Device for intratympanic delivery of a hearing drug formulation

Abstract

A drug delivery system for intratympanic injection, including an intratympanic drug delivery device, including a body having a first end with a first opening and a second end with a second opening, the body being an elongated housing having a hollow chamber running along a length of the body from the first opening to the second opening, the first opening of the body configured to be inserted through a tympanic membrane; and a catheter configured to be inserted through the hollow chamber of the elongated housing of the body of the intratympanic drug delivery device.

Description

Attorney Docket No. 553748WODEVICE FOR INTRATYMPANIC DELIVERY OF A HEARING DRUG FORMULATIONBACKGROUND

[0001] Cisplatin, also known as CDDP, is used extensively in the treatment of a broad range of neoplasms, including head and neck cancer, ovarian cancer, testicular cancer, and bladder carcinoma. Several other platinum based anticancer drugs have been developed and become a major component of cancer therapy; about half of all patients undergoing chemotherapy receive a platinum drug. However, the use of cisplatin and other platinum drugs are associated with side effects.

[0002] Ototoxicity is one of the dose limiting side effects. It is estimated that 60%-80% patients receiving cisplatin will develop hearing loss, which is irreversible. Notably, the cure rate with a cisplatin containing treatment is consistently increasing. For example, cisplatin based chemotherapy results in >90% cure rate for testicular cancer. Furthermore, cisplatin in combination with immune checkpoint inhibitors, such as programmed cell death 1 and ligand (PD-1 / L1), has been shown to synergize with PD-1 / L1 for antitumor activity. However, a majority of survivors developed irreversible hearing loss and other hearing disorders, such as tinnitus. Ototoxicity has also been frequently reported in patients receiving other platinum based anticancer drugs. This compromised the quality-of-life post-treatment and created a significant health and social burden. The hearing loss is irreversible, and there are no treatments or preventative approaches available as of today.

[0003] Both the therapeutic effects and the ototoxicity of CDDP are dose-dependent, and there is great interest in developing effective strategies to protect or rescue the auditory organ from CDDP ototoxicity without affecting the antitumoral activity of CDDP. While the exact mechanism for the ototoxicity induced by cisplatin or other platinum drugs is not entirely clear, it is reasonably believed that a portion of systemically dosed platinum enters the inner ear and causes cochlear damages in a dose-dependent manner.Attorney Docket No. 553748WO

[0004] There are some approaches to prevent platinum induced hearing loss, including platinum chelators (e.g., sodium thiosulfate (STS)) to inactivate platinum agents, dexamethasone to mitigate inflammation related damages, and N-acetylcysteine (NAC) to eliminate reactive oxygen species (ROS). NAC is also considered an efficient chelator. Among all strategies, chelators are the most promising.

[0005] Platinum (II) or platinum (IV) are considered a soft metal ion. Therefore, soft and / or intermediate soft chelating / coordinating groups should effectively inactivate platinum (II or IV). Thiosulfate is an endogenous ion and sodium thiosulfate (STS) has also been used in clinic. At high concentration, it can efficiently bind to cisplatin and deactivate cisplatin.

[0006] Some systemic administration of STS has been evaluated in humans. It was found that STS can mitigate cisplatin induced hearing loss. However, it can potentially compromise the antitumor activity of cisplatin. Studies showed that STS can be administrated 6 hours post the end of infusion of cisplatin to potentially avoid interference of the antitumor activity.Furthermore, only specific non-disseminated cancer types are suitable to the preventative treatment without the potential compromise of the antitumor activity, and the protection is moderate.

[0007] In view of the potential for systemic STS to reduce the tumoricidal effects of platinum agents, an alternate mode of delivery is desired. As such, locally delivered sodium thiosulfate can be an attractive way to avoid such interference.

[0008] The foregoing “Background” description is for the purpose of generally presenting the context of the disclosure. Work of the inventors, to the extent it is described in this background section, as well as aspects of the description which may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure.SUMMARYAttorney Docket No. 553748WO

[0009] The present disclosure relates to a drug delivery system for intratympanic injection, including an intratympanic drug delivery device, including a body having a first end with a first opening and a second end with a second opening, the body being an elongated housing having a hollow chamber running along a length of the body from the first opening to the second opening, the first opening of the body configured to be inserted through a tympanic membrane; and a catheter configured to be inserted through the hollow chamber of the elongated housing of the body of the intratympanic drug delivery device, wherein a length of the intratympanic drug delivery device is greater than or equal to about 7 mm.

[0010] Note that this summary section does not specify every embodiment and / or incrementally novel aspect of the present disclosure or claimed invention. Instead, this summary only provides a preliminary discussion of different embodiments and corresponding points of novelty. For additional details and / or possible perspectives of the invention and embodiments, the reader is directed to the Detailed Description section and corresponding figures of the present disclosure as further discussed below.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] A more complete appreciation of the disclosure and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:

[0012] Figure 1 A is an optical image of a drug delivery system 10 for intratympanic injection including an intratympanic drug delivery device 100, according to an embodiment of the present disclosure.

[0013] Figure IB is a schematic of an intratympanic drug delivery device 100 arranged in the tympanic membrane 106, according to an embodiment of the present disclosure.Attorney Docket No. 553748WO

[0014] Figure 2 is a schematic of an intratympanic drug delivery device 100, according to an embodiment of the present disclosure.

[0015] Figure 3 A is an optical image of the intratympanic drug delivery device 100 including the inner flange 205, the body 210, and the funnel 215, according to an embodiment of the present disclosure.

[0016] Figure 3B is an optical image of the intratympanic drug delivery device 100 including the body 210 and the funnel 215, according to an embodiment of the present disclosure.

[0017] Figure 3C is an optical image of the intratympanic drug delivery device 100 including the inner flange 205, the outer flange 207, the body 210, and the funnel 215, according to an embodiment of the present disclosure.

[0018] Figure 3D is an optical image of the intratympanic drug delivery device 100 with the catheter 108 inserted therein, according to an embodiment of the present disclosure.

[0019] Figure 3E is an optical image of the intratympanic drug delivery device 100 with the catheter 108 ejecting a fluid, according to an embodiment of the present disclosure.

[0020] Figure 4A is a schematic of the intratympanic drug delivery device 100, according to an embodiment of the present disclosure.

[0021] Figure 4B is a schematic of the intratympanic drug delivery device 100, according to an embodiment of the present disclosure.DETAILED DESCRIPTION

[0022] The terms “a” or “an”, as used herein, are defined as one or more than one. The term “plurality”, as used herein, is defined as two or more than two. The term “another”, as used herein, is defined as at least a second or more. The terms “including” and / or “having”, as used herein, are defined as comprising (i.e., open language). Reference throughout this document to "one embodiment", “certain embodiments”, "an embodiment", “anAttorney Docket No. 553748WO implementation”, “an example” or similar terms means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of such phrases or in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments without limitation.

[0023] This disclosure is directed towards new drug delivery device designs that circumvent the need for an office procedure by an ear, nose, and throat (ENT) doctor in typical transtympanic injections and enable more frequent dosing regimens. The combination of the device and inner ear medications enables preventative or therapeutic interventions that are difficult or impossible with existing methods. In particular, platinum (II or IV) chelators, such as sodium thiosulfate (STS), can be combined with devices and methods described herein to prevent cisplatin or other platinum anticancer drug induced hearing loss and associated otic disorders.

[0024] In general, there can be 2 types of local administration methods: (1) intracochlear injection; and (2) intratympanic injection (also called transtympanic injection).

[0025] Some inner ear delivery methods are not repeatable, affordable, and safe. Intracochlear administration includes introducing the drug directly into the cochlea at various sites, including round window membrane, oval window, or basal turn of the cochlea. In a clinical setting, direct intracochlear injection is performed only during surgery under general anesthesia. The procedure is highly invasive and carries a potential risk of introducing pathogens in the inner ear when the cochlea is opened via a cochleostomy. It is only used for a one-time treatment such as gene therapy for severe hearing loss patients. Besides the intracochlear injection, a variety of tools including cochlear implant coating and advanced devices has been employed for intracochlear administration.Attorney Docket No. 553748WO

[0026] Intracochlear injection requires surgical operation, is highly invasive, and is considered for one-time treatment. A physician can obtain access to the cochlea through a surgical procedure and inject medications via a punctured hole on the round window membrane or a drilled hole on the bony structure of the cochlea or the oval window. The procedure is highly invasive and required to be performed in a hospital setting. Currently, it is only suitable for a few special situations, such as co-administration with cochlear implant surgery, one-time treatment (e.g., gene therapy), and for deaf patients. It is not suitable for otoprotective applications.

[0027] A cochlear implant is a hearing device with an array implanted in the scala tympani that can directly stimulate the spiral ganglions neurons on a damaged cochlea. It is implanted by a surgery, which nevertheless leads to histological damages during insertion. Companion medications can be administrated during the surgery to improve the outcome of the cochlear implant. Furthermore, biodegradable polymeric coatings on the cochlear implant surface represent an interesting strategy to deliver drug along with the implant. The electrode can be embedded within a polymeric matrix containing a drug that will be released into the scala tympani for a prolonged period of time.

