the one or more fluid ports 116 may be removably coupled to a syringe or pump containing a conductive fluid (e.g., saline) to fill the housing 106 with the conductive fluid. The one or more fluid ports 116 may be removably coupled to a syringe or pump containing an irrigation solution to deliver the irrigation solution via the elongated tube 102 to a desired anatomical region (e.g., sinus cavity). The one or more fluid ports 116 may be configured to receive fluid from the elongated tube 102 to remove fluid from the catheter 100, and may be positioned in a fluid reservoir removably connected to the one or more fluid ports 116. The one or more fluid ports 116 may be removably coupled to a fluid source and / or fluid reservoir using connectors (e.g., quick-disconnect connectors, Luer connectors, threaded connectors, etc.) and / or tubing.

[0057] like Figure 1BAs shown and described above, conduit 100 can be electrically connected (e.g., via wired or wireless communication) to pulse generator 140. For example, conduit 100 can be electrically connected to pulse generator 140 via one or more cables and electrical ports 118. One or more wires can extend from pulse generator 140, through electrical ports 118, and through elongated tube 102 to transfer energy from pulse generator 140 to at least one shock wave emitter 104. The wires can include copper or another conductive material capable of transmitting electrical energy. The wires can be insulated with an insulating material to protect them from damage and wear over time, both inside elongated tube 102 and outside conduit 100.

[0058] Pulse generator 140 can be configured to generate energy pulses (e.g., voltage, laser) to cause at least one shock wave emitter 104 to generate at least one shock wave. For example, a voltage pulse generated by pulse generator 140 can be delivered to at least one shock wave emitter 104 to cause the shock wave emitter 104 to generate at least one shock wave based on the voltage pulse. The voltage pulse can include a voltage between 1 kV and 10 kV. In some examples, the voltage pulse can include a voltage between about 1 kV and 8 kV, 1 kV and 5 kV, 5 kV and 8 kV, or 5 kV and 10 kV. The voltage pulse can include a voltage greater than or equal to about 1 kV, 2 kV, 5 kV, or 8 kV. The voltage pulse can include a voltage less than or equal to about 2 kV, 5 kV, 8 kV, or 10 kV.

[0059] The pulse generator 140 can be configured to control at least one of the amplitude, pulse width, frequency, and duty cycle of the energy pulses applied across the electrodes of the shock wave transmitter 104. For example, based on the energy pulses delivered by the pulse generator 140 to at least one shock wave transmitter 104, at least one shock wave transmitter 104 can be configured to generate a series of shock waves according to a duty cycle or frequency (such as a frequency between about 1 Hz and 5 Hz). In some examples, at least one shock wave transmitter 104 can generate a series of shock waves according to a frequency greater than or equal to about 1 Hz, 2 Hz, 3 Hz, or 4 Hz. In some examples, at least one shock wave transmitter 104 can generate a series of shock waves according to a frequency less than or equal to about 2 Hz, 3 Hz, 4 Hz, or 5 Hz. In some examples, the pulse generator 140 can be configured to deliver packets of micropulses with frequencies between about 100 Hz and 10 kHz. The pulse generator 140 can deliver a series of micropulse packets according to the aforementioned frequencies between about 1 Hz and 5 Hz. In some examples, the amplitude of the energy pulse can be gradually increased (or decreased) over the duration of the procedure to allow drug particles to be released from the surface of the shell.

[0060] In an alternative example, pulse generator 140 may include a laser source configured to deliver energy to at least one shock wave transmitter 104 via an optical fiber. Pulse generator 140 may be configured to deliver laser pulses to at least one shock wave transmitter 104 such that the shock wave transmitter 104 generates at least one shock wave.

[0061] As described above, the shock wave catheter described herein may include one or more lumens for filling the housing and / or delivering an irrigation solution to a desired anatomical area, such as the sinus cavity. Figure 2A A side view of a shock wave conduit 200 is illustrated, which includes at least two lumens for these purposes. The conduit 200 may include, as described herein... Figures 1A to 1B Any one or more features of the described catheter 100.

[0062] The elongated tube 202 may include a lumen 213 for filling the housing 206. The lumen 213 may include at least one fluid outlet 215, which fluidly connects an internal region of the housing 206 to the lumen 213. Although in Figure 2A A single fluid outlet 215 is illustrated, but the lumen 213 may include multiple fluid outlets 215 (e.g., two, three, four or more fluid outlets 215) along the length of the elongated tube 202 surrounded by the housing 206.

[0063] The elongated tube 202 may include a flushing lumen 222 for delivering flushing solution to the anatomical region into which at least the distal portion of the catheter 200 is inserted. The lumen 222 may extend through the length of the elongated tube 202, including a length through the housing 206 to a fluid outlet 223 at the distal end of the elongated tube 202.

[0064] As described above, the shock wave duct described herein may include at least one shock wave emitter. Figure 2A The exemplary conduit 200 shown includes two shock wave emitters 204. Each shock wave emitter 204 may include an electrode assembly 224, also referred to herein as an electrode pair. The electrodes of the electrode assembly 224 may be positioned adjacent to each other. For example, the electrode assembly 224 may include an inner electrode 224a surrounded by an outer electrode 224b, with a gap 225 between the two electrodes. In another example, the electrodes of the electrode assembly 224 may be placed side by side or in another arrangement including a gap 225 between the two electrodes. When the housing 206 is filled with fluid and a suitable voltage pulse is applied across the electrode assembly 224, a spark is formed at the fluid-filled gap 225 between the electrodes of the electrode assembly 224. The spark causes cavitation bubbles to form at the shock wave emitter 204, which in turn allows shock waves to propagate from the shock wave emitter 204.

