Methods and devices for delivering substances to the inner ear

Abstract

This disclosure provides an apparatus (30) for delivering a substance to the inner ear. The apparatus (30) includes a pressure oscillator (32) configured to generate pressurized air at a predetermined oscillation frequency; an auditory probe (31) including an air passage extending from a first end of the auditory probe (31) to a second end of the auditory probe (31), the first end being the end to be inserted into the ear canal; a tube (33) connecting the second end of the auditory probe (31) to the pressure oscillator (32); and a pressure relief valve (34) disposed on the tube (33) and / or the auditory probe (31), the pressure relief valve (34) being configured to release a portion or the generated pressurized air from the tube (33) and / or the auditory probe (31) when the pressure within the tube (33) and / or the auditory probe (31) reaches a predetermined maximum pressure. This disclosure also provides a method for delivering a substance to the inner ear, the method comprising the steps of: (i) applying the substance to the middle ear; and (ii) generating an oscillating air pressure within the ear canal.

Description

Technical Field

[0001] The present invention relates to methods and devices for delivering substances to the inner ear of a mammal. Background Art

[0002] The inner ear of mammals is one of the least accessible parts of the body for drugs. Systemic administration of many drugs, such as the frequently used corticosteroids and aminoglycoside antibiotics, is severely limited by the blood-maze barrier. Drug delivery through the ear canal is ineffective because the tympanic membrane (ear drum) is impermeable to water. Direct drug delivery to the cochlea is highly invasive and requires surgical intervention. Therefore, current approaches include local intratympanic drug delivery, i.e., administration into the middle ear cavity. For many existing and emerging drug and therapeutic classes, including local anesthetics, antioxidants, apoptosis inhibitors, neurotransmitters and their antagonists, monoclonal antibodies, growth factors, signaling pathway modulators, and genetic material, local intratympanic delivery may be the only option.

[0003] Intratympanic drug delivery usually involves injection into the tympanic cavity through the tympanic membrane. This is a minimally invasive and routine procedure. However, retention of the administered substance within the tympanic cavity is not directly achievable. The Eustachian tube connects the tympanic cavity to the nasopharynx, resulting in relatively rapid clearance of the administered substance from the tympanic cavity.

[0004] The inner ear includes the cochlea, whose anatomy provides particular difficulties for delivering drugs and other substances to it. The cochlea is a bony spiral tube that includes three fluid-filled compartments. The upper and lower compartments (scala vestibuli and scala tympani, respectively) form the cochlear spiral and communicate through a direct connection at the spiral body and contain a fluid: perilymph. The interface between the cochlea and the tympanic cavity is the round window and the oval window; semipermeable membranes with only a small surface area (the larger window, the round window, has a surface area of ​​only 2.2 square millimeters in humans).

[0005] Substances that penetrate into the round window or oval window are not adequately and / or unevenly distributed along the length of the cochlear spiral. The extent of distribution of substances in the scala tympani and scala vestibuli is limited by the low flow rates of the perilymph in the cochlea. The longitudinal flow of perilymph in the cochlea is relatively slow, if present, so that the distribution of substances in the perilymph depends solely on passive diffusion. In addition, passive diffusion along the scala tympani is limited by the geometry of the cochlea, which consists of a long, narrow tube whose cross-section decreases gradually from the round window at the base to the apex. This produces a large base-to-apex concentration gradient within the cochlea.

[0006] Because the apex of the cochlea is the starting point for human speech processing, the delivery of substances to the cochlea has the greatest potential therapeutic and socioeconomic impact. Direct measurements of the distribution of labeled ions, corticosteroids, and antibiotics, or measurements of the physiological effects induced by drug diffusion into the cochlea have shown that the concentration of substances applied to the round window is much higher at the base of the cochlea than at the apex. It has been found that allowing substances to remain in contact with the round window for arbitrarily long periods of time has no significant effect on the large base-to-apex concentration gradient. It has been found that prolonged residence of substances at the round window results only in the establishment of a steady-state base-to-apex gradient of substance concentration, the magnitude of which depends on the characteristics of the particular substance.

[0007]

[0006] It would therefore be desirable to provide improved methods and devices for delivering and distributing substances to the inner ear, particularly to the cochlea, and particularly along the cochlear spiral. Summary of the invention

[0008] According to one aspect of the present invention, there is provided a device for assisting the distribution of substances within the inner ear, comprising: a pressure oscillator; a hearing probe having an end that can be inserted into the ear canal; and a fluid channel that connects the pressure oscillator and the end fluid of the hearing probe that can be inserted into the ear canal; wherein the pressure oscillator is configured to generate oscillating fluid pressure changes in the fluid channel.

[0009] The pressure oscillator may be configured to generate positive and negative pressures in the fluid channel.

[0010] The pressure oscillator may be configured to generate a biphasic oscillating pressure variation in the fluid channel.

[0011] The predetermined maximum positive and / or negative operating pressure may be between 0.5 kPa and 20 kPa, preferably between 0.5 kPa and 4 kPa, more preferably between 0.5 kPa and 2 kPa.

[0012] The maximum amplitude of the operating pressure may be 4 kPa, optionally 2 kPa. This arrangement allows the tympanic membrane to be driven to its extreme position even when the middle ear cavity is filled with fluid. The pressure oscillator is configured to generate air pressure oscillations at a frequency in the range of 1 to 20 Hz, optionally 2 to 20 Hz, optionally 4 to 18 Hz, and optionally 8 to 16 Hz.

[0013] The device may include a pressure relief valve in communication with the fluid channel and configured to open when the pressure within the fluid channel reaches a predetermined maximum positive and / or negative pressure.

[0014] According to one aspect of the invention, there is provided a method of operating a device for assisting in the distribution of a substance within the inner ear, the device comprising a hearing probe having an end insertable into the ear canal, the method comprising generating oscillating fluid pressure variations in a fluid channel of the device to provide positive and negative pressures at the end of the hearing probe.

[0015] The device can be used to assist in delivering a substance to the inner ear, wherein the substance has been administered to the middle ear and wherein the device generates an oscillating air pressure within the ear canal. References in this application to a device for delivering a substance correspond to a device for assisting in delivering a substance within the inner ear, the substance having previously been administered to the middle ear. This can include at least one of inducing or promoting transfer of a substance from the middle ear to the inner ear, and inducing or promoting distribution of a substance in the inner ear along the cochlear spiral.

[0016] According to one aspect of the present invention, there is provided a computer program product comprising instructions which, when executed by a processor, cause the processor to perform at least one of the above methods.

[0017] According to one aspect of the present invention, there is provided a computer readable medium having stored therein the above-mentioned computer program product.

[0018] According to one aspect of the present invention, there is provided a non-transitory computer-readable medium comprising computer-readable instructions which, when executed by a processor, result in the execution of the method as described above.

[0019] In one aspect, the present invention provides an apparatus for delivering a substance to the inner ear, comprising: a pressure oscillator configured to generate pressurized air at a predetermined oscillation frequency;

[0020] a hearing probe comprising an air passage extending from a first end of the hearing probe to a second end of the hearing probe, the first end being the end to be inserted into the ear canal;

[0021] a tube for connecting the second end of the hearing probe to the pressure oscillator; and

[0022] The pressure relief valve disposed at the tube and / or the hearing probe is configured to release a portion of the pressurized air from the tube and / or the hearing probe when the pressure in the tube and / or the hearing probe reaches a predetermined maximum pressure.

[0023] According to an embodiment of the present invention, the hearing probe can be inserted into, for example, the ear canal and mammalian objects such as human patients, and the pressure oscillator can be operated so that the pressurized air set at a predetermined oscillation frequency can be produced. Pressurized air is delivered to the hearing probe from the pressure oscillator, and the pressurized air of the oscillation causes the reciprocating motion of the round window and / or oval window membrane and / or stapes, causing the perilymph to flow. Pressurized air is delivered to the hearing probe from the pressure oscillator via a fluid channel, and the fluid channel can be provided by a tube. Due to the movement of the round window and / or oval window membrane and / or stapes caused by the device according to the preferred embodiment, once material has been deposited in the middle ear and diffused into the cochlear perilymph, it is possible to improve material delivery to the inner ear along the cochlear spiral, and it is possible to improve the delivery to the top of the cochlea. Material can be improved to be distributed to the inner ear along the cochlear spiral. If and when the pressure in the tube and / or the hearing probe approaches or exceeds a predetermined maximum amplitude (e.g., 4kPa), a pressure relief valve can be operated to release some pressure from the tube and / or the hearing probe. According to an embodiment, the pressure relief valve ensures that the patient does not experience discomfort and that the patient's eardrum and inner ear are not injured or otherwise damaged by excessive pressure, so that a pressure range up to a predetermined maximum pressure for the subject can be safely used.

