Intracochlear drug delivery systems: a novel approach whose time has come

Figures & data

Figure 1. Flow diagram illustrating the various classes of SensoriNeural Hearing Loss (SNHL) and the current Standard of Care (SoC) for each mode. For cisplatin chemotherapy, for instance, approximately 50% of patients suffer permanent hearing loss [4], while over 10% of the US population suffers from NIHL [7], and the NIDCD notes that 1/3 of adults 65 to 74 years of age suffers from significant hearing loss.

Table 1. Selected therapeutic compounds are organized by delivery method, class of action, disease target, and stage of development.

Intra-tympanic route
Auris	AM-111	JNK inhibitor	Sudden sensorineural hearing loss	Phase III
Auris	AM-101	NMDA receptor antagonist	Tinnitus	Phase III
Otonomy	Otividex	Dexamethasone	Ménière’s disease & cisplatin-induced hearing loss	Phase III
Synphora	Latanoprost	PGF2 alpha agonist	Ménière’s disease	Phase II
Strekin	STR001	PPAR gamma agonist	Sudden sensorineural Hearing Loss	Phase II
Otonomy	OTO-311	NMDA receptor antagonist	Tinnitus	Phase I
Frequency	FX-322	Undisclosed small molecules	Chronic noise-induced	Phase I
Intra-cochlear route
Auris and Cochlear	AM-111	JNK inhibitor	Sudden sensorineural hearing loss	Phase II
Oral route
Sensorion	SENS-111	Histamine H4 receptor antagonist	Vestibulopathy	Phase II
Edison pharmaceuticals	EPI-743	Antioxidant	Noise-induced hearing loss	Phase II
Sound pharmaceuticals	SPI-1005 (Ebselen)	NFE2L2 activator	Noise-induced hearing Loss, Ménière’s disease, chemo-induced	Phase II
Autifony	AUTO0063	KCNC1 modulator	Age-related hearing loss, Tinnitus, noise-induced hearing loss, Adjunct to cochlear implants	Phase II
GSK	Vestipitant	NK1 receptor antagonist	Tinnitus	Phase II
Otologic Pharmaceutics	NHPN-1010 (HPN-07 + NAC)	Antioxidant	Cisplatin-induced hearing loss, noise-induced hearing loss	Phase I
Sensorion	SENS-401	5-HT3 receptor antagonist	Sudden sensorineural hearing loss	Phase I
IV route
Fennec	STS	Sodium thiosulfate	Chemo induced (prevent)	Phase III
Intra-nasal route
Auris	AM-125	Histamine H1-receptor agonist + a H3-receptor antagonist	Ménière’s disease	Phase I
Intra-labyrinth route
GenVec/Novartis	CGF166	Gene therapy	Hearing loss & vestibular dysfunction	Phase II

Table 2. The effects of drugs on the inner ear depend in large part on the pharmacokinetics of the drug within the fluids of the inner ear, specifically what drug concentrations reach different regions of the ear and how long the drug stays in each region before disappearing.

	Systemic administration	Transtympanic injection	Intracochlear injection	Intra-cochlear drug delivery device
Efficiency (reaching perilymph)	Severely limited by low cochlear blood flow and BCB [26]	Limited, produce variable outcomes. Variability in dose control.	High Minimized systemic exposure. Good dose control.	High minimized systemic exposure. Excellent dose and time control.
Safety	Moderate. Drugs can induce systemic toxicity.	High, minimally invasive procedure that can be performed in a physician’s office	Moderate, precise surgery is needed, and complications may occur. Potential toxicity of a high drug concentration in the cochlea.	Moderate if introduced by cochleostomy, but development of surgical approach for the device through the RWM is possible.
Drug diffusion in the perilymph	Entry shows saturation kinetics, but concentrations never exceed plasma levels; drug not actively accumulated [26] Electrical charge affects drug entry into the scala media.	RWM an anatomic barrier to absorption; patient variability in RWM thickness and permeability. Large molecules (MW 70,000) cannot diffuse across easily. Drug may enter via oval window into scala vestibuli and vestibule [27].	Bypass middle ear, minimize side effects. Reduce variability and distribute uniformly along scala tympani [27]. Drug retention dependent on size of RWM perforation. Fluid leakage controlled by encasing drug in gel or use of adhesive.	Reciprocating flow enables zero-net-volume delivery and enhances drug mixing and apical transport. The base-to-apex concentration gradient reduced. Fouling reduced
Drug bioavailability	Very limited. Kinetics of drug entry from BCB depends on local properties.	Limited. Loss of drug in the middle ear through the Eustachian tube, highly variable. Difficult to reach the apex. Drug leakage to CSF via the cochlear aqueduct close to the RWM [28].	Substantially increase drug bioavailability in the inner ear, but may establish a base-to-apex gradient. Drug leakage to CSF via the cochlear aqueduct close to the RW [28].	Continuous drug application, enables access to cells of interest, increases target specificity. Multiple drugs could be injected.
Other				Can be conjugated with stimulating electrode. Possibility to make measurements of drug concentrations in real time [1]
Suitable for this type of drugs		Adapted for nanocarriers, hydrogels but not liquid formulations.	Can be used for liquid formulations and for large molecules (proteins, gene vectors, other macromolecules).	Can be used for liquid formulations and for large molecules (proteins, gene vectors, other macromolecules)

Figure 2. Schematic of the delivery chip component of an intracochlear drug delivery (ICDD) device comprising microfluidic drug storage and flow control. The ICDD device is connected, via a small tube inserted into the scala tympani, to the basal turn of the human cochlea to show potential clinical implementation.

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