[0065] The electrodes of the electrode assembly 224 may include conductive material. For example, a conductive material emitter strip may be disposed on the elongated tube 202 to form one or more electrodes of the electrode assembly 224. In some examples, the end of a conductive wire extending within the elongated tube 202 to the shock wave emitter 204 may form an electrode of the electrode assembly 224.

[0066] As described above, the shock wave transmitter of the shock wave duct (e.g., duct 200) described herein can be coupled to a pulse generator to deliver energy to the shock wave transmitter. Figure 2A The exemplary conduit 200 shown includes electrical wires 226 for electrically connecting each shock wave emitter 204 (i.e., the electrode assembly 224 of the shock wave emitter 204) to a pulse generator. The wires 226 may extend within an elongated tube 202 to the shock wave emitter 204. In some examples, the wires 226 may extend within a dedicated lumen within the elongated tube 202.

[0067] The housing 206 may be made of one or more compliant or semi-compliant (e.g., elastic, flexible) materials. For example, the housing 206 may be made of at least one of nylon, polyamide, polyether copolymer, polyurethane, another polymer, or mixtures thereof. The housing 206 may include a layered composition, wherein each layer comprises at least one of the above-described materials. In a non-limiting example, the housing 206 may consist of an inner layer comprising polyamide and an outer layer comprising nylon, or vice versa. In another non-limiting example, the housing 206 may consist of an inner layer comprising polyurethane and an outer layer comprising polyamide, or vice versa. The housing 206 may include more than two layers. In a non-limiting example, the housing 206 may consist of an inner layer comprising polyamide, an intermediate layer comprising polyamide (i.e., the same or different polyamide composition), and an outer layer comprising nylon, or vice versa. In another example, the housing 206 may consist of an inner layer comprising polyamide, an intermediate layer comprising polyurethane, and an outer layer comprising polyamide, or vice versa.

[0068] The dimensions (e.g., length, diameter, etc.) of the shell 206 can vary based on the patient's anatomy. For example, the length of the shell 206 can be between approximately 10mm-1000mm, 10mm-500mm, or 20mm-100mm. Figure 2A As shown, the length of housing 206 extends between the tapered ends of housing 106 and is denoted as "d".

[0069] When fully filled, the diameter of the shell 206 can be between approximately 3mm-40mm, 10mm-40mm, or 20mm-40mm. Physicians can select a combination of the dimensions (e.g., diameter and length) of the shell 206 based on patient characteristics such as age, sex, disease, anatomical limitations, etc.

[0070] Figures 2A to 2C An exemplary sequence of operations is illustrated for releasing a drug from the housing 206 of the catheter 200 using a shock wave. Figure 2A An example of a catheter 200 prior to shock wave generation is shown, wherein the housing 206 is in an unfilled state. The housing 206 may be unfilled when the catheter 200 is positioned in a desired anatomical region (such as a body cavity or cavity) for treatment. The housing 206 includes a drug coating 210 thereon.

[0071] Figure 2B At least one shock wave emitter 204 is illustrated, which emits a shock wave 228. The shock wave 228 can propagate outward to the housing 206. In some examples, the shock wave generates one or more microjets 230. The microjets 230 generated by the shock wave can propagate outward from at least one shock wave emitter 204 toward the inner surface of the housing 206 and can impact the inner surface of the housing 206.

[0072] Figure 2C An example is illustrated of drug particles 208 of a drug coating 210 ejected from the surface of a housing 206 due to a shock wave 228 and / or a microjets 230. In some examples, the housing 206 may be placed within a body cavity or cavity such that the housing 206 contacts the tissue of the body cavity / cavity. In this example, the generated shock wave 228 and / or microjets 230 can cause the drug particles 208 to displace from the surface of the housing 206 and adhere to the tissue for absorption. In some examples, the housing 206 may be placed near the tissue, with a space between the housing 206 and the tissue. In this example, the shock wave 228 and / or microjets 230 can cause the drug particles 208 to eject from the surface of the housing 206, and the shock wave 228 can further facilitate the movement of the drug particles 208 within the space between the housing 206 and the tissue. When the drug particles reach the tissue, they can adhere to the tissue for absorption.

[0073] In some examples, the shock wave 228 and / or microjets 230 can cause the drug particles 208 to break down into smaller particle sizes. Smaller drug particles can make it easier for the drug particles 208 to be ejected from the surface of the housing 206 and / or propelled from the surface of the housing 206 into the tissue by the shock wave 228.

[0074] In some examples, the shock wave 228 can cause drug particles 208 to embed within tissue. In some examples, the shock wave 228 can enable drug particles 208 to propagate through tissues via body cavities or lumens (e.g., sinus cavities) and into the CNS. For example, compared to drug uptake mechanisms that rely solely on the anatomy of the sinus cavities themselves to drive drug particles 208 through tissues and into desired locations in the CNS, the shock wave 228 can drive drug particles 208 deeper through tissues. This deeper propagation of drug particles 208 can increase the uptake of the active agent within drug particles 208 in the CNS.

[0075] As described above, the elongated tube 202 may include one or more lumens. Figure 3 A cross-sectional view of an elongated tube 302 surrounding several lumens is shown. The elongated tube 302 can be used for... Figures 1A to 1B and Figures 2A to 2C One or more of the elongated tubes 102 and 202. The elongated tube 302 includes a lumen 313 for filling the housing of the catheter, a flushing lumen 322 for delivering a flushing solution to a lumen or cavity for dissecting the desired area, and a guidewire lumen 332 for receiving a guidewire.