[0024] In an embodiment, the device may further include a pressure sensor connected to the tube, the pressure sensor being configured to determine the pressure within the tube. The pressure sensor may be located at the hearing probe or the pressure oscillator. The pressure sensor may be configured to determine the instantaneous pressure and / or the time-averaged pressure within the tube as desired.

[0025] In an embodiment, the device may further include a feedback module connected to the pressure sensor and the pressure oscillator, the feedback module being configured to compare the pressure within the fluid channel, such as a tube, determined by the pressure sensor with a predetermined operating pressure range, and to cause the pressure oscillator to make adjustments when generating pressurized air when the pressure within the tube is determined to be outside the predetermined operating pressure range.

[0026] Alternatively or additionally, embodiments of the device may further include a feedback module connected to the pressure sensor and the pressure relief valve, the feedback module being configured to compare the pressure within a fluid channel, such as a tube, determined by the pressure sensor with a predetermined maximum pressure, and to cause the pressure relief valve to release pressurized air within the tube and / or the hearing probe when the pressure within the tube is determined to be outside the predetermined maximum pressure.

[0027] In an embodiment, the feedback module may also be configured to continuously, intermittently or periodically perform the comparison and adjust the pressure within the tube based on the comparison. Thus, the pressure experienced by the patient may be monitored and maintained at a safe level.

[0028] According to the embodiment, the device can provide the beneficial technical effects described herein within any suitable and desired pressure and frequency range. However, in the embodiment, the predetermined operating pressure range of the pressure amplitude can be set between 0.5kPa and 4kPa, and / or the predetermined maximum pressure amplitude can be set to 4kPa to ensure the comfort and safety of the patient while providing maximum efficiency.

[0029] In an embodiment, the hearing probe may include an auxiliary air channel extending from the inner surface of the air channel to the outer surface of the hearing probe at the second end, the auxiliary air channel having a valve for closing or opening the auxiliary air channel. According to this embodiment, once the hearing probe is inserted and sealed in the patient's ear, the valve of the auxiliary air channel can be opened to balance the pressure on both sides of the tympanic membrane.

[0030] In an embodiment, the ear probe may include a Segal speculum or pneumatic otoscope arranged for visual inspection of tympanic membrane movement. This may be particularly useful when the patient is unable or unable to provide adequate feedback, for example, if the patient is a child or is under anesthesia.

[0031] In an embodiment, the hearing probe may include a seal for sealing the ear canal when the hearing probe is inserted into the ear canal. In some embodiments, the seal may include a disposal tip for improved convenience or hygiene.

[0032] In another aspect, the present invention provides a method for delivering a substance to the inner ear, the method comprising the steps of:

[0033] i) administering the substance to the middle ear; and

[0034] ii) Producing oscillating air pressure in the ear canal.

[0035] The present invention also provides a method for delivering a substance to the inner ear, wherein the substance has been applied to the middle ear, wherein the method comprises generating an oscillating air pressure in the ear canal.

[0036] Alternatively, the present invention provides a method for facilitating the delivery of a substance to the inner ear, the method comprising the steps of:

[0037] i) administering the substance to the middle ear; and

[0038] ii) Producing oscillating air pressure in the ear canal.

[0039] The present invention also provides a method for facilitating the delivery of a substance to the inner ear, wherein the substance has been applied to the middle ear, wherein the method comprises generating oscillating air pressure within the ear canal.

[0040] Alternatively, the present invention provides a method for facilitating the distribution of a substance within the inner ear, the method comprising the steps of:

[0041] i) administering the substance to the middle ear; and

[0042] ii) Producing oscillating air pressure in the ear canal.

[0043] The present invention also provides a method for aiding the distribution of a substance within the inner ear, wherein the substance has been administered to the middle ear, wherein the method comprises generating an oscillating air pressure within the ear canal.

[0044] In another aspect, the present invention provides a method for inducing or promoting the transfer of a substance from the middle ear to the inner ear, the method comprising the steps of:

[0045] i) administering the substance to the middle ear; and

[0046] ii) Producing oscillating air pressure in the ear canal.

[0047] The present invention also provides a method for inducing or promoting the transfer of a substance from the middle ear to the inner ear, wherein the substance has been administered to the middle ear, wherein the method comprises generating an oscillating air pressure in the ear canal.

[0048] In another aspect, the present invention provides a method of distributing a substance along a cochlear spiral, the method comprising the steps of:

[0049] i) administering the substance to the middle ear; and

[0050] ii) Producing oscillating air pressure in the ear canal.

[0051] The present invention also provides a method of distributing a substance along the cochlear spiral, wherein the substance has been administered to the middle ear, wherein the method comprises generating an oscillating air pressure in the ear canal.

[0052] The terms delivery and distribution are used interchangeably throughout.

[0053] The present invention also provides a method for inducing or promoting periodic flow of intraocular lymph and extraocular lymph in the inner ear, the method comprising generating oscillating air pressure in the ear canal.

[0054] In another aspect, the present invention provides a method for treating or preventing an inner ear disease, the method comprising the steps of:

[0055] i) administering a therapeutic compound to the middle ear; and

[0056] ii) Producing oscillating air pressure in the ear canal.

[0057] The invention also provides a method of treating or preventing an inner ear disorder wherein a therapeutic compound has been administered to the middle ear, wherein the method comprises generating oscillating air pressure within the ear canal.

[0058] Alternatively, the invention provides a therapeutic compound for use in a method for treating or preventing an inner ear disease, wherein the method comprises the steps of:

[0059] i) administering a therapeutic compound to the middle ear;

[0060] ii) Producing oscillating air pressure in the ear canal.

[0061] The invention also provides a therapeutic compound for use in a method of treating or preventing an inner ear disorder wherein the therapeutic compound has been administered to the middle ear and wherein the method comprises generating oscillating air pressure within the ear canal.

[0062] Alternatively, the invention provides the use of a therapeutic compound in a method for treating or preventing an inner ear disease, wherein the method comprises the following steps:

[0063] i) administering a therapeutic compound to the middle ear; and

[0064] ii) Producing oscillating air pressure in the ear canal.

[0065] The invention also provides for the use of a therapeutic compound in a method of treating or preventing an inner ear disorder, wherein the therapeutic compound has been administered to the middle ear, wherein the method comprises generating oscillating air pressure in the ear canal.

[0066] Alternatively, the present invention provides the use of a therapeutic compound in the preparation of a medicament for treating or preventing an inner ear disease, wherein the treatment or prevention comprises the following steps:

[0067] i) administering a therapeutic compound to the middle ear;

[0068] ii) Producing oscillating air pressure in the ear canal.

[0069] In all methods and uses of the invention, the generation of oscillating gas pressure is preferably achieved by use of the apparatus of the invention. Reference herein to an apparatus of the invention is a reference to any apparatus described herein.

[0070] Therefore, in another aspect, the present invention also provides the use of the device of the present invention in a method of the present invention. The method may be any method described herein.

[0071] Alternatively, the present invention provides the following uses:

[0072] The device of the present invention is used to generate oscillating air pressure in the ear canal.

[0073] The use of the device of the present invention to deliver substances to the inner ear comprises:

[0074] i) administering the substance to the middle ear;

[0075] ii) inserting the hearing probe of the device into the ear canal; and

[0076] iii) operating the device to generate an oscillating air pressure within the ear canal.

[0077] Use of a device of the invention to deliver a substance to the inner ear, wherein the substance has been administered to the middle ear, wherein the use comprises inserting an auditory probe of the device into the ear canal and operating the device to generate oscillating air pressure in the ear canal.

[0078] Use of the device of the present invention to assist in the delivery of a substance into the inner ear, said use comprising:

[0079] i) administering the substance to the middle ear;

[0080] ii) inserting the hearing probe of the device into the ear canal; and

[0081] iii) operating the device to generate an oscillating air pressure within the ear canal.

[0082] Use of a device of the invention to assist in the delivery of a substance into the inner ear, wherein the substance has been administered to the middle ear, wherein the use comprises inserting an auditory probe of the device into the ear canal and operating the device to generate oscillating air pressure in the ear canal

[0083] Use of the device of the present invention in assisting the distribution of substances in the inner ear, said use comprising:

[0084] i) administering the substance to the middle ear;

[0085] ii) inserting the hearing probe of the device into the ear canal; and

[0086] iii) operating the device to generate an oscillating air pressure within the ear canal.

[0087] Use of a device of the invention to aid distribution of a substance within the inner ear, wherein the substance has been administered to the middle ear, wherein the use comprises inserting an auditory probe of the device into the ear canal and operating the device to generate oscillating air pressure within the ear canal.

[0088] The use of the device of the present invention in inducing or promoting the transfer of substances from the middle ear to the inner ear includes:

[0089] i) administering the substance to the middle ear;

[0090] ii) inserting the hearing probe of the device into the ear canal; and

[0091] iii) operating the device to generate an oscillating air pressure within the ear canal.