[0028] One modified intracochlear injection is to use an implanted pump to continuously infuse medications into the inner ear. Reciprocating drug delivery includes delivering soluble drugs to closed fluid spaces in the body such as the cochlea via a single cannula without consequent fluid volume change. The core of the microfluidic reciprocating reservoir is a system for perfusion of drugs into the cochlear perilymph through a single hole in the basal turn of the cochlea. A critical issue for using this device lies in obtaining an overall size consistent with surgical implantation into the mastoid cavity behind the ear. The wearable device is tested in animals, but not in humans yet.Attorney Docket No. 553748WO

[0029] In practice, intratympanic (IT) injection is performed in an outpatient clinic setting. Intratympanic injection is minimally invasive and has been widely used with an established safety record. A physician opens an incision on the tympanic membrane and inserts a blunt syringe needle through the incision and blindly instills medication into the middle ear cavity and fills the middle ear cavity ensuring that the drug is in contact with the round window. The medication reaches the round window area, and the medicine can permeate through the round window membrane to enter the inner ear. The medication can leak out of middle ear cavity through the eustachian tube, and the patient is asked not to swallow any of the medication and must remain relatively still in the supine position with the patient’s head turned both during the injection and for some time afterwards (e.g., 15 minutes) to allow the medication to diffuse through the round window. The method has been used by physicians to treat inner ear or middle ear disorders, for example IT injection of corticosteroids. Overall, the intratympanic injection is less invasive and lower in cost compared to intracochlear injection. However, it is still a poor solution since it is required to be performed by a professional otologist with the assistance of an endoscope in an ear, nose, and throat (ENT) medical practitioner’s office. Furthermore, the frequency of injection is limited to avoid the risk of sustained perforation in tympanic membrane. However, this technique generally requires repeated injections, such as 2-5 times a week because the injected liquid is rapidly eliminated from the middle ear via the Eustachian tube. There is the aforementioned risk of tympanic membrane perforation due to frequent injection. Other adverse reactions related to intratympanic administration are pain or vertigo after injection.

[0030] Some studies have been done on these delivery methods in animal and human settings. In animal studies, intratympanic injection of STS prevented the cisplatin induced hearing loss. In contrast, intratympanic administration of STS has been explored in multiple clinical trials, but no meaningful hearing protection has been reported yet. A challengeAttorney Docket No. 553748WO associated with the intratympanic injection of STS in a clinical setting includes the fact that the clearance rate of STS in the perilymph is rather rapid. Therefore, it is ideal to shorten the time gap between the intratympanic injection of STS and the cisplatin infusion. However, intratympanic injection is performed by an ENT doctor in an ENT office. The cisplatin infusion site is unlikely suitable for the current intratympanic injection. This creates a logistics challenge in coordination of the time for intratympanic injection and cisplatin infusion, which was not a problem in the preclinical animal studies.

[0031] In order to reduce the dosing frequency of the IT injection, various hydrogel formulations have been evaluated to extend the contact of medication to the round window membrane. Some typical hydrogels are based on poloxamer 407, hyaluronic acid and chitosan. The clinical significance of hydrogel formulation is still to be determined. There are some potential complications associated with hydrogel formulation, such as transient conductive hearing loss, ototoxicity, etc.

[0032] In a clinical trial, a viscous hydrogel formulation was used to improve the inner ear exposure of thiosulfate. However, the viscous hydrogel formulation might be associated with lower spreadability and generating bubbles during the injection. Therefore, the contact of the formulation to the very small round window membrane can be compromised and the overall effective exposure of STS in the inner ear might not be better than an aqueous formulation. For example, an injection of the viscous hydrogel formulation can result in air bubbles mixed into the hydrogel formulation that contacts the round window membrane, which can result in the air bubbles (i.e., no formulation) also contacting the round window membrane and lead to a less effective or entirely ineffective delivery of the thiosulfate. Instead, a non-hydrogel formulation, such as an aqueous solution, will advantageously submerge and uniformly contact the round window membrane.Attorney Docket No. 553748WO

[0033] Additionally, the current intratympanic injection is not suitable for frequent repeated dosing. Certain cisplatin dosing regimens require daily infusions. For example, the testicular cancer regimen is to dose cisplatin every day for 5 days every cycle. This would require an STS intratympanic injection every day for those 5 days every cycle. This is not possible due to the high risk associated with the frequent repetitive and prolonged tympanic membrane perforation and the logistical difficulty of scheduling both each day within the timeframe required for both to be effective. Additionally, pre-hydration can be a regimen used prior to the infusion of cisplatin to mitigate or minimize potential renal damage caused by cisplatin. Hydration typically requires 1 hour or more to complete. Therefore, the proposed STS intratympanic delivery and the cisplatin infusion can be further separated apart.

[0034] Thus, there is a need for an effective and practical delivery method that can be performed without an otologist and no requirement for an ENT office visit during the injection.

[0035] Implantation of a (micro)catheter is difficult, requires surgery to manipulate the tympanic membrane, and requires a hospital operation. The microcatheter has two lumens, one for infusion of drugs and another for fluid withdrawal. The bulbous tip of 1.5, 2.0, or 2.5 mm diameter is placed and compressed in the round window niche. The other end of the catheter exits from the outer ear canal and can be connected to various pumping systems for infusion of drugs such as micropumps and osmotic pumps. The large catheter often leaves a defect in the tympanic membrane. Dislocation of the catheter opening tip and the round window membrane can also occur due to variable interpersonal round window niche sizes. Therefore, this can negatively impact delivery efficiency and consistency. Round window membrane erosion is a risk due to prolonged contact with the implanted structure. General anesthesia is required to expose the round window niche after performing a tympanomeatal flap procedure. Also, two operations are required for this technique - one for catheterAttorney Docket No. 553748WO insertion and another for its removal, where the associated complications include catheter dislocation, obstruction, and the formation of mild granulation tissue in the middle ear cavity. Regardless, the catheter, micro-pump, surgical procedure, and subsequent hospitalization are very expensive, implantation is difficult, and the large catheter often leaves a defect in the tympanic membrane. For intratympanic injection, it is important to retain an adequate path for air flow. The microcatheter implant has no room left after insertion of the catheter into the aperture of the tube.

[0036] Another technique includes the implantation of a ventilation tube on the tympanic membrane. The patient can self-dispense the drug fluid into the external ear canal whereby it is intended to pass through the opening into the middle ear, and then potentially the inner ear. This has the disadvantages of the passage of the liquid drug into the middle ear being inhibited by the surface tension of the liquid and pressing the tragus of the ear multiple times to pump drug into the middle ear cavity. The volume that can be introduced into the middle ear cavity is low and unlikely to reach the round window membrane. The loss of the drug fluid through the eustachian tube more readily occurs than the entry of drug fluid through the small hole in the tube. Therefore, the delivery to the inner ear has poor efficiency.

[0037] In addition, infectious debris can be carried into the middle ear from the external canal, with the risk of creating a middle ear infection. In practice, it was only used for the delivery of antibiotics to the middle ear cavity to treat middle ear infection.

[0038] Inserting a wick between the external ear canal and the middle ear can be performed. The Silverstein MicroWick is an absorbent polyvinyl acetate wick with a length of 9 mm and a diameter of 1 mm. This device is inserted through a ventilation tube in the tympanic membrane and placed overlying the round window. The insertion procedure requires only local anesthesia. Then, the patient instills the drug solution into the external ear canal, usually several times a day and for several weeks. The drug absorbed by the wick is delivered inAttorney Docket No. 553748WO contact with the round window for a passive diffusion to the inner ear. This method has the disadvantages of challenging microwick placement, possible patient noncompliance, errors in following directions, confusion of medications, failure of some or all of the instilled drops to reach or pass through the wick, delivery variability due to environmental factors (e.g., humidity), and chronic perforations due to the extended use of the wick. The wick, in contact with fluid (e.g., fluid produced due to the incision on tympanic membrane), can expand in size significantly, and make it difficult to insert through the ventilation tube. The capillary effect also decreases in the subsequent dose(s). Also, the contact of the wick to the round window membrane can cause increased fibrosis on the round window membrane and potentially damage hearing.

[0039] As the discussion above illustrates, there is a need for an improved method and device for treating inner ear diseases. The method should avoid invasive procedures and hospitalization, and minimize the need of an ENT office visit. It would be advantageous to enable dosing outside the ENT office and by a non-trained professional. In general, the nontrained professional can be a person not specializing in otic disorders or invasive procedures. For example, the non-trained professional can be a person in the healthcare field, such as a nurse. For example, the non-trained professional can have no medical training or receive instructions from a trained professional, such as the patient him / herself. The method can enable repeat dosing with minimal ENT office visits.

[0040] An advantage of the device designs discussed herein lies with the unique capability for the patient to administer dosing after implantation without the hazards and medicine loss of other patient dosing methods. The ability to self-dose decreases treatment costs, scheduling logistics, and time commitments while increasing effectiveness. While the focus of the present disclosure is related to hearing loss and other otic disorders caused by platinumAttorney Docket No. 553748WO anticancer drugs, the advantages of the described devices and methods will also extend to other applications, such as medicine delivery to the inner ear for other medical conditions.