[0076] Lumen 313 may be an inherent lumen of the elongated tube 302. Each of the flushing lumen 322 and the guidewire lumen 332 may also be a lumen of a tube (e.g., tubes 334 and 336, respectively). The guidewire lumen 332 may be disposed within the flushing lumen 322. Each of the guidewire lumen 332 and / or the flushing lumen 322 may be disposed within the lumen 313 of the elongated tube 302. Alternative arrangements of the lumen of the elongated tube 302 are also contemplated. For example, the flushing lumen 322 may be disposed within the guidewire lumen 332. In some examples, the elongated tube 302 may include a lumen (e.g., lumen 313) configured to receive both a guidewire and fluid for filling the housing. In this example, the flushing lumen 332 may be disposed within said lumen 313.

[0077] As described above, shock wave catheters (e.g., catheters 100, 200) can be operated in conjunction with an endoscope to visualize cavities, tubes, or other passages in the body. Figure 4An endoscopic imaging system 400 is illustrated, which can be used with the shockwave catheter described herein to visualize body cavities / cavities. The endoscopic imaging system 400 may include an endoscope 450 for insertion into the body together with a catheter (e.g., catheter 100, 200) to capture imaging data of the body cavity / cavity. The endoscope 450 may include an imaging sensor 452, which may be positioned at a distal portion 450a or a proximal portion 450b of the endoscope 450. The imaging sensor 452 is configured to capture images and / or videos of the body cavity, cavity, and passageway therein. For example, the endoscope 450 may be inserted into a sinus cavity, and the imaging sensor 452 may capture images / videos of the intranasal passageway, nasal cavity, sinuses, etc.

[0078] In some examples, the imaging sensor may be additionally or alternatively integrated into the shock wave duct itself. For example, at least one imaging sensor may be disposed within or near the housing along an elongated tube. Alternatively, a guidewire capable of being received by the shock wave duct described herein may include an imaging sensor (e.g., at the distal end of the guidewire).

[0079] The imaging sensor 452 of the endoscope 450 can be communicatively coupled (e.g., via a wired or wireless connection) to the endoscope camera control system 460. For example, as Figure 4 As shown, the endoscope 450 and the endoscope camera control system 460 can be communicatively connected via a wired connection 456. The endoscope camera control system 460 may include a processor 462 and a display 464. The processor 462 may be configured to process imaging data captured by the imaging sensor 452. The processor 462 may be configured to transmit the processed imaging data to the display 464 to display one or more images, videos, etc. (collectively referred to herein as media) on the display 464 during shockwave therapy. By using the displayed media, catheters (e.g., catheters 100, 200) can be positioned at the appropriate treatment site.

[0080] In some examples, the endoscopic imaging system 400 may include an illumination system for illuminating the body cavity / cavity during endoscopic imaging. The illumination system may include, for example, one or more light-emitting diodes (LEDs) disposed along the distal end of the endoscope 450 and / or at the distal end of the endoscope. In some examples, the illumination system may include an illuminator external to the endoscope, connected via a cable to the endoscope, for delivering light to the area being imaged by the endoscope.

[0081] In some examples, the shock wave catheter (e.g., catheter 100, 200) may include one or more position sensors configured to detect position data and transmit it to a processor (e.g., processor 462). For example, the distal portion of the catheter may include one or more position sensors. Processor 462 may process the data to track the movement of the distal portion of the catheter as it is advanced and positioned within the body.

[0082] Methods of using shockwave catheters to treat central nervous system (CNS) diseases

[0083] As described above, shockwave catheters (e.g., catheters 100, 200) can be disposed within the sinus cavity for delivering drugs coated on the catheter housing to the CNS via tissues of the sinus cavity. The sinus cavity may include the nasal cavity, sinus cavities, intranasal passages, etc. Figure 5A The use of an exemplary catheter 500 in the nasal cavity is illustrated for delivering a drug into the CNS via tissue from the sinus cavity. Catheter 500 may include, as described herein, [details about the catheter and its components]. Figures 1A to 1B , Figures 2A to 2C Any one or more features described in the catheters 100, 200 shown, and described in more detail above.

[0084] The catheter 500 can be positioned within the nasal cavity to deliver a drug to the CNS. The catheter 500 can be positioned within the nasal cavity via an intranasal passage (such as the nostril). The nasal cavity can be selected for sinus drug delivery because the olfactory nerves leading to the brain via the olfactory bulb and olfactory tract are accessible. Once the housing 506 of the catheter 500 is correctly positioned within the nasal cavity, at least one shock wave can be generated by at least one shock wave emitter 504 of the catheter 500 to eject drug particles 508 from the surface coating of the housing 506. When sprayed near the olfactory nerve, as shown, the drug particles 508 can be absorbed into the nasal tissue and travel from the olfactory nerve to the CNS. Thus, the shock wave generated by the shock wave emitter 504 can ultimately lead to the delivery of a drug (e.g., the active agent of the drug) to the brain by delivering an active agent to the nasal tissue, whereby the active agent can be absorbed into the tissue, move into the olfactory nerve, travel to the olfactory bulb, and travel via the olfactory duct to the brain.