[0092] Use of the device of the present invention for inducing or promoting the transfer of a substance from the middle ear to the inner ear, wherein the substance has been administered to the middle ear, and the use comprises inserting the hearing probe of the device into the ear canal and operating the device to generate oscillating air pressure in the ear canal.

[0093] The use of the device of the present invention for distributing a substance along the cochlear spiral includes:

[0094] i) administering the substance to the middle ear;

[0095] ii) inserting the hearing probe of the device into the ear canal; and

[0096] iii) operating the device to generate an oscillating air pressure within the ear canal.

[0097] Use of the device of the present invention for distributing a substance along the cochlear spiral, wherein the substance has been administered to the middle ear, and the use comprises inserting the hearing probe of the device into the ear canal and operating the device to generate oscillating air pressure in the ear canal.

[0098] The use of the device of the present invention in inducing or promoting the periodic flow of inner ear perilymph, wherein the use comprises inserting the hearing probe of the device into the ear canal, and operating the device to generate oscillating air pressure in the ear canal.

[0099] Use of the device of the present invention in treating or preventing inner ear diseases comprises the following steps:

[0100] i) administering a therapeutic compound to the middle ear;

[0101] ii) inserting the hearing probe of the device into the ear canal; and

[0102] iii) operating the device to generate an oscillating air pressure within the ear canal.

[0103] Use of the device of the present invention in the treatment or prevention of inner ear diseases, wherein the therapeutic compound has been administered to the middle ear, wherein the use comprises inserting the hearing probe of the device into the ear canal and operating the device to generate oscillating air pressure in the ear canal.

[0104] In the use of the present invention, the device may be as defined anywhere herein.

[0105] BRIEF DESCRIPTION OF THE DRAWINGS

[0106] Various embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0107] Figure 1Schematic diagram of the mammalian hearing organ, showing the ear canal (11), tympanic membrane (12), Eustachian tube (13), tympanic cavity (14), malleus (15), incus (16), stapes (17), oval window (18), round window (19), scala vestibuli (20), scala tympani (21) and cochlear foramen (22).

[0108] Figure 2 Representative examples of elevated auditory nerve pure tone threshold responses are shown when salicylate diffuses passively through the perilymph (A) or by generating oscillatory pressure redistribution in the ear canal (B). 5 μl of a 100 mM salicylate solution was applied to the round window at time = 0. Salicylate was washed out after 80 minutes (A) and 74 minutes (B) of application. (B) 4 Hz pressure oscillations were applied to the ear canal for 5 minutes before plotting each non-zero time point, and auditory nerve thresholds were measured during the next 5 minute interval in the absence of pressure oscillations. Similar results were observed in the other four preparations.

[0109] Figure 3 is a schematic diagram of a device for delivering a substance to the cochlea according to an embodiment.

[0110] Figure 4 Figure 2 shows the differential elevation of the auditory nerve threshold response in response to pure tones of frequencies 27 kHz (A), 21 kHz (B), 15 kHz (C), 11 kHz (D), 5 kHz (E), 3 kHz (F) and 1 kHz (G) after either untreated (passive diffusion, crossover) or after the generation of oscillatory pressure in the ear canal (oscillatory pressure, looping). Figure 2 Same as in . Pooled data from 5 experiments for each experimental protocol.

[0111] Detailed Description

[0112] In one aspect, the present invention provides a method for delivering a substance to the inner ear, the method comprising the steps of:

[0113] i) administering the substance to the middle ear; and

[0114] ii) Producing oscillating air pressure in the ear canal.

[0115] The method may alternatively be viewed as a method for aiding delivery of a substance to the inner ear, or a method for aiding distribution of a substance to the inner ear.

[0116] The inner ear includes the cochlea, the vestibular organ and the auditory nerve. According to the present invention, the delivery of substances to the inner ear can be delivery to any of these parts. However, preferably, delivery to the cochlea. The membrane barrier between the middle ear and the cochlea is the round window and the oval window. The two windows separate the middle ear (tympanic cavity) from the scala tympani and scala vestibuli of the cochlea. The scala tympani and scala vestibuli are filled with fluid; perilymph. The scala tympani and scala vestibuli form a cochlear spiral, winding and narrowing toward the top of the cochlea, where they are connected by the cochlear foramen. Therefore, the cochlea includes the cochlear bottom (near the round window and the oval window) and the narrower cochlear top. According to the present invention, delivery to the cochlea can be delivery to any of these cochlear parts. Preferably, delivery to the scala tympani and scala vestibuli. Preferably, delivery to the inner ear is delivery along the cochlear spiral. Preferably, delivery to the top of the cochlea.

[0117] Current methods of delivering substances to the inner ear do not adequately deliver substances along the cochlear spiral. Due to the geometry of the cochlea and the slow rate of intra- and extra-cochlear lymph flow, substances delivered to the middle ear are not delivered (i.e., distributed) along the cochlear spiral to a satisfactory extent by passive diffusion. The methods and devices of the present invention achieve delivery along the cochlear spiral, even to the top of the cochlea.

[0118] The cochlear spiral includes the cochlear base adjacent to the round window and the oval window and the cochlear top farthest from the round window and the oval window. Therefore, the base and the top can be considered as point positions; the end defines the length of the cochlear spiral. However, as used herein in the context of substance delivery, the term "cochlear base" is the region of the cochlear spiral closest to the round window and the oval window, and the region includes 25% of the length of the cochlear spiral. In other words, in the context of substance delivery, the cochlear base is the bottom region of the cochlear spiral, and the region includes 25% of the length of the cochlear spiral, or the bottom quarter of the cochlear spiral. Similarly, as used herein in the context of substance delivery, the term "cochlear top" is the region of the cochlear spiral farthest from the round window and the oval window (i.e., closest to the top), and the region includes 25% of the length of the cochlear spiral. In other words, in the context of substance delivery, the cochlear top is the top region of the cochlear spiral, and the region includes 25% of the length of the cochlear spiral, or the top quarter of the cochlear spiral. The middle region of the cochlear spiral is located between the base and the base region, and the region includes 50% of the length of the cochlear spiral. The base half of the cochlear spiral is the 50% of the length of the cochlear spiral near the round window and the oval window. The top half of the cochlear spiral is the 50% of the cochlear spiral distal to the round window and the oval window (i.e., close to the top).

[0119] As used herein, the term "along the cochlear spiral" includes delivery not only to the bottom region / quarter of the cochlear spiral but also to the middle region of the cochlear spiral, and preferably also includes delivery to the top region / quarter of the cochlear spiral. Preferably delivery is to the top half of the cochlear spiral, preferably delivery is to the top quarter of the cochlear spiral. The delivery of the substance is preferably a uniform distribution of the substance.

[0120] As described above, using current delivery methods, passive diffusion of substances within the cochlear spiral is limited and a significant base-to-apex concentration gradient is established. The methods of the present invention overcome such problems, resulting in a reduction of such concentration gradients. Using the methods of the present invention results in a reduction in the concentration difference of a substance between a first point closer to the base of the cochlea and a second point closer to the apex of the cochlea, as compared to the concentration difference observed between the same two points with the same substance and without performing the step of generating an oscillating air pressure within the ear canal.

[0121] The outer ear includes auricle and ear canal (also referred to as auditory canal). Tympanic membrane (ear drum) forms a barrier with the middle ear. The middle ear includes tympanic cavity (including the ossicular chain formed by malleus, incus and stapes) and Eustachian tube. According to the present invention, administering material to the middle ear can be to any one of these positions. For purposes of the present invention, administration to round window and oval window (membrane barrier between middle ear and inner ear) is considered to be administration to the middle ear, because administration is to the tympanic cavity side of the window. Preferably, administration is to the tympanic cavity or to round window or oval window. Preferably, administration is to the tympanic cavity or round window.

[0122] Administration to the middle ear is referred to as intratympanic administration. Methods for administering substances to the middle ear, particularly to the tympanic cavity, are well known in the art, and any such methods may be used in the methods of the present invention. Preferred methods include transtympanic injection, administration via an intratympanic device, and administration via the Eustachian tube.

[0123] The preferred method of drug delivery to the middle ear is transtympanic injection, a simple, low-risk outpatient procedure performed under local anesthesia. In these procedures, the tympanic membrane is perforated using a fine needle (preferably 22 to 25 G in humans and 27 to 30 G in animals) and a volume of solution is injected (preferably 0.4-0.6 mL in humans and 50-200 μL in animals), preferably filling the middle ear cavity. Injections can be performed using an otoscope device that includes a fiber optic lens for viewing and two working channels: a catheter channel equipped with a fine needle for delivering the drug and a suction channel for removing adhesions when the round window or oval window is blocked.

