Intracochlear PLGA based implants for dexamethasone release: Challenges and solutions

E Lehner,D Gündel,A Liebau,S Plontke,K Mäder

doi:10.1016/j.ijpx.2019.100015

E Lehner, D Gündel + Show 3 more

Open Access

https://doi.org/10.1016/j.ijpx.2019.100015

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Abstract

The effective treatment of diseases of the inner ear is currently an unmet medical need. Local controlled drug delivery to the cochlea is challenging due to the hidden location, small volume and high sensitivity of this organ. A local intracochlear delivery of drugs would avoid the problems of intratympanic (extracochlear) drug application, but is more invasive. The requirements for such a delivery system include a small size and appropriate flexibility. The delivery device must be rigid enough for surgical handling but also flexible to avoid traumatizing cochlear structures. We developed biodegradable dexamethasone loaded PLGA extrudates for the controlled intracochlear release. In order to achieve the desired flexibility, Polyethylene glycol (PEG) was used as a plasticizer. In addition to the drug release, the extrudates were characterized in vitro by differential scanning calorimetry (DSC) and texture analysis. Simulation of the pharmacokinetics of the inner ear support the expectation that a constant perilymph drug level is obtained after few hours and retained over several weeks. Ex vivo implantation of the extrudates into a guinea pig cochlea indicate that PEG containing extrudates have the desired balance between mechanical strength and flexibility for direct implantation into the cochlea. The location of the implant was visualized by computer tomography. In summary, we postulate that intracochlear administration of drug releasing biodegradable implants is a new and promising approach to achieve local drug delivery to the cochlea for an extended time.

Highlights

Drug delivery to the inner ear represents currently an unmet medical need (Plontke and Salt, 2018)
Very thin rod shaped dexamethasone loaded PLGA based implants with a drug load of 10% were prepared by hot-melt extrusion at 50 °C
The use of Polyethylene glycol (PEG) as an additional excipient was beneficial in two aspects: (i) PEG softens the extrudates and prevents the cracking during bending

Summary

Introduction

Drug delivery to the inner ear represents currently an unmet medical need (Plontke and Salt, 2018). The main administration sites for drug delivery to the inner ear in humans are extracochlear (intratympanic, IT) and intracochlear (IC) application. A detailed discussion of the main drug delivery systems has been recently published by Mäder et al (2018). Among the non-degradable systems, silicon based implants show great promise to improve drug delivery to the inner ear (Gehrke et al, 2019, 2016; Krenzlin et al, 2012). In a previous clinical pilot study we placed a Ozurdex® drug delivery implant into the RW niche and onto the RW membrane as a salvage therapy for idiopathic sudden sensorial hearing loss (ISSHL) (Plontke et al, 2014). We were able to show that the local administration of Ozurdex® implants to the RW showed encouraging results for the treatment of sudden hearing

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