[0041] The present disclosure relates to new medical devices designed to repeatedly deliver medicine to the inner ear without medical personnel. The design and application method described herein provides an increase in effectiveness and a decrease in cost to the patient.

[0042] Inner ear drug delivery remains quite challenging, and current methods are associated with various disadvantages. The present disclosure addresses this by providing an implant device that allows for a one-time implantation via a trained professional followed by administering or introducing the desired drug into the tympanic cavity using the implant device through a catheter having an inlet with a connector for attaching a fluid injecting device, such as a syringe. Notably, the administering of the drug can be performed by a nontrained professional, such as a nurse, or even the patient him / herself, at any time and in any location, and multiple subsequent injections can also be performed at any time and in any location, and the drug will always be administered successfully to the inner ear since the implant device (the catheter inlet) can be fastened securely to the patient and an outlet tip of the catheter is inserted through the tympanic membrane into the tympanic cavity such that any administered drug, e.g., a thiosulfate solution, fills the tympanic cavity until the drug contacts the round window membrane disposed therein.

[0043] Referring now to the drawings, Figure 1 A is an optical image of a drug delivery system 10 for intratympanic injection including an intratympanic drug delivery device 100, according to an embodiment of the present disclosure. In an embodiment, a catheter 105 can be arranged or delivered down an ear canal 104 (see FIG. IB) and inserted into a tympanic membrane 106 (also known as the ear drum). For example, an incision can be made on the tympanic membrane 106 through which the catheter 108 is inserted. The tympanic membrane 106 in a patient is a thin, usually circular piece of tissue that separates an outer ear and the earAttorney Docket No. 553748WO canal 104 from a middle ear including a tympanic cavity 110. The catheter 108, when inserted into the tympanic membrane 106, can extend from the ear canal 104 side, through the tympanic membrane 106, and into the tympanic cavity 110. The tympanic cavity 110 can include a round window membrane 120.

[0044] In an embodiment, an outlet tip of the catheter 108 can be inserted through the tympanic membrane 106 such that the outlet tip extends a distance or a length into the tympanic cavity 110, for example a distance as measured from the tympanic membrane 106. The tympanic membrane 106 tissue can be stretched and therefore the catheter 108 can be secured to the tympanic membrane 106 via a clamp force exerted on the catheter 108 by the tympanic membrane 106. An inlet end of the catheter 108 can be disposed outside of the patient’s ear canal 104. For example, an inlet end of the catheter 108 can be fluidly but reversibly connected to a syringe 118 disposed outside of the patient’s ear canal 104.

[0045] Notably, a catheter installed by itself through a tympanic membrane can be a difficult procedure since the opening formed in the tympanic membrane can preferably be as small as possible. This can require fine, accurate manipulation of the catheter outlet tip and, as previously described, need to occur under the care of a trained professional using specialized equipment, such as a microscope or an endoscope (e.g., ENT office setting). Furthermore, in the event the catheter is unseated due to accidental pulling of the catheter, the patient will need to return to the trained professional before the following treatment to reinstall the catheter. Thus, a device to facilitate arranging the catheter in the tympanic cavity 110 through the tympanic membrane 106 that can be installed outside a trained professional’s office or setting is desired.

[0046] To this end, Figure IB is a schematic of an intratympanic drug delivery device 100 arranged in the tympanic membrane 106, according to an embodiment of the present disclosure. In an embodiment, the initial implantation can be performed by an ENT doctor inAttorney Docket No. 553748WO a medical office. In an embodiment, the intratympanic drug delivery device 100 is arranged or delivered down the ear canal 104 and inserted into the tympanic membrane 106. Therefore, the intratympanic drug delivery device 100, when inserted into the tympanic membrane 106, can have a first portion of the intratympanic drug delivery device 100 disposed on the ear canal 104 side and a second portion of the intratympanic drug delivery device 100 disposed on a tympanic cavity 110 side.

[0047] In an embodiment, the tympanic membrane 106 tissue can be stretched and therefore the intratympanic drug delivery device 100 can be secured to the tympanic membrane 106 via a clamp force exerted on the intratympanic drug delivery device 100 by the tympanic membrane 106. As described below, the catheter 108 can be inserted through the intratympanic drug delivery device 100 in order to pass through the tympanic membrane 106 and into the tympanic cavity 110. Thus, in an embodiment, the intratympanic drug delivery device 100 is configured to receive the catheter 108. Notably, the intratympanic drug delivery device 100 can allow for easier arrangement of the catheter 108 through the tympanic membrane 106 and into the tympanic cavity 110 as described herein. This can be especially advantageous when there is an accidental pull on the catheter 108 that unseats the catheter 108 from the tympanic cavity 110.

[0048] Figure 2 is a schematic of an intratympanic drug delivery device 100, according to an embodiment of the present disclosure. In an embodiment, the intratympanic drug delivery device 100 can include a first end and a second end. The first end of the intratympanic drug delivery device 100 can be considered a tip or an outlet of the intratympanic drug delivery device 100, while the second end of the intratympanic drug delivery device 100 can be considered a base or an inlet of the intratympanic drug delivery device 100. The intratympanic drug delivery device 100 can include a body 210 spanning between the first end and the second end. The body 210 can be an enclosed housing with a hollow chamber orAttorney Docket No. 553748WO channel with openings at both ends of the body 210. That is, the body 210 can be configured to receive an object through the hollow channel and the object can traverse a length of the body 210 from end to end.

[0049] In an embodiment, the body 210 can be a hollow tube having a circular cross-section. The cross-sectional shape can also be, in a non-limiting example, ovular, triangular, square, pentagonal, hexagonal, or n-sided, where n is an integer and each side need not be equal in size. The cross-sectional shape can also be a unique, non-standard shape. The cross-sectional shape can be based on, for example, an anatomy of the patient. Additionally, an outer cross- sectional shape of the body 210 need not be the same as an inner cross-sectional shape of the body 210. For example, the outer cross-sectional shape of the body 210 can be square while the inner cross-sectional shape of the body 210 can be circular.

[0050] In an embodiment, the body 210 can include an inner diameter (label “A”) and an outer diameter. The inner diameter of the body 210 can be, for example, about or substantially or approximately 0.5 mm, or 0.8 mm, or 1 mm, or 1.5 mm, or of from 0.25 mm to 2 mm, or no less than 0.5 mm. Other dimensions described herein can be understood to also measure about equal to, substantially equal to, or approximately equal to the listed dimension. That is, there can be a deviation or tolerance for the listed dimension, such as due to manufacturing tolerances. The outer diameter of the body 210 can be, for example, 0.8 mm, or 1 mm, or 1.2 mm, or 1.5 mm, or 2 mm, or of from 0.75 mm to 2.25 mm, or no less than 0.5 mm. The body 210 can include a length (label “D”). The length of the body 210 can be, for example, 3 mm, or 5 mm, or 7 mm, or 10 mm, or 12 mm, or of from 2.5 mm to 15 mm, or greater than 7 mm. The body 210 can include a sidewall thickness. The sidewall thickness of the body 210 can be, for example, 0.3 mm, or 0.4 mm, or 0.5 mm, or 0.75 mm, or 1 mm, or of from 0.25 mm to 1.1 mm.Attorney Docket No. 553748WO

[0051] In an embodiment, the intratympanic drug delivery device 100 can include an optional inner flange 205 disposed at the first end (the tip) of the intratympanic drug delivery device 100. The inner flange 205 can be a projecting rim or collar structure wider in diameter than an outer diameter of the body 210. The inner flange 205 can alternatively be one or more protrusions along the tip of the intratympanic drug delivery device 100. Therefore, when the intratympanic drug delivery device 100 is inserted into the tympanic membrane 106, the inner flange 205 is pushed through the tympanic membrane, thus being disposed in the tympanic cavity 110. The clamp force of the tympanic membrane 106 then clamps onto the narrower body 210 of the intratympanic drug delivery device 100 and the wider inner flange 205 prevents translation of the intratympanic drug delivery in a direction away from the tympanic cavity 110. That is, the tympanic membrane 106 can reversibly deform around the inner flange 205 when the intratympanic drug delivery device 100 is inserted and clamp on the body 210. Then, when a force is applied to translate the intratympanic drug delivery device 100 in a direction away from the tympanic cavity 110, the tympanic membrane 106 can contact and abut the inner flange 205, preventing further translation of the intratympanic drug delivery device 100 until a sufficient force is applied that reversibly deforms the tympanic membrane 106 around the inner flange 205 again to release the intratympanic drug delivery device 100 from the tympanic membrane 106.

[0052] In an embodiment, the inner flange 205 can include a ramped or rounded surface along the tip of the intratympanic drug delivery device 100 to form more of a pointed tip of the intratympanic drug delivery device 100. The ramped or rounded surface of the inner flange 205 can help facilitate insertion of the intratympanic drug delivery device 100 by gradually deforming the tympanic membrane 106 over the inner flange 205, which can also help with pain for the patient. A side of the inner flange 205 opposite the tip of the intratympanic drug delivery device 100 can similarly be ramped or rounded to help facilitateAttorney Docket No. 553748WO extraction of the intratympanic drug delivery device 100 by gradually deforming the tympanic membrane 106 over the inner flange 205 again.