[0124] Alternatively, the middle ear can be administered by an intratympanic drug delivery device preferably selected from the group consisting of a microcore, a microcatheter, a biodegradable polymer device and a non-biodegradable polymer device. The microcore includes an absorbent core (wick) inserted through a ventilating tube in the tympanic membrane. The core delivers the solution administered to the external auditory canal to the middle ear. The microcatheter includes two lumens, one for administration to the middle ear and the other for extracting liquid. The microcatheter is inserted through a tympanomeatalflap, and the end of the catheter is withdrawn from the external auditory canal, allowing connection to a pump system to input drugs, such as osmotic pumps and micropumps. The polymer-based device is a solid sponge, bead or disc that is soaked in a drug solution and placed in the middle ear by surgery. Preferably, the polymer-based device is degradable, avoiding the need for surgical removal. The biodegradable materials used in these devices include gelatin sponge (sterile compressed sponge composed of purified porcine gelatin) and separapack (carboxymethyl cellulose and hyaluronic acid disc). Preferably, before generating oscillating air pressure in the ear canal, any drug delivery device is removed.

[0125] Alternatively, administration to the middle ear can be achieved through the Eustachian tube. This typically involves the use of intranasal medications, preferably drops or sprays, more preferably drops. Administration through the Eustachian tube orifice can also include its cannulation.

[0126] The present invention also provides methods for delivering a substance to the inner ear (i.e., assisting the delivery of a substance to the inner ear or assisting the distribution of a substance to the inner ear), and other methods, wherein the substance has already been applied to the middle ear, and wherein the method comprises generating oscillating air pressure within the ear canal. Such methods of the present invention do not include the active step of applying the substance to the middle ear; this is done previously, so the substance is already in place in the middle ear before the method of the present invention begins.

[0127] The method of the present invention is preferably performed on a human or mammalian subject, most preferably on a human subject. Therefore, the characteristics of the ear referred to herein are preferably characteristics of a human or mammalian ear, most preferably characteristics of a human ear.

[0128] The substance delivered according to the present invention can be any substance that can penetrate the round window and / or oval window membrane. Such compounds are well known and are easily identified by technicians. The permeability of the round window and oval window membrane is affected by different factors such as the size, concentration, hydrophilicity, charge of the substance and the thickness and condition of the window membrane. It is within the capabilities of those of ordinary skill in the art to determine the ability of the substance to penetrate the round window and / or oval window membrane. For example, the permeability of the round window membrane is discussed in Microscope Research and Technology (Goycoolea & Lundman, 1997, Microsc Res Tech.36 (3): 201-11) and Acta Otolaryngol (Goycoolea, 2001, Acta Otolaryngol.121 (4): 437-447).

[0129] Preferably, the delivered substance is a therapeutic compound. As used herein, the term "therapeutic compound" refers to any physical, chemical or biological substance that can be used to treat, cure, prevent, control or diagnose a pathological condition (such as a disease or disorder), or can be used to otherwise enhance physical, psychological or mental health. The terms "therapeutic compound," "active agent," and "drug" are used interchangeably herein.

[0130] However, the delivered material can be selected from the group consisting of therapeutic compounds, adjuvants, biologically inert compounds, dyes, imaging compounds (e.g., contrast agents), cosmetic agents, diagnostic agents, and physiologically acceptable excipients. Preferably, the physiologically acceptable excipient is selected from stabilizers, permeants, preservatives, tonicity agents, chelating agents, mucoadhesive agents, and penetration enhancers. The delivered material can be a mixture of two or more such materials. Preferred dyes include rhodamine B, carboxycyanine, and Nile red. The preferred contrast agent is gadolinium.

[0131] Preferably, the therapeutic compound is selected from antimicrobial agents (including antibacterial agents, antiviral agents and antifungal agents), antitumor agents, thrombin inhibitors, anticoagulants, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antibiotics, surface glycoprotein receptor inhibitors, antiplatelet agents, antimitotic agents, microtubule inhibitors, antisecretory agents, actin inhibitors, remodeling inhibitors, antimetabolites, antiproliferatives (including antiangiogenic agents), anticancer chemotherapeutic agents, anti-inflammatory steroids or non-steroidal anti-inflammatory agents, Immunosuppressants, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, extracellular matrix components, ACE inhibitors, reactive oxygen species scavengers and their inducers, chelating agents, antioxidants, anti-polymerases, photodynamic therapy agents, prostaglandin receptor agonists, JNK stress kinase inhibitors, peroxisome proliferator-activated receptor agonists, NOX and NOS enzyme inhibitors, RNAi agents, glutamate receptor blockers, glutathione peroxidase inducers, anti-apoptotic agents, differentiation regulators and genetic material (plasmids and viral vectors).

[0132] Preferably, the substance is selected from the group consisting of antibiotics, antiseptics, local anesthetics, dyes, proteins, genetic material, viruses or nanoparticles.

[0133] Preferably, the therapeutic compound is a therapeutic compound for treating inner ear diseases. Preferably, the therapeutic compound is selected from the group consisting of proteins, peptides, non-protein drugs, chemical small molecules, carbohydrates, lipids, lipopolysaccharides, nucleic acids, viral vectors and stem cells.

[0134] Preferably, the therapeutic compound is selected from a steroid, an antibiotic, an antioxidant, an anesthetic, an n-methyl-d-aspartate receptor antagonist, an antiviral agent, an antifungal agent, an apoptosis inhibitor, an enzyme inhibitor, a neurotrophic factor or a neuroprotectant, an antibody, a nucleic acid, a viral vector or a stem cell.

[0135] Preferably, the steroid is a corticosteroid, preferably dexamethasone or methylprednisolone. Preferably, the antibiotic is an aminoglycoside antibiotic, preferably gentamicin, streptomycin or kanamycin. Preferably, the antioxidant is n-acetylcysteine, d-methionine or thiourea. Preferably, the anesthetic is a local anesthetic, preferably lidocaine. Preferably, the n-methyl-d-aspartate receptor antagonist is esketamine, gacyclidine or ifenprodil. Preferably, the antiviral agent is cidofovir or ganciclovir. Preferably, the apoptosis inhibitor is a JNK inhibitor, preferably an AM-111 peptide. Preferably, the neurotrophic factor is brain-derived neurotrophic factor (BDNF), neurotrophin-3 or a growth factor. Preferably, the antibody is a monoclonal antibody, preferably infliximab (Infliximab), golimumab (Golimumab), anakinra (Anakinra) or rituximab (Rituximab). Preferably, the nucleic acid is a polynucleotide, an antisense nucleotide, an RNA molecule, a DNA molecule, an siRNA molecule, an miRNA molecule, a gene or a vector. Preferably, the vector is a plasmid or a viral vector, preferably a plasmid. Preferably, the nucleic acid is used for gene therapy.

[0136] The administered substance, such as a therapeutic compound, is preferably administered in the form of a pharmaceutically acceptable salt, solvate, clathrate, prodrug, tautomer or metabolic derivative thereof.

[0137] The substance to be administered, such as a therapeutic compound, is preferably in the form of a pharmaceutical composition that also includes one or more pharmaceutically acceptable diluents, carriers or excipients. The pharmaceutical composition can be formulated in any convenient manner according to techniques and procedures known in the pharmaceutical field. As used herein, "pharmaceutically acceptable" refers to ingredients that are compatible with the other ingredients of the composition and physiologically acceptable to the recipient. The properties, dosage, etc. of the composition and the carrier or excipient materials can be selected in a conventional manner according to the selected and desired route of administration, therapeutic purpose, etc. The dosage can also be determined in a conventional manner and may depend on the properties of the molecule, therapeutic purpose, patient age, mode of administration, etc.

[0138] Preferably, the excipient is selected from the group consisting of stabilizers, osmotic agents, preservatives, tonicity agents, chelating agents, mucoadhesive agents and penetration enhancers. Preferably, the therapeutic compound is in the form of a pharmacologically acceptable salt.

[0139] Preferably, the substance, e.g., therapeutic compound, is administered in combination with one or more auxiliary compounds selected from the group consisting of another therapeutic compound, an adjuvant, a biologically inert compound, a dye or imaging compound (e.g., a contrast agent), a cosmetic agent, and a diagnostic agent.

[0140] The substance to be administered is preferably in the form of a liquid, hydrogel or nanocarrier or contained in a liquid, hydrogel or nanocarrier, most preferably a liquid. Preferably, the liquid is an aqueous solution or a lipid-based formulation.

[0141] The hydrogel has high viscosity and viscoelasticity, which can reduce the flow rate through the Eustachian tube, thereby extending the residence time in the middle ear. The hydrogel used in the present invention preferably contains a synthetic thermosensitive polymer, preferably poloxamer 407, PLGA-PEG-PLGA copolymer or a derivative thereof, or a natural polymer, preferably chitosan, hyaluronic acid, collagen, gelatin or a derivative thereof, in addition to the substance to be delivered. The preparation of hydrogels is well known in the art, and a skilled person will be able to easily prepare a hydrogel containing a substance of interest for administration to the middle ear.