[0085] By advancing the catheter 500 through the intranasal passage into the sinus cavity and reaching the sinus cavity, the catheter 500 can be positioned in areas of the sinus cavity other than the nasal cavity, such as within the sinus cavity itself. For example, as... Figure 5BAs shown, the catheter 500 can be advanced to a position at least partially within a sinus cavity. In this illustrated example, the distal portion of the housing 506 is positioned within the frontal sinus, while the remainder of the housing 506 is positioned within the frontal sinus infundibulum. The intranasal passage connecting the frontal sinus to the nasal cavity may include the frontal sinus ostium and the ostial canal. Although not explicitly shown, it should be understood that substantially all of the housing 506 can be positioned within a sinus cavity (e.g., the frontal sinus) or an intranasal passage (e.g., the frontal sinus ostium, the ostial canal). In some examples, the catheter 500 can be advanced through an intranasal passage and positioned at least partially within the anterior ethmoid sinus or sphenoid sinus. From the tissue of any of the aforementioned sinus cavities and intranasal passages, the shockwave generated by the catheter 500 can deliver drugs to the CNS, for example, via the olfactory nerve, olfactory bulb, and olfactory tract.

[0086] As described above, the shock wave catheter described herein can be operated in conjunction with an endoscope. Figure 5B An example is illustrated of a catheter 500 used in conjunction with an endoscope 550 for visualization of the sinus cavities (including the intranasal passages therein). The endoscope 550 can be used during placement of the catheter 500 and / or during drug delivery via the catheter 500. Although in Figures 5A to 5B Not explicitly shown, but placement of catheter 500 may additionally or alternatively include the use of a guidewire extending through the catheter, as described above at least regarding Figures 1A to 1B and Figure 3 As stated above.

[0087] Figure 6 Examples of using shock wave ducts (such as those related to...) Figures 1A to 1B , Figures 2A to 2C and Figures 5A to 5B The exemplary method of treating CNSD using catheters 100, 200, and 500 described herein.

[0088] exist Figure 6 At box 610 of method 600, the distal portion of the catheter is advanced through an intranasal passage into the nasal cavity, such that the catheter housing is at least partially positioned within the nasal cavity. The catheter housing may be in a deflated (e.g., unfilled) state as it is advanced through the sinus cavities. In some examples, advancing the distal portion of the catheter through the intranasal passage may include advancing the catheter via a guidewire.

[0089] exist Figure 6 At box 615 of method 600, an irrigation solution can be delivered via a catheter into the intranasal passage and / or nasal cavity to clean the intranasal passage and / or nasal cavity. The irrigation solution may include a physiological saline solution. Figure 7A An example of rinsing an intranasal passage with a catheter is illustrated, wherein the catheter 700 is used to deliver rinsing solution 701 into an intranasal passage 703. Figures 7A to 7C The catheter 700 shown may include, respectively, those described herein. Figures 1A to 1B , Figures 2A to 2C and Figures 5A to 5B Any one or more features of the described catheters 100, 200, and 500. For example, catheter 700 may include a flushing lumen that extends through the length of elongated tube 702 and exits at the distal end of catheter 700.

[0090] exist Figure 6 In method 600, at box 620, the housing of the catheter can be filled to allow the housing to expand within the nasal cavity. Figure 7B An example is shown of an expanded (filled) housing 706 within a nasal cavity 705. Filling the housing 706 may include pressurizing the housing to a pressure less than about 10 atm. The housing 706 may be filled with a conductive fluid, such as saline solution. In some examples, the housing 706 may additionally or alternatively be filled with an X-ray contrast agent for observation of the housing 706.

[0091] exist Figure 6 At block 630 of method 600, a shock wave can be generated by at least one shock wave emitter of the catheter to deliver a therapeutically effective amount of active agent from the drug coating to the CNS via nasal tissue. One or more shock waves can be generated when a suitable energy (e.g., voltage, laser) pulse is applied to the electrode assembly of at least one shock wave emitter. For example, one or more shock waves can be generated by a spark formed at a fluid-filled gap between the electrodes of the electrode assembly. The shock wave can cause particles from the drug coating to be removed from the surface of the housing. Figures 7B to 7C An example is illustrated by a shock wave 728 generated at a shock wave emitter 704. Drug particles 708, removed from the surface of the housing 706, can be deposited on the tissue of the nasal cavity 705. Due to the increased pressure within the housing caused by the shock wave 728, a drug coating 710 can be removed from the surface of the housing 706. In some examples, one or more shock waves generate microjets within the housing that impact the inner surface of the housing, causing drug particles to be removed from the surface of the housing.

[0092] Method 600 may include generating a series of shock waves according to a set frequency or duty cycle. For example, the frequency may be between about 1 Hz and 5 Hz, such as about 1 Hz, 2 Hz, 3 Hz, 4 Hz, or 5 Hz. In some examples, method 600 may include generating one or more micropulse bursts. The micropulse may be generated rapidly and continuously, for example, at a frequency of about 100 Hz to 10 kHz. Several bursts may be generated at the aforementioned frequencies between about 1 Hz and 5 Hz. This series of shock waves may drive the ejected drug particles of the drug-coated layer through tissue and into the CNS. The pulse duration of the energy pulse applied to the electrodes of the shock wave emitter may depend on the surface area of ​​the electrodes. For example, the pulse duration may be on the order of several microseconds (e.g., between about 1 μs and 5 μs).