[0053] In an embodiment, a cross-sectional shape of the inner flange 205 can be circular, ovular, triangular, square, or n-sided, where n is an integer and each side need not be equal in size. The inner flange 205 can include an outer diameter (label “B”) and an inner diameter (label “H”). The outer diameter of the inner flange 205 can be, for example, 2 mm, or 2.2 mm, or 2.5 mm, or 2.8 mm, or 3 mm, or of from 1.8 mm to 3.2 mm. The inner diameter of the inner flange 205 can be, for example, 0.5 mm, or 0.8 mm, or 1 mm, or 1.5 mm, or of from 0.25 mm to 2 mm, or match the inner diameter of the body 210. The inner flange 205 can include a thickness (label “G”), which can be measured along a direction of the length of the body 210. The thickness of the inner flange 205 can be, for example, 0.25 mm, or 0.5 mm, or 0.6 mm, or 0.75 mm, or 1 mm, or 1.5 mm, or of from 0.2 mm to 2 mm.

[0054] In an embodiment, the intratympanic drug delivery device 100 can include an optional outer flange 207. The outer flange 207 can be disposed proximal to the inner flange 205 at the tip of the intratympanic drug delivery device 100. The outer flange 207 can be a projecting rim or collar structure wider in diameter than an outer diameter of the body 210. The outer flange 207 can alternatively be one or more protrusions along the body 210 of the intratympanic drug delivery device 100. The outer flange 207 can also be wider in diameter than an outer diameter of the body 210. The outer flange 207 can have dimensions similar to the inner flange 205. The outer flange 207 can, for example, prevent excess insertion into the tympanic cavity 110. Thus, the intratympanic drug delivery device 100 can be inserted and arranged on the tympanic membrane 106 where the inner flange 205 is disposed in the tympanic cavity 110 while the outer flange 207 remains disposed in the ear canal 104. In such an arrangement, the inner flange 205 and the outer flange 207 can sandwich the tympanic membrane 106. A gap (label “I”) between the inner flange 205 and the outer flange 207 canAttorney Docket No. 553748WO be, for example, less than 1 mm, or 1 mm, or 1.5 mm, or 2 mm, or 3 mm, or a gap of from 0.5 mm to 5 mm.

[0055] In an embodiment, the intratympanic drug delivery device 100 can include a funnel 215 disposed at the second end (the base) of the intratympanic drug delivery device 100. The funnel 215 can be an extruded, expanded opening or aperture at the second end of the intratympanic drug delivery device 100. That is, the funnel 215 can be substantially funnel- shaped with a wide opening that tapers or narrows towards the body 210. The wide opening of the funnel 215 can be wider than the inner diameter of the body 210. The funnel 215 can be configured to receive an object inserted therein and guide the object into the body 210 of the intratympanic drug delivery device 100. Together with the body 210 having a sufficiently long length to allow the funnel 215 to be visible and accessible from an opening of the (outer) ear canal 104, the funnel 215 can therefore facilitate easier insertion of the catheter 108 through the intratympanic drug delivery device 100 and into the tympanic cavity 110. Advantageously, this can allow the catheter 108 placement or installation (or re-installation) to be performed (i) without the need of a microscope or endoscope, and (ii) by non-trained professionals, such as a nurse (and, e.g., outside an ENT office setting). The administration of medication thereafter (the fluid in the syringe 118 configured to be injected) can be performed anywhere and at any time by a nurse, or by the patient him / herself if needed. For example, once a patient has the intratympanic drug delivery device 100 installed, the administration of cisplatin chelator such as sodium thiosulfate (STS) can be performed right before the initiation of cisplatin infusion without an additional ENT visit or ENT coordination. Additional dosing can be performed as needed.

[0056] In an embodiment, the funnel 215 can include an inner diameter (label “C”) and an outer diameter (label “F”). The inner diameter of the funnel 215 can be, for example, 1.4 mm, or 1.5 mm, or 2.75 mm, or 3 mm, or of from 1.25 mm to 4 mm, or no less than 1.5 mm, or noAttorney Docket No. 553748WO less than 2.0 mm. The outer diameter of the funnel 215 can be, for example, 1.5 mm, or 1.6 mm, or 2.85 mm, or 3.1 mm, or of from 1.35 mm to 4.1 mm. The funnel 215 can include a length (label “J”). The length of the funnel 215 can be, for example, 2.5 mm, or 3 mm, or 4 mm, or 5 mm, or 6 mm, or 7.5 mm, or of from 2.5 mm to 8 mm.

[0057] In an embodiment, the intratympanic drug delivery device 100 can include a length (label “E”). The length of the intratympanic drug delivery device 100 can be, for example, 5 mm, or 7 mm, or 9 mm, or 11 mm, or 12 mm, or 13 mm, or 15 mm, or of from 4 mm to 17 mm, or no less than 7 mm, or no less than 10 mm.

[0058] In an embodiment, the intratympanic drug delivery device 100 includes just the body 210. The body 210 can be substantially constant in cross-sectional shape and dimensions along the length of the body 210. As described previously, the intratympanic drug delivery device 100 can be inserted through the tympanic membrane 106 and a first end of the body 210 can be configured to sit in the tympanic membrane 106.

[0059] In an embodiment, the intratympanic drug delivery device 100 includes the body 210 and the inner flange 205. As described previously, the intratympanic drug delivery device 100 can be inserted through the tympanic membrane 106 where the inner flange 205 is inserted through the tympanic membrane 106. Thus, the inner flange 205 is disposed in the tympanic cavity and can be configured to prevent accidental removal of the intratympanic drug delivery device 100 by abutting the tympanic membrane 106.

[0060] In an embodiment, the intratympanic drug delivery device 100 includes the body 210, the inner flange 205, and the outer flange 207. As described previously, the intratympanic drug delivery device 100 can be inserted through the tympanic membrane 106 where the inner flange 205 is inserted through the tympanic membrane 106 and the outer flange 207 is not, and both flanges sandwich the tympanic membrane 106. Thus, the inner flange 205 is disposed in the tympanic cavity and can be configured to prevent accidental removal of theAttorney Docket No. 553748WO intratympanic drug delivery device 100 by abutting the tympanic membrane 106, and the outer flange 207 is disposed in the ear canal 104 and can be configured to prevent accidental over-insertion of the intratympanic drug delivery device 100 also by abutting the tympanic membrane 106.

[0061] In an embodiment, the intratympanic drug delivery device 100 includes the body 210 and the outer flange 207. As described previously, the intratympanic drug delivery device 100 can be inserted through the tympanic membrane 106 where the outer flange 207 is not inserted through the tympanic membrane 106. Thus, the outer flange 207 is disposed in the ear canal 104 and can be configured to prevent accidental over-insertion of the intratympanic drug delivery device 100 by abutting the tympanic membrane 106.

[0062] In an embodiment, a material of the intratympanic drug delivery device 100 can be, for example, a polymer or a metal. For example, the polymer can be fluoroplastic, polyethylene, or silicone elastomer. For example, the metal can be stainless steel or titanium.

[0063] In an embodiment, the inner diameter of the inner flange 205 and the inner diameter of the body 210 are 0.8 mm, the outer diameter of the inner flange 205 is 2.2 mm, the length of the body 210 is 7 mm, the inner diameter of the funnel 215 is 1.5 mm, the outer diameter of the funnel 215 is 1.6 mm, and the length of the intratympanic drug delivery device 100 is 12 mm.

[0064] In an embodiment, the catheter 108 can have an outer diameter and an inner diameter. The outer diameter of the catheter 108 can be, for example, 0.3 mm, or 0.35 mm, or 0.4 mm, or 0.5 mm, or of from 0.25 mm to 1.3 mm. The inner diameter of the catheter 108 can be, for example, 0.13 mm, or 0.15 mm, or 0.17 mm (28G), or 0.19 mm, or 0.21 mm, or of from 0.12 mm to 0.23 mm. In an embodiment, a length of the catheter 108 is more than 0.5 cm, or more than 1 cm, or more than 2 cm, or more than 3 cm as measured from the inlet to the outlet tip.Attorney Docket No. 553748WOFor example, the catheter 108 is a Neo-Magic 1.9 Fr x 6 cm EPIV. For example, the catheter 108 is a Premicath Model 1261.080 central venous polyurethane catheter.

[0065] In an embodiment, the catheter 108 can be made from a soft material (e.g., thermosensitive polyurethane, silicon, etc.), and the material can become softer when the catheter 108 is inserted into the tympanic cavity 110 where the temperature is close to that of the body. That is, the catheter 108 tube softens upon warming such as upon insertion in the tympanic cavity 110 and warming to body temperature. The catheters 108 are configured to soften upon warming, but not to such a degree that the catheter 108 tube integrity is compromised. This can minimize the potential of scratching any surface in the tympanic cavity 110 by the catheter 108. For example, one type of catheter can be described as those used with neonatal and premature newborns for vascular introduction of drugs and nutrients.