[0142] Nanocarriers suitable for administration to the middle ear are also well known in the art (see, e.g., Kechai et al., (2015) International Journal of Pharmaceutics 494:83-101)) and any such nanocarriers may be used in the methods of the present invention.

[0143] Preferably, the nanocarrier is selected from liposomes, lipid nanocapsules, glycerol monooleate-based nanoparticles, poly(lactic-co-glycolic acid) nanoparticles, polymerosomes and dendrimer-based nanoparticles. The polymerosomes used in the present invention include self-assembled amphiphilic block copolymers such as poly(ethylene glycol)-b-poly(e-caprolactone) (PEG-b-PCL) and poly(2-hydroxyethylasparagine (PHEA). Dendrimer-based nanoparticles are randomly branched dendrimers. Preferred dendrimer-based nanoparticles include hyperbranched poly-L-lysine (HBPL).

[0144] Preferably, the nanocarrier has a size range of 10 to 640 nm in diameter, preferably 10 to 250 nm in diameter.Preferably, the nanocarrier comprises a surface modification, preferably with PEG, antibodies, peptides, carbohydrates, chitosan, hyaluronic acid, synthetic cationic lipids or folic acid.

[0145] The methods of the present invention all include the step of generating an oscillating air pressure in the ear canal. The ear canal, also known as the auditory canal, external ear canal, external auditory canal, external acoustic meatus and external auditory meatus (EAM), is the passageway extending from the auricle (external ear) to the tympanic membrane (eardrum).

[0146] The resting pressure in the ear canal is equal to the ambient pressure in mammals, including humans, adults and children. The resting pressure in the tympanic cavity is the same as the resting pressure in the ear canal; this balance is a function of the Eustachian tube.

[0147] Therefore, the method of the present invention includes the step of generating pressurized air at a predetermined oscillation frequency. The means for performing such steps are preferably described elsewhere herein. In order to generate air pressure changes in the ear canal, it is best to first seal the ear canal to prevent air leakage. This is easily achieved by inserting the tip of the probe into the ear canal. These steps are preferred in the method of the present invention. Then, air pressure oscillations are generated by using a pressure pump connected to the probe. This will be within the capabilities of a person of ordinary skill in the art.

[0148] When the hearing probe is inserted or pushed into the ear canal, the action of insertion or pushing may cause a static positive pressure to build up in the area between the probe and the tympanic membrane. In some embodiments of the device, a closable (e.g., by a valve) auxiliary air passage is provided through the probe, which, when operated (e.g., the valve is open), allows the pressure on either side of the tympanic membrane to be balanced after the probe is positioned and before the device is operated. Therefore, the method of the present invention includes the step of balancing the air pressure in the ear canal and the air pressure in the tympanic cavity after the hearing probe is inserted into the ear canal and before the oscillating air pressure is generated.

[0149] The oscillating or reciprocating pressure changes may then be generated by any means known in the art. A suitable pressure generating device known in the art may be used as the pressure oscillator of the device and connected to the hearing probe as required. For example, the oscillating pressure may be generated by the reciprocating displacement of a moving part within the pressure generating device, such as by the displacement of a diaphragm or membrane. Alternatively, the oscillating pressure may be generated by regulating the pressure from a constant pressure source within the pressure generating device. Thus, the step of generating an oscillating pressure within the ear canal includes operating the pressure generating device to generate the oscillating pressure, which is within the capabilities of a person of ordinary skill in the art.

[0150] Typically, the oscillating pressure is generated by a pressure pump connected or otherwise coupled to the hearing probe. The hearing probe preferably includes an air passage extending from a first end inserted into the ear canal and a second end. Typically, a pressure generating device, such as a pressure pump or an oscillator, is connected to the second end of the hearing probe, preferably via a tube.

[0151] A tympanometer is a device known in the art that causes pressure changes in the sealed ear canal by means of a pressure pump. Tympanometers are known in the art for testing middle ear function. They generate sound in a single cycle of very slow pressure changes in the ear canal and measure the reflectivity of this sound.

[0152] The air pressure oscillations may be provided by a pressure pump connected to a pressure oscillator, which may be configured to generate or otherwise output pressurized air at a predetermined oscillation frequency. In some embodiments, the pressure oscillator may include a multiplexer for switching alternately between atmospheric pressure (i.e., applying zero differential pressure across the tympanic membrane) and the pressure pump at a predetermined frequency to an input from the hearing probe (e.g., through a tube) to generate air pressure at a predetermined pressure, thereby generating pressure pulses at a predetermined amplitude at a predetermined oscillation frequency.

[0153] By "oscillating air pressure" is meant that the pressure generated in the ear canal oscillates between a maximum pressure and a minimum pressure. The pressure generated in the ear canal corresponds to the pressure generated in the device. The pressure change applied in the ear canal corresponds to the pressure change applied in the device. The fluid channel is defined in the device between the pressure generating device and the port of the device that communicates with the ear canal. The pressure change generated may be single-phase (i.e., deviating from the resting pressure in the positive or negative direction) or biphasic (i.e., deviating from the resting pressure in both the positive and negative directions). In other words, the maximum positive pressure generated is greater than the resting pressure and / or the maximum negative pressure generated is lower than the resting pressure. The pressure change generated may be biphasic. In other words, the method and use may include the step of generating a biphasic oscillating air pressure in the ear canal. In some embodiments, the deviation from the resting pressure in the positive and negative directions is sinusoidal.

[0154] In all cases, the maximum deviation from the resting pressure, i.e. the maximum magnitude (i.e. the amplitude) of the pressure variation generated in the ear canal should not exceed 20 kPa, i.e. ±20 kPa, and preferably should not exceed 4 kPa, i.e. ±4 kPa, and more preferably should be 2 kPa, i.e. ±2 kPa relative to the resting pressure in the ear canal. Thus, the amplitude of the applied pressure variation is limited. As mentioned above, preferably the tympanic cavity pressure is equalized to the ear canal pressure before generating the oscillating pressure in the ear canal. This ensures that the pressure generated in the ear canal does not damage the eardrum, which would occur if the pressure difference between the ear canal and the tympanic cavity exceeds 20 kPA, i.e. ±20 kPa.

[0155] The maximum deviation from the resting pressure, ie the maximum amplitude of the pressure change produced in the ear canal, is in an embodiment at least 0.5 kPa, ie ±0.5 kPa.

[0156] In an embodiment, the oscillating pressure generated in the ear canal has a maximum magnitude (i.e., amplitude) between 0.5 kPa and 4 kPa, i.e., between ±0.5 kPa and ±4 kPa. Such an amplitude allows for maximum deflection of the ear drum while limiting any possible damage to the ear drum.

[0157] The oscillations are configured to produce maximum, harmonic fluid motion.

[0158] By providing a sinusoidal pressure variation, the movement of the tympanic membrane can be maximized and, therefore, the movement of the fluid in the cochlea maximizes the distribution of the drug along it. The pressure amplitude generated is provided by the resting pressure. Therefore, this movement of the tympanic membrane towards the end can be maximized.

[0159] The generation of pure harmonic pressure avoids signal distortion and the generation of harmonics (signals at frequencies 2f, 3f, ... of the main frequency). This limits the stimulation of the cochlea, which could deafen the user if the pressure oscillations contained high-order harmonics.

[0160] In an embodiment, the method comprises generating air pressure oscillations at a frequency in the range of 1 to 20 Hz, more preferably 2 to 20 Hz, still more preferably 4 to 18 Hz, still more preferably 8 to 16 Hz. Oscillations with a frequency in the range of 2 to 10 Hz may be used.

[0161] The step of generating an oscillating pressure in the ear canal is preferably performed immediately after the substance is applied to the middle ear. However, the step of generating an oscillating pressure in the ear canal can be performed in a short time, preferably up to 15 minutes, more preferably up to 10 minutes, and even more preferably up to 5 minutes. In other words, the step of generating an oscillating pressure in the ear canal can be started within 15 minutes after the step of applying the substance to the middle ear, more preferably within 10 minutes, more preferably within 5 minutes, and most preferably immediately after the step of applying the substance to the middle ear is completed.

[0162] After administering the drug to the middle ear, the patient is usually asked to lie still for about 30 minutes. This period of time after the intratympanic administration is the preferred time to perform the oscillating pressure generating step of the present method. Preferably, the patient lies down during the execution of the oscillating pressure generating step. Therefore, preferably, the oscillating air pressure in the ear canal lasts for 1 to 30 minutes, more preferably 5 to 30 minutes, more preferably 5 to 20 minutes, more preferably 10 to 20 minutes, and most preferably about 15 minutes. It is also possible to use a duration of 1 to 20 minutes, 1 to 15 minutes, 1 to 10 minutes, 1 to 5 minutes, 5 to 10 minutes, 5 to 15 minutes, 10 to 30 minutes or 10 to 15 minutes.