[0093] As described above, drug delivery to the CNS via the sinus cavity may include contacting the sinus cavity tissue with the shell or separating at least a portion of the shell from the sinus cavity tissue. Figure 7B In the diagram, the housing 706 is shown spaced apart from the tissue of the nasal cavity 705 when generating and emitting a shock wave 728. The minimum distance between the tissue of the nasal cavity 705 and the housing 706 may depend on the amplitude, direction, frequency, etc., of the shock wave generated by the shock wave emitter therein. Figure 7C An alternative arrangement of the housing 706 of the catheter 700 within the nasal cavity 705 is illustrated. Figure 7C In this embodiment, when a shock wave 728 is generated and emitted, at least a portion of the housing 706 can be positioned to contact the tissue of the nasal cavity. For example, at least about 25%, 50%, 75%, or substantially all of the housing 706 can contact the tissue of the nasal cavity 705. In some examples, the housing 706 may contact the tissue on a first side of the housing 706, but may be spaced apart from the tissue on a second side of the housing 706 opposite to the first side (e.g., spaced apart by the aforementioned amount). In another example, the housing 706 may contact the tissue at a distal end of the housing and may be spaced apart from the tissue at a proximal end of the housing 706 (e.g., spaced apart by the aforementioned amount), and vice versa.

[0094] In some cases, method 600 may include generating and delivering a shock wave simultaneously or nearly simultaneously with the delivery of the rinsing solution to the sinus cavity (e.g., via an intranasal passage, sinus cavity, and / or nasal cavity). In this way, excess fluid (e.g., mucus) can be drained from the sinus cavity approximately at the same time as the release of the drug from the surface of the shell begins.

[0095] Although method 600 primarily describes drug delivery to the CNS via the sinus cavities, the methods described herein are not intended to be limited to this anatomical region of the body. For example, the shockwave catheter described herein can be inserted into alternative body cavities and spaces through which access to the CNS is possible. For instance, the shockwave catheter described herein can be inserted into cavities and / or tubules of the eye and spinal cord or their vicinity for drug delivery to the CNS by bypassing the BBB in these regions.

[0096] The methods described in this article can be used to treat a variety of central nervous system disorders (CNSDs). CNSDs that can be treated using the methods described in this article may include, but are not limited to: Parkinson's disease, Alzheimer's disease, Huntington's disease, epilepsy, schizophrenia, brain cancer, lung cancer, tracheal cancer, prostate cancer, encephalomyelitis, seizures, myasthenia gravis, atherosclerosis, multiple sclerosis, amyloid angiopathy, ischemic injury, type 1 spinocerebellar ataxia, karyocytic induced apoptosis (KAIA), hypoxia-induced oxidative stress, tau proteinosis, ADHD, sleep deprivation, obesity, eating disorders, depression, anxiety, autism, addiction, and / or stroke.

[0097] The active agent for the drug coating may be determined based on the CNSD treated using the shockwave catheter and methods provided herein. Exemplary active agents may include, but are not limited to, any one or more of the following: tyrosine kinase inhibitors, NAP peptides, [Ser(2)] lizard exopeptides (1-9), pituitary adenylate cyclase-activated peptides, recombinant human nerve growth factor, L-DOPA, insulin-like growth factor 1, 22C4 single-chain variable fragment antibody, erythropoietin + insulin-like growth factor 1, nerve growth factor, vascular endothelial growth factor, transforming growth factor β1, fibroblast growth factor, mesenchymal stem cells, glycopeptide-like peptide, leptin, interferon β-1b, apolipoprotein B-100, fusion protein mCTA1-T146, herpes simplex virus type 2 ΔRR + ICP10PK and / or filamentous phage + myelin oligodendrocyte glycoprotein. Additional active agents for treating CNSD will be apparent to those skilled in the art and are understood to be covered by the disclosure provided herein.

[0098] In some examples, in addition to or instead of using the shockwave catheters described herein to deliver drugs to the CNS, shockwave catheters can be used to perform focused ultrasound therapy on specific areas of the CNS using shockwaves. For example, the shockwave catheters described herein can be used to deliver shockwaves to the brain, such as to the cortical and / or subcortical regions of the brain.

[0099] As used herein, the term "inflate" a shell is intended to indicate the introduction of fluid into the shell, thereby increasing the fluid pressure within the shell. Similarly, "deflate" a shell is intended to indicate the removal of fluid from the shell, thereby reducing the fluid pressure within the shell. Inflating and deflating a shell is not intended to imply that the material forming the shell undergoes elastic stretching (or contraction) when the fluid pressure within the shell changes.

[0100] Although the electrode assemblies and catheters described herein are primarily discussed in the context of drug delivery to the CNS (central nervous system) via the sinuses, these assemblies and catheters can be used for drug delivery in other locations with access to the CNS via vascular systems. For additional examples, similar catheter designs can be used for drug treatment of soft tissues, such as the removal of cancers and tumors, blood clots, fibromas, cysts, organs, and scar and fibrotic tissue. Electrode assemblies and catheter designs can also be used for nerve stimulation therapy, targeted drug delivery, treatment of tumors in body cavities (e.g., tumors in blood vessels, esophagus, intestines, stomach, or vagina), wound management, non-surgical resection and tissue destruction, or as an alternative to heat treatment or cauterization for venous insufficiency and tubal ligation (i.e., for permanent female contraception).