[0066] In an embodiment the catheter can be made of a radiopaque material so that it is visible by x-rays. For example, the catheter material could include barium sulfate.

[0067] Figure 3 A is an optical image of the intratympanic drug delivery device 100 including the inner flange 205, the body 210, and the funnel 215, according to an embodiment of the present disclosure. In an embodiment, the intratympanic drug delivery device 100 does not include the outer flange 207.

[0068] Figure 3B is an optical image of the intratympanic drug delivery device 100 including the body 210 and the funnel 215, according to an embodiment of the present disclosure. In an embodiment, the intratympanic drug delivery device 100 does not include the inner flange 205 or the outer flange 207.

[0069] Figure 3C is an optical image of the intratympanic drug delivery device 100 including the inner flange 205, the outer flange 207, the body 210, and the funnel 215, according to an embodiment of the present disclosure. In an embodiment, the outer flange 207 (as shown) is a protrusion disposed along the body 210 of the intratympanic drug delivery device 100.Attorney Docket No. 553748WO

[0070] Figure 3D is an optical image of the intratympanic drug delivery device 100 with the catheter 108 inserted therein, according to an embodiment of the present disclosure. In an embodiment, the intratympanic drug delivery device 100 includes the inner flange 205, the body 210, and the funnel 215, and does not include the outer flange 207. The catheter 108 insertion can be aided by the funnel 215, which can catch or receive the catheter 108 more easily when the catheter 108 is inserted due to the wider aperture of the funnel 215.

[0071] Figure 3E is an optical image of the intratympanic drug delivery device 100 with the catheter 108 ejecting a fluid, according to an embodiment of the present disclosure. In an embodiment, the catheter 108 can be configured to receive a fluid via the catheter 108 inlet and eject the fluid via the catheter 108 outlet tip. For example, the syringe 118 can hold the fluid and be attached to the catheter 108 inlet. Upon injection of the fluid from the syringe 118 into the catheter 108, the fluid can traverse a length of the catheter 108 from the inlet to the outlet tip and exit the outlet tip. When the intratympanic drug delivery device 100 is arranged to dispose the tip of the intratympanic drug delivery device 100 in the intratympanic cavity 110, the catheter 108 can eject the fluid into the intratympanic cavity 110.

[0072] In an embodiment, the catheter 108 inserted through the tympanic membrane 106 via the intratympanic drug delivery device 100 can have the outlet tip disposed in the tympanic cavity 110 without coming into contact with a wall of the tympanic cavity 110. For example, the catheter 108 does not contact the round window membrane 120 along the wall of the tympanic cavity 110.

[0073] In an embodiment, the catheter 108 can be arranged or inserted into the tympanic cavity 110 through the intratympanic drug delivery device 100. The catheter 108 can have an outer diameter smaller than the inner diameter of the intratympanic drug delivery device 100 to allow airflow out of the tympanic cavity 110 even when the catheter 108 is in use. The catheter 108 can extend from the tympanic cavity 110 to outside the ear canal 104. TheAttorney Docket No. 553748WO catheter 108 can have position markers near the outlet tip of the catheter 108 to facilitate determination of a depth of the catheter 108 while inserting the catheter 108 into the tympanic cavity 110.

[0074] In an embodiment, the catheter 108 can be made from a soft material (e.g., thermosensitive polyurethane, silicon, etc.), and the material can become softer when the catheter 108 is inserted into the tympanic cavity 110 where the temperature is close to that of the body. That is, the catheter 108 tube softens upon warming such as upon insertion in the tympanic cavity 110 and warming to body temperature. The catheters 108 are configured to soften upon warming, but not to such a degree that the catheter 108 tube integrity is compromised. This can minimize the potential of scratching any surface in the tympanic cavity 110 by the catheter 108. For example, one type of catheter can be described as those used with neonatal and premature newborns for vascular introduction of drugs and nutrients.

[0075] Figure 4A is a schematic of the intratympanic drug delivery device 100, according to an embodiment of the present disclosure. In an embodiment, the inner diameter of the body 210 is 1 mm, the outer diameter of the body 210 is 2 mm, the sidewall thickness of the body 210 is 0.5 mm, the length of the body 210 is 12 mm, the inner diameter of the funnel 215 is 2 mm, the length of the funnel 215 is 3 mm, and the length of the intratympanic drug delivery device 100 is 15 mm.

[0076] Figure 4B is a schematic of the intratympanic drug delivery device 100, according to an embodiment of the present disclosure. In an embodiment, the inner diameter of the body 210 and the inner diameter of the inner flange 205 are 0.5 mm, the outer diameter of the body 210 is 1.2 mm, the sidewall thickness of the body 210 is 0.5 mm, the length of the body 210 is 4 mm, the inner diameter of the funnel 215 is 1.5 mm, the outer diameter of the funnel 215 is 2 mm, the length of the funnel 215 is 3 mm, the outer diameter of the inner flange 205 isAttorney Docket No. 553748WO2.5 mm, the thickness of the inner flange 205 is 0.6 mm, and the length of the intratympanic drug delivery device 100 is 7.6 mm.

[0077] In an embodiment, the syringe 118 is a pump including processing circuitry communicatively coupled to a remote processing device, such as a smart phone, tablet, personal computer, or the like, and configured to transmit data to and receive data from the remote processing device. The pump can include sensors, such as a pressure sensor, and transmit sensor data to the remote processing device. The remote processing device can, based on the sensor device, transmit instructions to the processing circuitry. The instructions can be, for example, to run the pump and inject the fluid at a set injection flow rate. The instructions can be, for example, to stop the pump if a pressure threshold is reached to prevent injury to the patient. The patient can, via the remote processing device, adjust settings, such as the pressure threshold and injection flow rate. The remote processing device can be set to instruct the pump to run an injection schedule or regimen automatically based on the treatment for the patient.

[0078] Some of the medications suitable for use with the delivery implant 100 are summarized in Table 1.Attorney Docket No. 553748WO

[0079] Other medicines that can be used with the device and method of the present disclosure are described in Table 2.Attorney Docket No. 553748WOTable 2 - Indications and corresponding agents for treatment.

[0080] As described herein, an aqueous solution of a thiosulfate salt ranging from 0.0 IM to 2.5M, preferably 0.025M to 2.0M, preferably 0.05M to 1.5M, preferably 0.075M to 1.0M, preferably 0.09M to 0.75M, preferably 0.1M to 0.5M. In an embodiment, the aqueous solution of a thiosulfate salt has a calculated osmolarity of, for example, <9500 mOsm / L, preferably 100-8500 mOsm / L, preferably 200-7500 mOsm / L, preferably 250-6500 mOsm / L, preferably 300-5000 mOsm / L was used. That is, the molarity of STS can be, for example,Attorney Docket No. 553748WO0.1M, O.15M, 0.2M, 0.25M, O.3M, O.35M, 0.4M, 0.45M, O.5M, 0.75M, l.OM, 1.5M, 2.0M, 2.5M, etc. It may be appreciated that the volumes and concentrations described herein can be adjusted based on the properties of the chelator used. The simple aqueous formulation performs equally or better than a hydrogel. The medication is injected into middle ear cavity via trans-tympanic or intratympanic injection no earlier than 1 hour prior to the start of cisplatin infusion and no later than 8 hours after the completion of cisplatin infusion. The systemic thiosulfate concentration was increased after STS local administration. A dosing volume of 0.1-0.5 mL was used. The Tmax was approximately 25 to 35 mins and the concentration recovered to normal after around 1 hour. Systemic exposure (Cmax) resulting from lower STS concentration (<0.5M, >0.1M) should not impact cisplatin. The STS formulation used herein can have lower STS concentration (lower osmolarity). In a nonlimiting example, an upper limit of 600 mOsm / kg can be used, while a lower limit of 250 mOsm / kg can be used.

[0081] In an embodiment, a method of administering, to a tympanic cavity, a pharmaceutical composition using a drug delivery device implanted through a tympanic membrane is described. First, the doctor fluidly connects the drug delivery device to an injection system via an inlet of a flexible catheter of the drug delivery device. Then, a volume of the pharmaceutical composition can be introduced, via the drug delivery device, to the tympanic cavity.

[0082] In an embodiment, the pharmaceutical composition comprises an effective amount of an aqueous solution of a platinum chelator. The effective amount can be based on, for example, a volume sufficient to fill the tympanic cavity and for the pharmaceutical composition to contact the round window membrane in the tympanic cavity. For example, a volume of the administered pharmaceutical composition is from 0.05 mL to 1.0 mL, or 0.075 mL to 0.75 mL, or 0.1 mL to 0.5 mL.Attorney Docket No. 553748WO

[0083] In an embodiment, the method can further include forming an incision in the tympanic membrane having a length greater than an outer diameter of the flexible catheter and inserting the flexible catheter 108 through the incision. In an embodiment, the flexible catheter 108 when inserted into the tympanic cavity 110 extends into the tympanic cavity 110 but does not contact the round window membrane.

[0084] In an embodiment, the platinum chelator solution is a thiosulfate salt solution having a concentration of from 0.01M to 2.5M, preferably 0.025M to 2.0M, preferably 0.05M to 1.5M, preferably 0.075M to 1.0M, preferably 0.09M to 0.75M, preferably 0.1M to 0.5M.

