Simulation of application strategies for local drug delivery to the inner ear

Abstract

Local, rather than systemic, drug delivery to the inner ear is becoming more widely used to treat inner ear disorders. While many substances are undergoing preclinical and clinical studies, it is equally important to develop appropriate drug delivery systems. Pharmacokinetic studies are technically demanding in animals and almost impossible in humans. Computer simulations have helped establish the basic principles of drug distribution in the inner ear. The distribution of methylprednisolone in the guinea pig cochlea has been simulated for different drug delivery systems based on kinetic parameters established in prior studies. Results were compared for different rates of drug clearance from the middle ear. Absolute and relative drug levels in the perilymph were highly dependent on how long the drug remained in the middle ear. For a brief (30 min) application, the basal to apical drug gradient was higher than for longer delivery times. These findings show that controlling middle ear drug clearance is of critical importance.

Fig. 1

Application systems for local drug delivery to the inner ear. a Intratympanic injection. b Microotoscope ‘Model Tübingen’, GYRUS Medical GmbH (former Explorent®/STUEMED®): outer diameter: 1.2 mm; including an optical channel (0.5 mm) with 6,000 fibers and two working or suction channels (0.27 and 0.3 mm), which may be used for targeted intratympanic drug delivery after visualization of the round window niche (from Plontke et al. [27], with permission of S. Karger AG, 2002). c Silverstein Micro Wick™ [8], printed with permission of Micromedics Inc., St. Paul, Minn., USA. d Totally implantable drug delivery system [14, 28] (printed with permission of R. Lehner and H.P. Zenner, Germany). e Temporarily implantable catheter approved for intratympanic drug delivery (RW μ/ECath™, printed with permission of DURECT™, Cupertino, Calif., USA). f Poly-lactic/glycolic acid nanoparticles (arrow) loaded with rhodamine entering the scala tympani after placement at the RWM of the guinea pig (from Tamura et al. [11], with permission of Lippincott Williams & Wilkins, 2005). ^* = Scala tympani.

Fig. 2

Summary of calculated methylprednisolone distribution in the scala tympani of the guinea pig as a function of distance and time for four application conditions: absolute drug levels achieved in the perilymph depend greatly on how long the drug remains in the middle ear. For a brief (30 min) application, the basal/apical gradient is higher than for longer delivery times. The clearly different intracochlear concentration-time curves calculated for different clearance values show the importance of controlling middle ear clearance (b, c). Note that d has a different time axis.

Fig. 3

Comparison of maximum concentration and total dose for different locations in the scala tympani and for different application systems: the physiologic effects of an applied drug depend on whether the ear is most sensitive to the maximum concentration (C_max) or whether exposure time and total dose play a role. Calculated C_max and total dose (AUC) demonstrate a strong dependence of drug level on the time the drug stays in the middle ear. Gradients for C_max along the scala tympani are greater for brief applications and become markedly reduced with prolonged application. Gradients for AUC are independent of application time. Note logarithmic scale of normalized values in c and d. ME = Middle ear.