[0101] In one or more examples, the electrode assemblies and conduits described herein can also be used in tissue engineering approaches, such as for mechanical tissue decellularization to generate bioactive scaffolds in which new cells (e.g., exogenous or endogenous cells) replace old cells; and for introducing porosity to sites to improve cell retention, cell infiltration / migration, and diffusion of nutrients and signaling molecules, thereby promoting angiogenesis, cell proliferation, and tissue regeneration, similar to cell replacement therapy. Such tissue engineering approaches can be used to treat ischemic heart disease, fibrotic liver, fibrotic intestine, and traumatic spinal cord injury (SCI). For example, for treating spinal cord injury, the devices and assemblies described herein can facilitate the removal of scarred spinal cord tissue prior to the injection of an anti-inflammatory hydrogel loaded with lentiviruses to genetically engineer spinal cord neuronal regeneration, acting as a barrier to neuronal reconnection.

[0102] The elements and features of the exemplary electrode assemblies and conduits discussed above can be rearranged, recombined, and modified without departing from the invention. Furthermore, numerical indicators such as “first,” “second,” “third,” “fourth,” etc., are merely descriptive and do not indicate the relative order, position, or identity of the elements or features described by the indicators. For example, a “first” shock wave may be immediately followed by a “third” shock wave, and then a “second” shock wave. As another example, a “third” transmitter can be used to generate a “first” shock wave, and vice versa. Therefore, the numerical indicators of the various elements and features are not intended to limit this disclosure and can be modified and interchanged without departing from the invention.

[0103] It should be noted that elements and features of the exemplary conduits illustrated throughout this specification and drawings can be rearranged, recombined, and modified without departing from the invention. For example, while this specification and drawings describe and illustrate conduits having several exemplary housing designs, this disclosure is intended to include conduits having various housing configurations. The number, placement, and spacing of the electrode pairs of the shock wave generator can be modified without departing from the invention. Furthermore, the number, placement, and spacing of the conduit housings can be modified without departing from the invention.

[0104] It should be understood that the foregoing is merely an explanation of the principles of the invention, and various modifications, alterations, and combinations can be made by those skilled in the art without departing from the scope and spirit of the invention. Any variation of the various catheters disclosed herein may include the features described by any other catheter or combination of catheters herein. Furthermore, any method may be used with any of the disclosed catheters. Therefore, the invention is not intended to be limited except for the appended claims. Claims (as amended under Article 19 of the Treaty) 1. A method for treating a central nervous system disease via the nasal cavity, the method comprising: The distal portion of the catheter is advanced through an intranasal passage to the nasal cavity, such that the housing of the catheter is at least partially positioned within the nasal cavity, the distal portion of the catheter including at least one shock wave emitter surrounded by the housing, and at least a portion of the surface of the housing being coated with a drug coating. Fill the housing to inflate it within the nasal cavity; and At least one shock wave is generated by the at least one shock wave emitter, the at least one shock wave causing a therapeutically effective amount of active agent of the drug coating to be delivered from the surface of the housing to the central nervous system (CNS) via the tissue of the nasal cavity. 2. The method according to claim 1, wherein the method comprises generating a series of shock waves based on a frequency between 1 Hz and 5 Hz. 3. The method of claim 1, wherein generating the at least one shock wave comprises generating at least one bubble within the housing, the at least one bubble impacting the inner surface of the housing to eject at least a portion of the drug coating from the surface of the housing. 4. The method of claim 1, wherein the method comprises delivering one or more voltage pulses to the at least one shock wave transmitter to generate the at least one shock wave. 5. The method of claim 4, wherein the one or more voltage pulses comprise a voltage between 1 kV and 10 kV. 6. The method of claim 1, wherein the method comprises delivering one or more laser pulses to the at least one shock wave transmitter to generate the at least one shock wave. 7. The method of claim 1, wherein filling the housing comprises pressurizing the housing to a pressure of less than 10 atm. 8. The method of claim 1, the method comprising delivering an irrigation solution to at least one of the intranasal passage and the nasal cavity prior to generating the at least one shock wave, to clear the intranasal passage and the at least one of the nasal cavity. 9. The method according to claim 8, wherein the flushing solution comprises physiological saline and / or a drug. 10. The method of claim 1, wherein the intranasal passage includes the frontal sinus ostium, and the nasal cavity includes the frontal sinus. 11. The method of claim 1, wherein generating the at least one shock wave causes the active agent of the drug coating to be delivered to the CNS via the olfactory nerve. 12. The method of claim 1, wherein advancing the distal portion of the catheter through the intranasal passage comprises advancing the catheter via a guidewire. 13. The method of claim 1, wherein, when the at least one shock wave is generated, at least a portion of the housing contacts the tissue of the nasal cavity. 14. The method of claim 1, wherein, when the at least one shock wave is generated, at least a portion of the housing is spaced apart from the tissue of the nasal cavity. 15. The method of claim 1, wherein the drug coating comprises a crystalline form, an amorphous form, or a combination thereof. 16. The method of claim 1, wherein the drug coating comprises a plurality of microcapsules containing the active agent. 17. The method of claim 16, wherein the plurality of microcapsules comprises a plurality of microspheres and / or a plurality of microcapsules having a diameter between 0.5 micrometers and 500 micrometers. 18. A device for intranasal drug delivery, the device comprising: Slender tube; At least one shock wave emitter, the at least one shock wave emitter being configured to generate at least one shock wave; and A housing, sealed to the distal portion of the elongated tube and surrounding the at least one shock wave emitter, the housing being capable of being filled with a conductive fluid, and at least a portion of the surface of the housing being coated with a drug coating. The at least one shock wave is configured to deliver a therapeutically effective amount of the active agent of the drug coating from the surface of the housing to the central nervous system (CNS) via nasal tissue. 19. The apparatus of claim 18, wherein the at least one shock wave emitter is configured to generate the at least one shock wave, the at least one shock wave being configured to cause the active agent of the drug coating to be delivered to the CNS via the olfactory nerve. 20. The apparatus of claim 18, wherein the at least one shock wave emitter is configured to generate at least one bubble within the housing, the at least one bubble impinging on the inner surface of the housing to eject at least a portion of the drug coating from the surface of the housing. 21. The apparatus of claim 18, wherein the at least one shock wave transmitter is configured to generate a series of shock waves at frequencies between 1 Hz and 5 Hz. 22. The apparatus of claim 18, wherein the housing is configured to be pressurized to a pressure of less than 10 atm. 23. The apparatus of claim 18, wherein the elongated tube is configured to deliver an irrigation solution into at least one of the intranasal passage and the nasal cavity to clean the intranasal passage and the at least one of the nasal cavity. 24. The apparatus of claim 18, the apparatus comprising a guidewire lumen disposed within the elongated tube and configured to receive a guidewire to guide the housing through an intranasal passage and into the nasal cavity. 25. The apparatus of claim 18, wherein the elongated tube includes a guidewire lumen configured to receive a guidewire and an irrigation lumen configured to deliver an irrigation solution to at least one of the intranasal passage and the nasal cavity. 26. The apparatus of claim 25, wherein the guidewire lumen is disposed within the flushing lumen in the elongated tube. 27. The apparatus of claim 25, wherein the flushing lumen extends through the length of the housing to a fluid outlet at the distal end of the housing. 28. The apparatus of claim 18, wherein the elongated tube is configured to be coupled to a syringe to fill the housing with the conductive fluid. 29. The apparatus of claim 18, wherein the housing is capable of being filled with an X-ray contrast agent to facilitate observation of the housing. 30. The device of claim 18, wherein the housing comprises at least one of an elliptical balloon, a spherical balloon, and a hemispherical balloon. 31. The device of claim 18, wherein at least 20% of the surface of the housing is coated with the drug coating. 32. The device of claim 18, wherein the entire surface of the housing is coated with the drug coating. 33. The apparatus of claim 18, wherein the drug coating comprises a crystalline form, an amorphous form, or a combination thereof. 34. The apparatus of claim 18, wherein the drug coating comprises a plurality of microcapsules containing the active agent. 35. The device of claim 34, wherein the plurality of microcapsules comprises a plurality of microspheres and / or a plurality of microcapsules having a diameter between 0.5 micrometers and 500 micrometers. 36. A system for intranasal drug delivery, the system comprising: The apparatus according to claim 18; and A pulse generator, which is coupled to the at least one shock wave transmitter and configured to generate energy pulses so that the at least one shock wave transmitter generates the at least one shock wave. 37. The system of claim 36, wherein the pulse generator is configured to generate the energy pulse such that the at least one shock wave emitter generates a series of shock waves at a frequency between 1 Hz and 5 Hz. 38. The system of claim 36, wherein the pulse generator is configured to generate one or more voltage pulses such that the at least one shock wave transmitter generates a series of shock waves. 39. The system of claim 38, wherein the one or more voltage pulses comprise a voltage between 1 kV and 10 kV. 40. The system of claim 36, wherein the pulse generator is configured to generate one or more laser pulses such that the at least one shock wave emitter generates the at least one shock wave. 41. The system of claim 36, the system comprising an endoscope disposed adjacent to the device and including an imaging sensor located at a distal portion of the endoscope, the imaging sensor being configured to capture images of at least one of an intranasal passage and the nasal cavity.