[0085] In an embodiment, the thiosulfate salt solution has a pH of from, for example, 5.0 to 10.0, or 6.0 to 9.75, or 7.0 to 9.5 buffered with boric acid.

[0086] In an embodiment, the thiosulfate salt solution has a pH of from, for example, 5.0 to 10.0, or 6.0 to 9.75, or 7.0 to 9.5 buffered with tris base.

[0087] In an embodiment, the thiosulfate salt solution has a pH of from, for example, 5.0 to 10.0, or 6.0 to 9.75, or 7.0 to 9.5 buffered with Tris / Borate / EDTA.

[0088] In an embodiment, the platinum chelator is a thiosulfate salt.

[0089] In an embodiment, the introducing the pharmaceutical composition to the tympanic cavity occurs at from 1 hour prior to 1 hour after administering one or more platinum-based antineoplastic agents, or at from 30 minutes prior to 30 minutes after administering one or more platinum-based antineoplastic agents, or at from 15 minutes prior to 15 minutes after administering one or more platinum-based antineoplastic agents, or at from 5 minutes prior to 5 minutes after administering one or more platinum-based antineoplastic agents.

[0090] In an embodiment, the one or more platinum-based antineoplastic agent is cisplatin. In an embodiment, the composition further comprises PD-1 or PDL-1 inhibitors.

[0091] In an embodiment, the pharmaceutical composition is administered multiple times per day.Attorney Docket No. 553748WO

[0092] In an embodiment, the pharmaceutical composition is administered at least once per day for at least two days. The treatment period can be, for example, every day, or every other day, or every 3 days, or every n days.

[0093] In an embodiment, the flexible catheter has an outer diameter of from 1 Fr to 2 Fr.

[0094] In an embodiment, the flexible catheter is constructed of a biocompatible material having a reduced rigidity when exposed to a body temperature of a patient. In an embodiment, the biocompatible material is polyurethane.

[0095] In an embodiment, the inlet of the flexible catheter is connected to a connector of the injection system having a Luer lock, the inlet having a complementary lock to the Luer lock configured to twi stably receive the connector.

[0096] In an embodiment, the method further includes attaching the inlet of the flexible catheter, via a suture, to a surface exterior to an ear canal.

[0097] In an embodiment, the method further includes attaching the inlet of the flexible catheter, via an adhesive tape, to a surface exterior to an ear canal.

[0098] In an embodiment, the method further includes inserting an outlet of the flexible catheter through the tympanic membrane such that the outlet extends into the tympanic cavity with a distance of from 2 mm to 5 mm from the tympanic membrane.

[0099] In an embodiment, the flexible catheter is used on multiple days to administer the platinum chelating agent.

[0100] In an embodiment, the platinum chelating agent is at least one selected from the group consisting of an alkali metal thiosulfate salt, an alkaline earth thiosulfate salt, an ammonium thiosulfate salt, and an organoammonium thiosulfate salt. In an embodiment, the platinum chelator is sodium thiosulfate.Attorney Docket No. 553748WO

[0101] In an embodiment, the effective amount of the aqueous solution of the platinum chelator is introduced to a level at or above a round window membrane in the tympanic cavity.

[0102] In an embodiment, the platinum chelator solution is administered to the patient by intratympanic or transtympanic injection via the catheter 108. For example, the platinum chelator solution is stored in the syringe 118 attached to the inlet end of the catheter 108.

[0103] In an embodiment, the platinum chelator solution is administered to fill the tympanic cavity 110 and cover the round window membrane disposed therein. This can be, for example, a volume of from 0.1 mL to 1.0 mL, or 0.15 mL to 0.6 mL, or 0.2 to 0.35 mL, or 0.1 mL to 0.5 mL.

[0104] In an embodiment, the intratympanic or transtympanic injection via the catheter 108 occurs at a set timeframe prior to beginning a cisplatin infusion. For example, the set timeframe can be from 0 to 1 hour prior, or 0 to 30 minutes prior, or 0 to 5 minutes prior. Advantageously, since the injection can occur without the ENT doctor, the patient can perform the injection him / herself before the cisplatin infusion at the location where the cisplatin infusion occurs.

[0105] In an embodiment, a subsequent intratympanic or transtympanic injection, or a booster dose, of the platinum chelator solution can be administered. In an embodiment, the subsequent intratympanic or transtympanic injection via the catheter 108 occurs at a set timeframe after the prior intratympanic or transtympanic injection. For example, the set timeframe can be from 1 hour to 12 hours after, or 1 hour to 6 hours after, or 1 hour to 3 hours after the prior intratympanic or transtympanic injection.

[0106] In an embodiment, the thiosulfate is a thiosulfate salt. In an embodiment, the thiosulfate salt refers to salts of thiosulfuric acid, e.g., sodium thiosulfate Na2S20s. Examples of thiosulfate salts include, but are not limited to, lithium thiosulfate, sodium thiosulfate,Attorney Docket No. 553748WO magnesium thiosulfate, calcium thiosulfate, and potassium thiosulfate. In an embodiment, the platinum chelating agent is at least one selected from the group consisting of an alkali metal thiosulfate salt, an alkaline earth thiosulfate salt, an ammonium thiosulfate salt, and an organoammonium thiosulfate salt.

[0107] In an embodiment, the thiosulfate salt is present in the pharmaceutical composition at a concentration of from 0.1M to 0.4M, or 0.125M to 0.3M, or 0.15M to 0.25M.

[0108] In an embodiment, the pharmaceutical composition has a pH between 5.0 and 9.5.

[0109] In an embodiment, the pharmaceutical composition further comprises a buffer agent.

[0110] In an embodiment, the buffer agent is boric acid.

[0111] EXPERIMENTAL RESULTS

[0112] PROTOCOL - Animal preparation and methods

[0113] Albino guinea pigs (Hartley), body weight at 220-350 g were used in the study. 3 days acclimation was performed. 30 guinea pigs were assigned to PK study. 26 guinea pigs were assigned for pharmacology efficacy study. Animals were excluded in the efficacy study with otitis media after otoscopy and Auditory Brainstem Response (ABR) exam.EXAMPLE 1: The preparation of the STS formulation.

[0114] Formulation 1 (5%, w / v, 0.2M)

[0115] 1.153 mL of pure water was added to sodium thiosulfate pentahydrate (57.67 mg) in a vial. The resulting mixture was gently vortexed for 1 min and sonicated for 1 min. The solution is ready for use freshly.

[0116] Formulation 2 (10%, w / v, 0.4M)

[0117] 1.324 mL of pure water was added to sodium thiosulfate pentahydrate (132.39 mg) in a vial. The resulting mixture was gently vortexed for 1 min and sonicated for 1 min. The solution is ready for use freshly.Attorney Docket No. 553748WO

[0118] Formulation 3 (2.5%, w / v, 0.1M)

[0119] 2.424 mL of pure water was added to sodium thiosulfate pentahydrate (60.60 mg) in a vial. The resulting mixture was gently vortexed for 1 min and sonicated for 1 min. The solution is ready for use freshly.

[0120] Formulation 4 (5%, w / v, 0.2M) with Tris Buffer

[0121] 2.806 mL of Tris buffer (25 mM, in water, pH~8) was added to sodium thiosulfate pentahydrate (140.32 mg) in a vial. The resulting mixture was gently vortexed for 1 min and sonicated for 1 min. The solution is ready for use freshly (pH 8.16).EXAMPLE 2: Pharmacology efficacy study.

[0122] Step 1: preparation of cisplatin dosing formulation

[0123] 10 mL of saline (0.9% w / v sodium chloride in water) was added to cisplatin dry powder (20 mg) in a vial. The resulting mixture was gently vortexed for 1 min and sonicated for 1 min. The solution is ready for use (2 mg / mL) freshly.

[0124] Step 2: ABR measurement

[0125] The 26 animals were anesthetized with zolazepam hydrochloride (Zoletil) and Xylazine and were recorded for their auditory brainstem responses (ABR) using TDT RZ6 Multi-I / O processor. Acoustic stimuli were delivered via an earphone. Needle electrodes were placed near the ear canal at the caudoventral position, the vertex of the skull, and a ground at the lower leg. The stimulus level was from 10 to 90 dB in 5 dB steps, and the tonepip frequencies were 4, 24, and 32 kHz. The ceiling sound pressure level was 90 dB. ABR threshold was observed by visual inspection of stacked waveforms as the lowest sound pressure level, at which the waveform was above the noise floor.Attorney Docket No. 553748WO

[0126] Prior to the cisplatin infusion, ABR baseline data from 26 animals were recorded bilaterally from each animal. Elevated ABR data related to otitis media or genetic problems were excluded as the baseline.

[0127] Animals were measured again 1 week after STS local delivery and cisplatin infusion treatment. A comparison was performed between the treated ear and the untreated contralateral ear and the baseline.