[0163] The inventors of the present invention have recognized that, contrary to conventional practice, the generation of oscillating air pressure, particularly when the pressure changes generated are biphasic, can result in the entry of substances from the tympanic cavity into the cochlea and along the cochlear spiral via the cyclical flow of the perilymph. Without wishing to be bound by theory, it is believed that the generation of oscillating air pressure in the ear canal, particularly the changes in biphasic pressure, results in the reciprocating movement of the round window membrane and / or the oval window membrane and / or the stapes, resulting in the flow of perilymph. Using the method of the present invention, substances deposited in the middle ear, particularly in the tympanic cavity and on the round window and the oval window, can be successfully diffused into the cochlear perilymph and along the entire cochlear spiral. Using the method of the present invention, the inventors have demonstrated that the delivery of substances to the inner ear is improved by improving the distribution along the cochlear spiral, and even the delivery of substances to the top of the cochlea is improved.

[0164] Therefore, the present invention also provides a method for inducing or promoting the transfer of substances from the middle ear to the inner ear, the method comprising the steps of:

[0165] i) administering the substance to the middle ear; and

[0166] ii) Producing oscillating air pressure in the ear canal.

[0167] The present invention also provides a method of inducing or promoting transfer of a substance from the middle ear to the inner ear, wherein the substance has been administered to the middle ear and wherein the method comprises generating an oscillating air pressure in the ear canal.

[0168] As used herein, "induce" refers to the initiation of transfer, while "promote" refers to increasing the amount or rate of transfer as compared to the amount or rate of transfer that would occur without the generation of oscillating air pressure within the ear canal.

[0169] The present invention also provides a method for distributing a substance along a cochlear spiral, the method comprising the following steps:

[0170] i) administering the substance to the middle ear; and

[0171] ii) Producing oscillating air pressure in the ear canal.

[0172] The present invention also provides a method of distributing a substance along a cochlear spiral, wherein the substance has been administered to the middle ear, wherein the method comprises generating an oscillating air pressure within the ear canal.

[0173] The present invention also provides a method for inducing or promoting periodic flow of intraocular lymph and extraocular lymph in the inner ear, the method comprising generating oscillating air pressure in the ear canal.

[0174] As used herein, the term "periodic flow" refers to a perilymph flow pattern having a repetitive nature that results from the oscillatory nature of the pressure variations generated in the ear canal.

[0175] The definitions, preferred and optional features and embodiments disclosed for the method of delivering a substance to the inner ear apply mutatis mutandis to each and all of these additional methods of the invention.

[0176] Given that the methods of the present invention enable improved delivery of substances, including therapeutic compounds, to the inner ear, they have significant advantages in the treatment and prevention of inner ear diseases.

[0177] Therefore, in another aspect, the present invention provides a method for treating or preventing an inner ear disease, the method comprising the steps of:

[0178] i) administering a therapeutic compound to the middle ear; and

[0179] ii) Producing oscillating air pressure in the ear canal.

[0180] The invention also provides a method of treating or preventing an inner ear disorder wherein a therapeutic compound has been administered to the middle ear and wherein the method comprises generating oscillating air pressure within the ear canal.

[0181] Alternatively, the invention provides a therapeutic compound for use in a method for treating or preventing an inner ear disease, wherein the method comprises the steps of:

[0182] i) administering a therapeutic compound to the middle ear; and

[0183] ii) Producing oscillating air pressure in the ear canal.

[0184] The invention also provides a therapeutic compound for use in a method of treating or preventing an inner ear disorder, wherein the therapeutic compound has been administered to the middle ear, and wherein the method comprises generating oscillating air pressure within the ear canal.

[0185] Alternatively, the invention provides the use of a therapeutic compound in a method for treating or preventing an inner ear disease, wherein the method comprises the following steps:

[0186] i) administering a therapeutic compound to the middle ear; and

[0187] ii) Producing oscillating air pressure in the ear canal.

[0188] The invention also provides for the use of a therapeutic compound in a method of treating or preventing an inner ear disorder, wherein the therapeutic compound has been administered to the middle ear, and wherein the method comprises generating oscillating air pressure within the ear canal.

[0189] Alternatively, the present invention provides the use of a therapeutic compound in the preparation of a medicament for treating or preventing an inner ear disease, wherein the treatment or prevention comprises the following steps:

[0190] i) administering a therapeutic compound to the middle ear; and

[0191] ii) Producing oscillating air pressure in the ear canal.

[0192] As used herein, "treatment" includes any therapeutic application that can benefit humans or non-human animals (such as non-human mammals). Both human and veterinary treatments are within the scope of the present invention, although the present invention is primarily directed to human treatments. Treatment can be for an existing disease or condition, or it can be preventative. Therefore, both treatment and prevention are included in the present invention.

[0193] Preferably, in the treatment methods of the present invention, a pharmaceutically effective amount of a therapeutic compound is administered to the middle ear, or has been previously administered to the middle ear. "Pharmaceutically effective amount" refers to an amount that will result in the desired pharmacological and / or therapeutic effect, i.e., an amount of a medicament that is effective to achieve its intended purpose. Although the needs of individual patients may vary, it is within the capabilities of those skilled in the art to determine the optimal range of an effective amount of an active agent. In general, the dosage regimen for treating a disease or condition using any of the compounds described herein is selected based on a variety of factors, including factors such as the nature of the condition and its severity.

[0194] The dosage required to achieve the desired activity of the compounds described herein will depend on various factors, such as the compound selected, whether the treatment is therapeutic or preventive, and the nature and severity of the disease or condition. Generally, the physician will determine the actual dosage that is most suitable for the individual subject. The specific dosage level and frequency of administration for any particular patient may vary, depending on factors such as the activity of the specific compound used, the metabolic stability and duration of action of the compound, the age of the patient, the timing of administration, and the severity of the particular condition.

[0195] The method of the present invention is generally applicable because it enhances the passage of general substances to the inner ear. Thus, the inner ear disease treated or prevented according to the present invention may be any ear disease.

[0196] Preferably, the inner ear disease is selected from hearing loss, preferably age-related hearing loss (ARHL), sensorineural hearing loss (SNHL), chemical hearing loss (CIHL), noise-induced hearing loss (NIHL); ototoxicity; Meniere's disease; tinnitus; infection, preferably bacterial, viral or fungal infection; inflammation; autoimmune diseases, preferably immune-mediated cochleo-vestibular diseases (IMCVDs) and autoimmune inner ear diseases (AIED); congenital diseases or disorders and inner ear vestibular dysfunction.

[0197] The therapeutic compound for treating inner ear diseases is well defined and any therapeutic compound can be used according to the present invention. The therapeutic compound is preferably as defined above. The therapeutic compound is preferably present in a pharmaceutical composition as described above, preferably as a liquid, hydrogel or nanocarrier as described above.

[0198] Preferably, the therapeutic compound and the inner ear disease are selected from the following:

[0199]

[0200] Reference now Figure 3 , shows an embodiment of a device for delivering a substance into the cochlea. The device 30 includes an auditory probe 31, a pressure oscillator 32, and a tube 33. A fluid channel is defined in the device 30. The fluid channel defines a fluid path between the pressure oscillator 32 and the end of the auditory probe 31 inserted into the patient's ear. The auditory probe 31, the pressure oscillator 32, and the tube 33 may at least partially define the fluid channel. The device 30 has a pressure relief valve 34.

[0201] The hearing probe 31 is configured to be inserted into the patient's ear, for example, into the patient's ear canal, and the hearing probe 31 includes a hole through which pressurized air is delivered to the patient's ear. The hearing probe 31 includes an air channel, which extends from a first end to a hole to a second end opposite to the first end, and the first end is the end to be inserted into the ear canal. The opening at the first end defines the end of the fluid channel. The oscillating air pressure applied to the patient's tympanic membrane can cause the reciprocating motion of the tympanic membrane. The air pulses pressurized with the suitable and desired pressure within a predetermined range are produced or otherwise exported by the pressure oscillator 32 at a predetermined frequency. In some embodiments, a pressure pump (not shown) connected to the pressure oscillator 32 is provided for producing or outputting air pressure oscillations with a predetermined oscillation frequency. In an embodiment, the pressure pump forms a part of the pressure oscillator 32 or forms the pressure oscillator 32. According to the present embodiment, the pressure oscillator preferably includes a multiplexer, which alternately switches the input of the hearing probe between atmospheric pressure (or zero pressure difference across the tympanic membrane) and the pressure pump group at a predetermined frequency, to produce air pressure under a predetermined pressure, thereby producing pressure pulses with a predetermined oscillation frequency with a predetermined amplitude. In an embodiment, the oscillating air pressure is produced with a frequency in the range of 2 to 20Hz. The oscillating air pressure can be transmitted to the hearing probe 31 from the pressure oscillator 32 by pipe 33. Pipe 33 is made of flexible materials such as rubber and silicone, but other flexible, rigid or semi-flexible materials are also considered. In an embodiment, pipe 33 is connected to the hearing probe 31 by a pressure reducing valve 34. The pressure reducing valve 34 is configured to allow pressurized air to escape from pipe 33 or the hearing probe 31 before reaching the patient's ear, so as to avoid excessive stimulation of the tympanic membrane due to excessive air pressure, thereby preventing the tympanic membrane from rupturing. The pressure reducing valve 34 can be configured to manually release the pressurized air in the pipe 33 and / or the hearing probe 31 by switches, buttons, etc., or can be configured to automatically release the pressurized air by a feedback mechanism.