Claims

1. A method for treating a central nervous system disease via the nasal cavity, the method comprising: The distal portion of the catheter is advanced through an intranasal passage to the nasal cavity, such that the housing of the catheter is at least partially positioned within the nasal cavity, the distal portion of the catheter including at least one shock wave emitter surrounded by the housing, and at least a portion of the surface of the housing being coated with a drug coating. The housing is filled to inflate it within the nasal cavity; as well as At least one shock wave is generated by the at least one shock wave emitter, the at least one shock wave causing a therapeutically effective amount of active agent of the drug coating to be delivered from the surface of the housing to the central nervous system (CNS) via the tissue of the nasal cavity.

2. The method according to claim 1, wherein the method comprises generating a series of shock waves based on a frequency between 1 Hz and 5 Hz.

3. The method according to claim 1 or 2, wherein, Generating the at least one shock wave includes generating at least one bubble within the housing, the at least one bubble impacting the inner surface of the housing to eject at least a portion of the drug coating from the surface of the housing.

4. The method according to any one of claims 1 to 3, the method comprising delivering one or more voltage pulses to the at least one shock wave transmitter to generate the at least one shock wave.

5. The method according to claim 4, wherein, The one or more voltage pulses include voltages between 1kV and 10kV.

6. The method according to any one of claims 1 to 5, the method comprising delivering one or more laser pulses to the at least one shock wave emitter to generate the at least one shock wave.

7. The method according to any one of claims 1 to 6, wherein, Filling the housing includes pressurizing the housing to a pressure of less than 10 atm.

8. The method according to any one of claims 1 to 7, the method comprising delivering an irrigation solution to at least one of the intranasal passage and the nasal cavity prior to generating the at least one shock wave, to clear the intranasal passage and the at least one of the nasal cavity.

9. The method according to claim 8, wherein, The flushing solution includes physiological saline and / or drugs.

10. The method according to any one of claims 1 to 9, wherein, The intranasal passage includes the frontal sinus ostium, and the nasal cavity includes the frontal sinus.