[0128] Step 3: Dosing procedure

[0129] Sodium thiosulfate trans-tympanic (TT) injection

[0130] The subjection guinea pig was anesthetized with zolazepam hydrochloride (Zoletil) and Xylazine. A solution of freshly prepared sodium thiosulfate solution was loaded in a Hamilton syringe with 26G needle. The needle was carefully inserted into the left middle ear cavity via the tympanic membrane. ~50 uL of dosing solution was injected. The animal was positioned for ~30 min prior to waking up for the cisplatin infusion.

[0131] Sodium thiosulfate intra-tympanic (IT) injection

[0132] After the guinea pig is anesthetized with the cocktail (Zoletil and Xylazine), it is put in prone neutral position. A postauricular incision is made to expose bulla. Using a 22-gauge sharp needle, a hole is made on the bulla by means of surgical microscope. Visualize the round window through the hole which is facing upward. Carefully drop lOuL freshly prepared STS on the round window niche without overflowing to the other place of the middle ear. Keep it in neutral position for 30 minutes while closing the wound with suture. ~30 minutes, the animal was applied cisplatin intravenously.

[0133] Cisplatin infusion

[0134] Cisplatin saline solution (lOmg / kg) was infused through a foot dorsal venin (about 1 min infusion) after 30 min post the injection of sodium thiosulfate solution. 7 days after infusion, all animals were tested ABR again. Selecting some cochleae for histology studies.Attorney Docket No. 553748WO

[0135] Step 4: Efficacy exams

[0136] ABR recorded as below:

[0137] All groups (2.5%, 5% and 10% sodium thiosulfate) showed nearly completed protection of the sodium thiosulfate treated ears. Animals showing significant signs of otitis media / middle ear inflammation were excluded from the analysis.

[0138] Cochleae Confocal Microscopy

[0139] Extraction of temporal bones from guinea pig skull. Post-fix temporal bones in 10% NBF 16-24 hours. Decalcify the temporal bones 7 days in 10% EDTA. Micro dissect organ of Corti from cochlea for surface preparation. Immunostaining with Fluorescently Tagged Antibodies to dissected basilar membranes. Phalloidin (green) counterstained the structure of the three rows of OHCs and one row of IHCs. Pou4f3 (red) stained the three rows of OHCs and one row of IHCs. DAPI (blue) stained limbus and spiral ligament tissue. Take a photo on a mounted slide by using a fluorescent microscope. Show the location of 4, 8, 16, 24 and 32 kHz on the image. Count inner hair cells (IHC) and outer hair cells (OHC) in the 200um distance rangeEXAMPLE 3: Pharmacokinetic study.

[0140] The time-concentration data was used for calculations. The area under the concentration-time curve (AUC) was determined by the trapezoidal rule. Terminal elimination half-lives of sodium thiosulfate (STS) in perilymph and plasma were determined by use of WIN NONLIN version 2.0 SCI.

[0141] Animals’ preparation

[0142] 30 guinea pigs (250-350g) without sign of otitis media stayed for ~3 days acclimation, and ready for PK study. Two anesthesia methods (Zoletil + Xylazine with head up 30 min)Atorney Docket No. 553748WO and Isoflurane (animal wake up immediately post-injection)] were used. 15 animals for each group.

[0143] Sodium thiosulfate trans-tympanic (TT) injection

[0144] The subjection guinea pig was anesthetized with zolazepam hydrochloride (Zoletil) and Xylazine or isoflurane inhalation. A solution of freshly prepared sodium thiosulfate solution was loaded in a Hamilton syringe with 26G needle. The needle was carefully inserted into the left middle ear cavity via the tympanic membrane aiming to cochlear round window. ~50 uL of dosing solution was injected. The animal was positioned head up for ~30 min prior to waking up in Zoletil and Xylazine or wake up immediately in isoflurane inhalation.

[0145] Perilymph collection

[0146] After euthanasia, the animal was stripped of excess skin and muscle tissue to obtain a complete auditory bulla, and the bulla wall was cut with small forceps to expose the cochlea. The basal turn of bulla was cleaned by using a small cotton ball. The cochlear bottom circle and the round window were coated with bio glue. After drying, a unique micro hole was hand-drilled in the top circle of the cochlea. ~5 pL volume of perilymph was then collected using a microcapillary inserted into the cochlear top circle. Perilymph samples were added to a vial containing 15 pL of ACN / H2O (v / v, 1 : 1) stored at -80° C. until analysis.

[0147] Plasma collection

[0148] In C-subgroup of each group, animal blood was systemically drawn (~100uL) via bilateral saphenous vein at the multiple time points. Put the collection blood in heparinized tube and stay ~20min. ~50uL of plasma was collected in microtube and put in -80°C for future analysis.

[0149] Bio-analytical methodAttorney Docket No. 553748WO

[0150] STS concentrations were quantitatively analyzed by HPLC using an LC-20AT with a SPD-M20A UV-Vis detector (Shimadzu, Kyoto, Japan) and a LiChrospher RP-select B LiChroCART 250-4 anion exchange column (EMD Millipore Corp, Darmstadt, Germany). All samples were prepared using a method similar to that described by Togawa et al. (1992).

[0151] As described above, in vivo efficacy data (via guinea pig trials and cisplatin hearing loss model) was obtained to demonstrate a simple aqueous formulation without a gelling agent can achieve similar or better delivery to the inner ear. Further, full hearing protection was achieved at lower dose levels. For example, the 0.2M concentration achieved said full hearing protection. The lower concentrations still maintained or improved patient comfort levels.

[0152] In an embodiment, the pharmaceutical composition comprises an aqueous solution of a platinum chelator at a concentration between 0.01M to 2.5M, preferably 0.025M to 2.0M, preferably 0.05M to 1.5M, preferably 0.075M to 1.0M, preferably 0.09M to 0.75M, preferably 0.1M to 0.5M.

[0153] In an embodiment, embodiment, the pharmaceutical composition comprises an aqueous solution of a platinum chelator at a calculated osmolarity of, for example, <9500 mOsm / L, preferably 100-8500 mOsm / L, preferably 200-7500 mOsm / L, preferably 250-6500 mOsm / L, preferably 300-5000 mOsm / L.

[0154] In an embodiment, the platinum chelator is sodium thiosulfate.

[0155] In an embodiment, the thiosulfate salt is present in the pharmaceutical composition at a concentration of from 0.01M to 2.5M, preferably 0.025M to 2.0M, preferably 0.05M to 1.5M, preferably 0.075M to 1.0M, preferably 0.09M to 0.75M, preferably 0.1M to 0.5M.

[0156] In an embodiment, the thiosulfate salt is at least one selected from the group consisting of lithium thiosulfate, sodium thiosulfate, magnesium thiosulfate, calcium thiosulfate, and potassium thiosulfate.Attorney Docket No. 553748WO

[0157] In an embodiment, the platinum chelator is alkaline diethyldithiocarbamate salt, amifostine, methionine, N-acetylcysteine, cysteine, 2-aminoethanethiol, glutathione (GSH) or a C1-C6 alkyl ester thereof, dimercaptosuccinic acid, dimercapto-propane sulfonate salt, penicillamine, a-lipoic acid, or fursultiamine.

[0158] In an embodiment, the thiosulfate concentration is between about 0.1M and 0.3M.

[0159] In an embodiment, the thiosulfate concentration is between about 0.15M and 0.25M.

[0160] In an embodiment, the aqueous solution is a water-based solution having a pH between 5 and 9.5.

[0161] In an embodiment, the aqueous solution includes a buffer agent.

[0162] In an embodiment, the buffer agent is boric acid.

[0163] In an embodiment, a method for the prevention of platinum-induced hearing loss in a subject undergoing a treatment with one or more platinum -based antineoplastic agents includes administering the aqueous solution of thiosulfate to the subject by intratympanic or transtympanic injection via a catheter, an outlet of the catheter being inserted into a middle ear cavity through a intratympanic drug delivery device disposed in an opening on a tympanic membrane at the end of an ear canal, and the aqueous solution of thiosulfate filling the middle ear cavity and covering a round window membrane disposed in the middle ear cavity.

[0164] In an embodiment, the volume of the injected aqueous solution of thiosulfate is 0.1mL-0.5mL.

[0165] In an embodiment, an inlet of the catheter is arranged outside the outer ear.

[0166] In an embodiment, the inlet end of the catheter includes a Luer lock for connecting to a syringe.

[0167] In an embodiment, the catheter has outer diameter of from 0.3 mm to 1.0 mm, or 0.3 mm to 0.6 mm, or 1 Fr to 2 Fr.Attorney Docket No. 553748WO

[0168] In an embodiment, a material of the catheter is biocompatible and soft, such as polyurethane and silicon. In an embodiment, biocompatible can be generally defined as compatibility with living tissue or a living system by assuring that the product poses minimal toxicity, injury potential, or physiological / immunological reactivity.

[0169] In an embodiment, the opening on the tympanic membrane is an incision.

[0170] In an embodiment, the opening on the tympanic membrane is a intratympanic drug delivery device mounted on the tympanic membrane through an incision on the tympanic membrane.

[0171] In an embodiment, the outlet tip of the catheter is inserted through an aperture of the intratympanic drug delivery device and into the middle ear cavity.

[0172] In an embodiment, the catheter outer diameter is smaller than the inner diameter of the body of the intratympanic drug delivery device.