[0202] A processor 37 is provided. The processor 37 is part of a control unit configured to control the pressure oscillator 32 and / or the pressure reducing valve 34. The control unit includes a memory. The processor 37 is operable to control the oscillator 32 and / or the pressure reducing valve 34 to adjust the pressure in the device and thus the pressure in the ear canal. The control unit in some embodiments is part of the pressure oscillator 32.

[0203] In some embodiments, a pressure sensor 35 may be provided for measuring the air pressure within the tube 33. The pressure sensor 35 may be configured to continuously monitor the air pressure within the tube 33, or may be configured to intermittently or periodically determine the air pressure within the tube 33. As desired, the pressure sensor 35 may be configured to determine the instantaneous pressure within the tube 33, or may be configured to determine the time-averaged pressure within the tube 33 over a period of time. Thus, the air pressure delivered to the patient's ear may be continuously or periodically monitored and the air pressure may be manually adjusted as needed using the pressure oscillator 32 or the pressure reducing valve 34.

[0204] In a further embodiment, a feedback mechanism may be provided between the pressure sensor 35 and the pressure reducing valve 34, including a feedback signal line 36 and a processor 37. The signal from the pressure sensor 35 is processed by the processor 37 to determine whether the pressure in the tube 33 exceeds a predetermined maximum pressure. If it is determined that the pressure in the tube 33 exceeds the predetermined maximum pressure, the pressure reducing valve 34 is activated to release the pressurized air from the tube 33. Alternatively or additionally, the feedback signal line 36 may be provided between the pressure sensor 35 and the pressure oscillator 32. For example, the desired air pressure may be set by the user, and the signal from the pressure sensor 35 is processed by the processor 37 to determine whether the pressure in the tube 33 is within a predetermined tolerance range of the desired air pressure. When the processor 37 determines that the air pressure in the tube 33 exceeds the tolerance range, the processor 37 causes the pressure oscillator 32 to adjust the output air pressure upward or downward as required. The feedback signal line 36 and the processor 37 may be provided as an integrated feedback module. Alternatively, the processor 37 is part of a control unit configured to control the pressure oscillator 32 and / or the pressure reducing valve 34. Thus, the air pressure delivered to the patient's ear may be continuously monitored and automatically adjusted.

[0205] In further embodiments, a Siegel speculum or pneumaticotoscope (not shown) may be used as an alternative or in addition to the auditory probe 31. The auditory probe 31 may include a Siegel speculum or pneumaticotoscope (not shown). The Siegel speculum or pneumaticotoscope allows observation of the movement of the tympanic membrane in the patient's ear and is therefore particularly useful for patients who are unable to provide adequate verbal feedback during the procedure, such as young children or patients who have had their tympanic membrane desensitized by anesthesia.

[0206] According to the present disclosure, oscillating air pressure in the ear canal causes oscillatory motion of the eardrum, which is transmitted to the cochlear fluid through the middle ear bones. The substance can be pre-installed in the middle ear cavity by any suitable means, such as applying the substance to the round window membrane and / or the oval window membrane, and the substance diffuses into the cochlea through the round window membrane and the oval window membrane. The reciprocating motion of the round window membrane and the oval window membrane of the cochlea and the associated periodic fluid motion can improve the distribution of the substance along most or even the entire length of the cochlear spiral. Without being bound by theory, this process may be due to the combined effects of cochlear duct narrowing and chaotic advection.

[0207] Application to human patients

[0208] In embodiments of the method and / or apparatus 30 implemented on a human patient, the drug solution can be loaded into the patient's middle ear through the tympanic membrane or through the Eustachian tube. The patient's head can be positioned to prevent the drug solution from escaping through the Eustachian tube.

[0209] In this embodiment, the hearing probe 31 is sealed in the patient's ear canal. In conventional clinical use, an airtight seal with the ear canal can be provided by a series of hearing probes of different shapes and sizes to allow for the natural variation in ear shape and size of different patients. In some embodiments, for convenience and / or hygienic reasons, a series of disposable tips can be used in conjunction with a common probe base to achieve this.

[0210] Optionally, since the hearing probe 31 is to be sealed in the patient's ear canal, it may be necessary to provide a closable auxiliary air channel 38 through the probe 31, so that the pressure on either side of the tympanic membrane can be equalized after the hearing probe 31 is placed in the patient's ear and before the device 30 is operated. The auxiliary air channel 38 is arranged to extend from the inner surface of the air channel of the hearing probe 31 to the outer surface of the hearing probe at the second end, and preferably includes a closable valve for opening or closing the auxiliary air channel.

[0211] In this embodiment, an oscillating air pressure having a frequency of 2 to 20 Hz is generated by a pressure oscillator 32 and delivered to an auditory probe 31. The oscillating air pressure is transmitted through a flexible tube 33. A maximum oscillation frequency can be set to avoid irritating the sensory organs of the cochlea and potentially causing permanent hearing loss. For example, the maximum frequency of the pressure oscillation can be set to 20 Hz, which corresponds approximately to the cutoff frequency of the human cochlear aperture.

[0212] The stimulation of pressure oscillations preferably starts from a low peak pressure value, such as 0.5 kPa, preferably from a zero peak pressure value, and gradually increases the air pressure as needed, while ensuring that the patient does not experience any unpleasant sensations or pain. A Segal otoscope or pneumatic otoscope may be substituted for or added to the auditory probe 31 to allow visualization of tympanic membrane movement, particularly in patients who are unable to provide adequate feedback during the procedure, such as young children or patients with tympanic membrane desensitization through anesthesia.

[0213] At a pressure of about 20 kPa or higher, a mild, moderate to severe eardrum rupture may occur. Therefore, it may be necessary to pre-set the pressure relief valve 34 to a maximum pressure of 20 kPa or less to avoid over-stimulation and eardrum rupture due to excessive air pressure.

[0214] Setting the pressure oscillator 32 to displace the same volume of air does not guarantee a constant pressure at the tympanic membrane. During surgery, the pressure at the tympanic membrane may change due to movement of the hearing probe 31, changes in the shape of the ear canal, changes in the mechanical impedance of the middle ear, etc. Therefore, it may be necessary to set a pressure sensor 35 to periodically measure the instantaneous pressure in the tube 33 to continuously monitor the actual pressure at the tympanic membrane and continuously adjust the tube pressure to the desired value automatically through the feedback signal line 36 or using manual control of the pressure oscillator 32.

[0215] Further embodiments, optional and alternative features are contemplated. For example, while preferred embodiments have been described with respect to pressure stimulation through the ear canal, the pressure changes may alternatively or additionally be produced through the Eustachian tube, or differently through the Eustachian tube and the ear canal. For patients with tympanic membrane damage, fluid movement and distribution of intra-cochlear material may be achieved by direct movement of the ossicular chain or portions thereof, or by means of the round window membrane of a mechanical probe. Embodiments of the device may be stand-alone units or as part of an ENT (ear, nose and throat) workstation / therapy unit, for example, including a powered suction system and / or a pressurized air system, which may be incorporated to provide pressure oscillations.

[0216] Although the present invention has been described with reference to preferred embodiments, workers skilled in the art will understand that various changes in form and details may be made without departing from the scope of the invention as described in the following claims.

[0217] The present invention will now be further described in the following non-limiting examples: Example

[0218] animal

[0219] Pigmented guinea pigs (350-360 g) of similar body weight were anesthetized using a neurosomnia technique (0.06 mg / kg body weight atropine sulfate sc, 30 mg / kg pentobarbital ip, 500 μl / kg Hypnorm im). Additional injections of Hypnorm were given every 40 min. Additional doses of pentobarbital were given as needed to maintain the non-reflex state. Heart rate was monitored by a pair of skin electrodes placed on both sides of the chest. The animals were tracheotomized and artificially ventilated, and their core temperature was maintained at 38°C with a heating blanket and heated headrest.

