Principles of Local Drug Delivery to the Inner Ear

Abstract

As more and more substances have been shown in preclinical studies to be capable of preventing damage to the inner ear from exposure to noise, ototoxic drugs, ischemia, infection, inflammation, mechanical trauma and other insults, it is becoming very important to develop feasible and safe methods for the targeted delivery of drugs to specific regions in the inner ear. Recently developed methods for sampling perilymph from the cochlea have overcome major technical problems that have distorted previous pharmacokinetic studies of the ear. These measurements show that drug distribution in perilymph is dominated by passive diffusion, resulting in large gradients along the cochlea when drugs are applied intratympanically. Therefore, in order to direct drugs to specific regions of the ear, a variety of delivery strategies are required. To target drugs to the basal cochlear turn and vestibular system while minimizing exposure of the apical cochlear turns, single one-shot intratympanic applications are effective. To increase the amount of drug reaching the apical cochlear turns, repeated intratympanic injections or controlled-release drug delivery systems, such as biodegradable biopolymers or catheters and pumps, are more effective. However, if the applied substance does not easily pass through the round window membrane, or if a more widespread distribution of drug in the ear is required, then intralabyrinthine injections of the substance may be required. Intralabyrinthine injection procedures, which are currently in development in animals, have not yet been proven safe enough for human use.

Cisplatin‐Induced Ototoxicity and the Effects of Intratympanic Diltiazem in a Mouse Model

“…22 This makes IT injections even more appealing as a therapeutic option since cisplatin tends to affect high-frequency basal-turn OHCs. Histologic examination of hair cells exposed to cisplatin with and without diltiazem would also be a useful next step in evaluating otoprotection from cisplatin at a cellular level.…”

Enhanced bioavailability of nerve growth factor with phytantriol lipid-based crystalline nanoparticles in cochlea

“…Although the intracochlear route of tropic agents is feasible, it has not been applied in humans because of unknown safety concerns. 30 A major obstacle with respect to clinical application of neurotrophin is whether continuous treatment is required for maintaining its pharmacological function. Based on the neurotrophin hypothesis, it is believed that cessation of provided neurotrophic agents would result in the degeneration of SGCs.…”

Intratympanic Injections: An Unsolved Mystery

“…In IT therapy concentration of the drug and the duration for which it stays over the RWM is more important than the volume [16]. Injected volumes in published studies range from <0.3 ml [17] to 1 ml [18] [19] at the higher end.…”

“…Also animal data has shown basal-apical concentration differences of over 1000-fold [16]. While direct determination of the gradient in a human cochlea is not feasible, it has been estimated in a computer-based simulation for IT gentamicin at around 100:1 (basal to apical levels) [31].…”