11. The method according to any one of claims 1 to 10, wherein, The generation of the at least one shock wave causes the active agent in the drug coating to be delivered to the CNS via the olfactory nerve.

12. The method according to any one of claims 1 to 11, wherein, Advancing the distal portion of the catheter through the intranasal passage includes advancing the catheter via a guidewire.

13. The method according to any one of claims 1 to 12, wherein, When the at least one shock wave is generated, at least a portion of the housing comes into contact with the tissue of the nasal cavity.

14. The method according to any one of claims 1 to 13, wherein, When the at least one shock wave is generated, at least a portion of the housing is spaced apart from the tissue of the nasal cavity.

15. The method according to any one of claims 1 to 14, wherein, The drug coating may be in crystalline form, amorphous form, or a combination thereof.

16. The method according to any one of claims 1 to 15, wherein, The drug coating comprises a plurality of microcapsules containing the active agent.

17. The method according to claim 16, wherein, The plurality of microcapsules include a plurality of microspheres and / or a plurality of microcapsules having a diameter between 0.5 micrometers and 500 micrometers.

18. A device for intranasal drug delivery, the device comprising: Slender tube; At least one shock wave emitter, the at least one shock wave emitter being configured to generate at least one shock wave; and A housing, sealed to the distal portion of the elongated tube and surrounding the at least one shock wave emitter, the housing being capable of being filled with a conductive fluid, and at least a portion of the surface of the housing being coated with a drug coating. The at least one shock wave is configured to deliver a therapeutically effective amount of the active agent of the drug coating from the surface of the housing to the central nervous system (CNS) via nasal tissue.

19. The apparatus according to claim 18, wherein, The at least one shock wave emitter is configured to generate the at least one shock wave, which is configured to deliver the active agent of the drug coating to the CNS via the olfactory nerve.

20. The apparatus according to claim 18 or 19, wherein, The at least one shock wave emitter is configured to generate at least one bubble within the housing, the at least one bubble impacting the inner surface of the housing to eject at least a portion of the drug coating from the surface of the housing.

21. The apparatus according to any one of claims 18 to 20, wherein, The at least one shock wave transmitter is configured to generate a series of shock waves at frequencies between 1 Hz and 5 Hz.

22. The apparatus according to any one of claims 18 to 21, wherein, The housing is configured to be pressurized to a pressure of less than 10 atm.

23. The apparatus according to any one of claims 18 to 22, wherein, The elongated tube is configured to deliver an irrigation solution into at least one of the intranasal passage and the nasal cavity to clean the intranasal passage and the nasal cavity.

24. The device according to any one of claims 18 to 23, the device comprising a guidewire lumen disposed within the elongated tube and configured to receive a guidewire to guide the housing through an intranasal passage and into the nasal cavity.

25. The apparatus according to any one of claims 18 to 24, wherein, The elongated tube includes a guidewire lumen configured to receive a guidewire and an irrigation lumen configured to deliver an irrigation solution to at least one of the intranasal passage and the nasal cavity.

26. The apparatus according to claim 25, wherein, The guidewire lumen is disposed within the flushing lumen of the slender tube.

27. The apparatus according to claim 25 or 26, wherein, The flushing lumen extends through the length of the housing to the fluid outlet at the distal end of the housing.

28. The apparatus according to any one of claims 18 to 27, wherein, The elongated tube is configured to be connected to a syringe to fill the housing with the conductive fluid.

29. The apparatus according to any one of claims 18 to 28, wherein, The housing can be filled with an X-ray contrast agent to facilitate observation of the housing.

30. The apparatus according to any one of claims 18 to 29, wherein, The shell includes at least one of an elliptical balloon, a spherical balloon, and a hemispherical balloon.

31. The apparatus according to any one of claims 18 to 30, wherein, At least 20% of the surface of the housing is coated with the drug coating.

32. The apparatus according to any one of claims 18 to 31, wherein, The entire surface of the housing is coated with the drug coating.

33. The apparatus according to any one of claims 18 to 32, wherein, The drug coating may be in crystalline form, amorphous form, or a combination thereof.

34. The apparatus according to any one of claims 18 to 33, wherein, The drug coating comprises a plurality of microcapsules containing the active agent.

35. The apparatus according to claim 34, wherein, The plurality of microcapsules include a plurality of microspheres and / or a plurality of microcapsules having a diameter between 0.5 micrometers and 500 micrometers.

36. A system for intranasal drug delivery, the system comprising: The apparatus according to any one of claims 18 to 35; and A pulse generator, which is coupled to the at least one shock wave transmitter and configured to generate energy pulses so that the at least one shock wave transmitter generates the at least one shock wave.

37. The system according to claim 36, wherein, The pulse generator is configured to generate the energy pulses such that the at least one shock wave emitter generates a series of shock waves at a frequency between 1 Hz and 5 Hz.

38. The system according to claim 36 or 37, wherein, The pulse generator is configured to generate one or more voltage pulses so that the at least one shock wave transmitter generates a series of shock waves.

39. The system according to claim 38, wherein, The one or more voltage pulses include voltages between 1kV and 10kV.

40. The system according to any one of claims 36 to 39, wherein, The pulse generator is configured to generate one or more laser pulses such that the at least one shock wave emitter generates the at least one shock wave.

41. The system according to any one of claims 36 to 40, the system comprising an endoscope disposed adjacent to the device and including an imaging sensor located at a distal portion of the endoscope, the imaging sensor being configured to capture images of at least one of an intranasal passage and the nasal cavity.

Images