[0173] In an embodiment, the inlet end of the catheter is a drug reservoir.

[0174] In an embodiment, a material of the intratympanic drug delivery device is fluoroplastics, polyethylene, or silicone with an inner diameter of 0.6 mm to 1.5 mm.

[0175] In an embodiment, a length of the catheter is more than 0.5 cm, or more than 1 cm, or more than 2 cm, or more than 3 cm as measured from the inlet end to the outlet tip.

[0176] In an embodiment, the material of the catheter is radiopaque (e.g., includes barium) for x-ray confirmation of the position of the catheter.

[0177] In an embodiment, the intratympanic or transtympanic injection of the aqueous thiosulfate solution is performed one or more times during the same day of the platinumbased antineoplastic agent infusion, and any single intratympanic or transtympanic injection is performed no later than 1 hour prior to the beginning of the platinum-based antineoplastic agent infusion.Attorney Docket No. 553748WO

[0178] In an embodiment, the intratympanic or transtympanic injection is between 0 and 1 hour prior to the beginning of cisplatin infusion.

[0179] In an embodiment, the intratympanic or transtympanic injection is between 0 and 30 min prior to the beginning of cisplatin infusion.

[0180] In an embodiment, the intratympanic or transtympanic injection is between 0 and about 5 min prior to the beginning of cisplatin infusion.

[0181] In an embodiment, a subsequent intratympanic or transtympanic injection (a booster dose) is administered between 1 hour and about 12 hours after the prior intratympanic or transtympanic injection.

[0182] In an embodiment, a subsequent intratympanic or transtympanic injection (the booster dose) is administered between 1 hour and about 6 hours after the prior intratympanic or transtympanic injection.

[0183] In an embodiment, a subsequent intratympanic or transtympanic injection (the booster dose) is administered between 1 hour and about 3 hours after the prior intratympanic or transtympanic injection.

[0184] Embodiments of the present disclosure may also be as set forth in the following parentheticals.

[0185] (1) A drug delivery system for intratympanic injection, comprising: an intratympanic drug delivery device, including a body having a first end with a first opening and a second end with a second opening, the body being an elongated housing having a hollow chamber running along a length of the body from the first opening to the second opening, the first opening of the body configured to be inserted through a tympanic membrane; and a catheter configured to be inserted through the hollow chamber of the elongated housing of the body of the intratympanic drug delivery device, wherein a length of the intratympanic drug delivery device is greater than or equal to about 7 mm.Attorney Docket No. 553748WO

[0186] (2) The system of (1), wherein the intratympanic drug delivery device further includes a funnel disposed at a first end of the body, the funnel having an aperture, the aperture defining and inner diameter of an opening of the funnel, the aperture having a diameter wider than a diameter of the first opening.

[0187] (3) The system of either (1) or (2), wherein the intratympanic drug delivery device is configured to be inserted into an ear canal and through the tympanic membrane, and when the intratympanic drug delivery device is inserted into the tympanic membrane, the funnel is disposed at an opening of the ear canal.

[0188] (4) The system of any one of (1) to (3), wherein a length of the intratympanic drug delivery device is greater than or equal to about 7 mm..

[0189] (5) The system of any one of (1) to (4), wherein a length of the intratympanic drug delivery device is greater than or equal to about 10 mm.

[0190] (6) The system of any one of (1) to (5), wherein a length of the intratympanic drug delivery device is about 12 mm.

[0191] (7) The system of any one of (1) to (6), wherein the diameter of the aperture is greater than or equal to about 1.5 mm.

[0192] (8) The system of any one of (1) to (7), wherein the diameter of the aperture is greater than or equal to about 2.0 mm.

[0193] (9) The system of any one of (1) to (8), wherein a material of the intratympanic drug delivery device is at least one selected from the group consisting of fluoroplastic, polyethylene, silicone elastomer, stainless steel, and titanium.

[0194] (10) The system of any one of (1) to (9), wherein a material of the intratympanic drug delivery device is at least one selected from the group consisting of fluoroplastic and polyethylene.Attorney Docket No. 553748WO

[0195] (11) The system of any one of (1) to (10), wherein an outer diameter of the catheter is less than the diameter of the first opening and a diameter of the second opening.

[0196] (12) The system of any one of (1) to (11), wherein an outer diameter of the catheter is about 0.35 mm and an inner diameter of the catheter is about 0.17 mm.

[0197] (13) The system of any one of (1) to (12), wherein the diameter of the first opening and a diameter of the second opening is greater than or equal to about 0.5 mm.

[0198] (14) The system of any one of (1) to (13), wherein a material of the catheter is polyurethane.

[0199] (15) The system of any one of (1) to (14), further comprising a syringe fluidly connected to the catheter, the syringe configured to hold a fluid.

[0200] (16) The system of any one of (1) to (15), wherein a length of the funnel is greater than or equal to 2.5 mm.

[0201] (17) The system of any one of (1) to (16), wherein a length of the body is greater than or equal to 4 mm.

[0202] (18) The system of any one of (1) to (17), wherein the intratympanic drug delivery device further includes an inner flange disposed at the second end of the intratympanic drug delivery device, the inner flange having an outer diameter wider than an outer diameter of the body.

[0203] (19) The system of any one of (1) to (18), wherein an outer diameter of the inner flange is 2.2 mm.

[0204] (20) The system of any one of (1) to (19), wherein the intratympanic drug delivery device further includes an outer flange disposed proximal to the inner flange at the second end of the intratympanic drug delivery device, the outer flange having an outer diameter wider than the outer diameter of the body.Attorney Docket No. 553748WO

[0205] (21) The system of any one of (1) to (20), wherein the second end of the intratympanic drug delivery device includes a rounded tip formed as part of the inner flange.

[0206] Obviously, numerous modifications and variations are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, embodiments of the present disclosure may be practiced otherwise than as specifically described herein.

[0207] Thus, the foregoing discussion discloses and describes merely exemplary embodiments of the present disclosure. As will be understood by those skilled in the art, the present disclosure may be embodied in other specific forms without departing from the spirit thereof. Accordingly, the disclosure of the present disclosure is intended to be illustrative, but not limiting of the scope of the disclosure, as well as other claims. The disclosure, including any readily discernible variants of the teachings herein, defines, in part, the scope of the foregoing claim terminology such that no inventive subject matter is dedicated to the public.

Claims

Attorney Docket No. 553748WOCLAIMS1. A drug delivery system for intratympanic injection, comprising: an intratympanic drug delivery device, including a body having a first end with a first opening and a second end with a second opening, the body being an elongated housing having a hollow chamber running along a length of the body from the first opening to the second opening, the first opening of the body configured to be inserted through a tympanic membrane; and a catheter configured to be inserted through the hollow chamber of the elongated housing of the body of the intratympanic drug delivery device, wherein a length of the intratympanic drug delivery device is greater than or equal to about 7 mm.

2. The system of claim 1, wherein the intratympanic drug delivery device further includes a funnel disposed at a first end of the body, the funnel having an aperture, the aperture defining and inner diameter of an opening of the funnel, the aperture having a diameter wider than a diameter of the first opening.

3. The system of claim 2, wherein the intratympanic drug delivery device is configured to be inserted into an ear canal and through the tympanic membrane, and when the intratympanic drug delivery device is inserted into the tympanic membrane, the funnel is disposed at an opening of the ear canal.

4. The system of claim 1, wherein a length of the body is greater than or equal to about 7 mm.Attorney Docket No. 553748WO5. The system of claim 1, wherein a length of the intratympanic drug delivery device is greater than or equal to about 10 mm.

6. The system of claim 1, wherein a length of the intratympanic drug delivery device is about 12 mm.

7. The system of claim 2, wherein the diameter of the aperture is greater than or equal to about 1.5 mm.

8. The system of claim 2, wherein the diameter of the aperture is greater than or equal to about 2.0 mm.

9. The system of claim 1, wherein a material of the intratympanic drug delivery device is at least one selected from the group consisting of fluoroplastic, polyethylene, silicone elastomer, stainless steel, and titanium.

10. The system of claim 1, wherein a material of the intratympanic drug delivery device is at least one selected from the group consisting of fluoroplastic and polyethylene.

11. The system of claim 1, wherein an outer diameter of the catheter is less than the diameter of the first opening and a diameter of the second opening.

12. The system of claim 1, wherein an outer diameter of the catheter is about 0.35 mm and an inner diameter of the catheter is about 0.17 mm.Attorney Docket No. 553748WO13. The system of claim 1, wherein the diameter of the first opening and a diameter of the second opening is greater than or equal to about 0.5 mm.

14. The system of claim 1, wherein a material of the catheter is polyurethane.

15. The system of claim 1, further comprising: a syringe fluidly connected to the catheter, the syringe configured to hold a fluid.

16. The system of claim 2, wherein a length of the funnel is greater than or equal to about 2.5 mm.

17. The system of claim 1, wherein a length of the body is greater than or equal to about 4 mm.

18. The system of claim 1, wherein the intratympanic drug delivery device further includes an inner flange disposed at the second end of the intratympanic drug delivery device, the inner flange having an outer diameter wider than an outer diameter of the body.

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