[0220] Signal generation and recording

[0221] The middle ear cavity of the ear used for measurement was opened to expose the round window. The compound action potential of the auditory nerve was measured from the bony ridge of the cochlea near the round window membrane using a polytetrafluoroethylene-coated silver wire connected to an extracellular amplifier designed and built in the laboratory (James Hartley). The threshold of the N1 peak of the compound action potential was visually estimated using a 10 ms tone stimulus at a repetition rate of 10 Hz.

[0222] For acoustic stimulation, sound was delivered to the tympanic membrane via a closed acoustic system consisting of two Bruel and Kjaer 41341 / 2” microphones for delivering the sound and a single Bruel and Kjaer 41331 / 2” microphone for monitoring the sound pressure in the tympanic cavity. The microphones were connected to the ear canal via 1 cm long, 4 mm diameter tubes to a conical speculum with a 1 mm diameter opening located approximately 1 mm from the tympanic cavity. The closed sound system was calibrated in situ at frequencies between 1 and 50 kHz. The known sound pressure levels were expressed in dB SPL re 2x10 -5 pa. All acoustic stimuli in this work were shaped with a raised cosine of 0.5 ms duration at the beginning and end of the stimulus. White noise for acoustic calibration and tone sequences for auditory stimulation were synthesized by a Data Conversion 3010 board at a 250 kHz sampling rate and passed to the microphone through a low-pass filter (100 kHz cutoff frequency). The signal from the acoustic measurement amplifier (James Hartley) was digitized using the same board at a 250 kHz sampling rate and averaged in the time domain. Experimental control, data acquisition and data analysis were performed using a PC with programs written in MATLAB.

[0223] Use a pipette to place 5 μl of 100 mM sodium salicylate solution in Hanks' balanced salt solution on the round window. Use a paper wick to remove the solution from the round window and observe the flushing effect.

[0224] Experiments were performed on deeply anesthetized guinea pigs, which have a cochlear structure similar to that of humans for the purposes of the experiments. All procedures involving animals were performed in accordance with UK Home Office regulations and were approved by the local ethics committee.

[0225] Sodium salicylate is a model drug that diffuses through the round window membrane and has good physiological effects. One of these effects is that the threshold response of the auditory nerve to pure tone stimulation is increased, that is, when salicylates diffuse along the cochlea and affect its function, higher pure tone sound pressure in the ear canal is required to cause the response of the auditory nerve. The cochlea is organized by tone. That is, high-frequency sounds produce the greatest response at the base of the cochlea and low-frequency sounds (Journal of the Acoustical Society of America (Greenwood, 1990 J. Acoust. Soc. Am. 87, 2592-2605)). Therefore, by sweeping the audio frequency, the salicylate effect of different cochlear parts can be studied. The spatial presentation of frequencies along the cochlea is not linear, but logarithmic and higher frequencies are represented in a denser pattern near the bottom of the cochlea.

[0226] In the first experiment, 5 μl of a 100 mM salicylate solution was placed over the round window of a guinea pig and then allowed to passively diffuse into the cochlea.

[0227] In the second experiment, the same volume of salicylate solution was placed on the round window, and then the ear was stimulated with oscillating air pressure in the ear canal for 5 minutes, and the stimulation when the auditory nerve threshold was measured without oscillating air pressure for 5 consecutive minutes. The cycle of pressure stimulation / no pressure stimulation was repeated 8 times until the auditory nerve threshold increased to saturation. The oscillating air pressure was generated by the device of the present invention, and the auditory probe (31) was inserted into the ear canal. Low-frequency air pressure oscillations with a frequency of 4 Hz caused large-scale oscillations of the tympanic membrane, which were transmitted to the stapes through the middle ear bones. The stapes oscillations (peak value of about 100 μm) caused perilymph oscillations and reciprocating movements of the round window membrane. In both experiments, the pure tone sound pressure level that caused the auditory nerve threshold response was measured using a sound system inserted into the ear canal.

[0228] like Figure 2 In the first experiment, no effect of salicylate on auditory nerve thresholds was observed for tone frequencies below 5 kHz, which corresponds to approximately 55% of the cochlear length, as shown in A. Thus, passive diffusion was demonstrated not to result in a significant distribution of salicylate along the cochlear spiral.

[0229] In contrast, Figure 2As shown in B, the salicylic acid effect was observed after 5-10 minutes of oscillatory pressure generation, even with a 1 kHz tone, corresponding to the top 25% of the cochlear spiral. The effect saturated after 15-20 minutes of total pressure stimulation time (not taking into account the 5 minutes of no pressure stimulation time), at which time the drug could be evenly distributed along the entire cochlea. No threshold increase was recorded in the control experiment during pressure stimulation without the use of salicylate. Therefore, the observed threshold increase was not due to any damage caused by the pressure stimulation, but was entirely due to the action of salicylate. This shows that the generation of oscillatory pressure in the ear canal according to the present invention leads to an improved distribution of the substance along the length of the cochlear spiral. From the round window ( Figure 2 ) after washing out the salicylate served as additional confirmation that sensory cell integrity was preserved.

[0230] Summary data of different elevations in auditory nerve threshold responses after unprocessed (passive diffusion, crossover) or generation of oscillatory pressure (oscillatory pressure, circles) in the ear canal in response to pure tones of frequencies 27 kHz (A), 21 kHz (B), 15 kHz (C), 11 kHz (D), 5 kHz (E), 3 kHz (F), and 1 kHz (G) as shown in Figure 5. Figure 4 As shown. The cochlea is organized according to tone. High-frequency sounds produce the greatest response at the apex of the cochlea, and low-frequency sounds produce the greatest response at the apex of the cochlea (Journal of the Acoustical Society of America (Greenwood, 1990 J. Acoust. Soc. Am. 87, 2592-2605)). Figure 4 showed that the threshold response of the cochlea to pure tones of all frequencies, especially the low frequencies corresponding to the apical part of the cochlear spiral, increased much more after the generation of oscillatory pressure in the ear canal than when salicylate was only allowed to diffuse passively into the cochlea. This suggests that the generation of oscillatory pressure in the ear canal can significantly improve the distribution of the substance along the entire length of the cochlear spiral, even in the apical part.

Claims

1. A device for assisting the distribution of substances in the inner ear, comprising: Pressure oscillator; an auditory probe having an end insertable into the ear canal; as well as a fluid channel fluidly connecting the pressure oscillator to an end of a hearing probe insertable into the ear canal; wherein the pressure oscillator is configured to generate oscillating fluid pressure changes in the fluid channel; Wherein, the pressure oscillator is configured to generate positive pressure and negative pressure in the fluid channel.

2. The device according to claim 1, wherein: The pressure oscillator is configured to generate a biphasic oscillatory pressure variation in the fluid channel.

3. The device according to claim 1, wherein: The predetermined maximum pressure amplitude is less than 20 kPa.

4. The device according to claim 3, wherein: The predetermined maximum pressure amplitude is less than 4 kPa.

5. The device according to claim 3, wherein: The predetermined maximum pressure amplitude is less than 2 kPa.

6. The device according to claim 3, wherein: The predetermined maximum pressure amplitude is greater than 0.5 kPa.

7. The device according to claim 1, wherein: The pressure oscillator is configured to generate air pressure oscillations at a frequency in the range of 1 to 20 Hz.

8. The device according to claim 7, wherein: The pressure oscillator is configured to generate air pressure oscillations at a frequency in the range of 2 to 20 Hz.

9. The device according to claim 7, wherein: The pressure oscillator is configured to generate air pressure oscillations at a frequency in the range of 4 to 18 Hz.

10. The device according to claim 7, wherein: The pressure oscillator is configured to generate air pressure oscillations at a frequency in the range of 8 to 16 Hz.

11. An apparatus according to any preceding claim, comprising a pressure relief valve in communication with the fluid passage and configured to open when the pressure within the fluid passage reaches a predetermined maximum positive and / or negative operating pressure.

12. A device for delivering a substance to the inner ear, comprising: a pressure oscillator configured to generate pressurized air at a predetermined oscillation frequency; a hearing probe including an air passage extending from a first end of the hearing probe to a second end of the hearing probe, the first end being the end to be inserted into the ear canal; a fluid passage between the pressure oscillator and the first end of the hearing probe; as well as a pressure relief valve disposed at the fluid passage, configured to release a portion or generated pressurized air from the fluid passage when the pressure in the tube and / or the hearing probe reaches a predetermined maximum pressure; Wherein, the pressure oscillator is configured to generate positive pressure and negative pressure in the fluid channel.

13. The apparatus of claim 12, comprising a tube arranged to connect the second end of the hearing probe to the pressure oscillator.

14. The apparatus of claim 12 or 13, further comprising a pressure sensor connected to the fluid channel, the pressure sensor being configured to determine the gas pressure within the fluid channel.

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