Innovative Inner Ear Treatments – INI

Drug-loaded intracochlear implants are prepared by blending different types of drugs with medical grade silicones, followed by injection molding. Drug-loaded liposomes are manufactured using thin lipid film methods. Appropriate polymer powders (e.g. hyaluronic acid) are hydrated with liposome suspensions to form liposome-containing hydrogels. The novel drug delivery systems are first thoroughly characterized in vitro, for example using differential scanning calorimetry, scanning electron microscopy, Raman imaging, drug release measurements, thermogravimetric and mechanical or rheological analyses. Based on these experimental results, novel mechanistically realistic mathematical theories are developed, taking into account the dominant mass transport phenomena controlling drug release out of the implants and hydrogels in vitro. The theories are used to predict the impact of formulation and processing parameters on the resulting drug release kinetics. The validity of these theoretical predictions is evaluated by independent experiments.
The most promising drug delivery systems are then tested in vivo (animals). This includes the measurements of drug perilymph and plasma drug concentrations (pharmacokinetics, PK) as well as of indicators for the therapeutic efficacy of the treatments (pharmacodynamics, PD). The obtained experimental results will be used as a basis to extend the mathematical models, taking also into account the in vivo fate of the drug. These comprehensive and mechanistically realistic mathematical theories will allow for the identification of the dominant physico-chemical and biological phenomena controlling drug release and drug transport in vivo. The novel theories will be used to theoretically predict the impact of formulation and processing parameters on the resulting pharmacokinetics/pharmacodynamics and to optimize the innovative local drug delivery systems. The validity of these predictions will be evaluated by independent in vivo studies.

So far (in the first 18 months of the project) the following main results have been obtained:
1) Thin films based on different types of medical grade silicone have been prepared. Drugs like dexamethasone have been incorporated, varying their loading between 1 and 10 % with respect to the polymer content. The film thickness as well as the drug distribution within the polymeric networks were homogeneous.
2) Different prototypes of cylindrical extrudates have been manufactured, incorporating dexamethasone and varying the dimensions (diameter and length) of the systems.
3) First prototypes of miniaturized implants have been prepared via injection molding and cross-linking. Different types of drugs have been incorporated in a homogeneous manner. The geometry as well as the size of the implants have been altered.
4) Liposomes loaded with dexamethasone and drug-loaded hydrogels have been manufactured. The drug(s) is(are) located within the liposomes in the hydrogels, or is(are) directly distributed in the polymeric networks.
5) The physico-chemical characterization of the different types of films, cylindrical extrudates miniaturized implants, liposomes and hydrogels has started. This includes for example measurements of the resulting drug release kinetics under different in vitro conditions, the long term stability of the drug delivery systems, as well as the determination of their mechanical properties and morphologies.
6) First mathematical theories have been developed allowing to describe the drug transport phenomena within the different dosage forms (e.g. miniaturized implants). These models take into account the diffusion of the drug through the polymeric matrices, the initial distribution of the systems’ compounds as well as the conditions in the release medium.

The consortium partners will focus on the following key features:
1) The most promising miniaturized implants and liposome containing hydrogels will be studied in vivo (in animals). The selected systems will have been optimized with respect to their compositions, geometries, dimensions and manufacturing procedures.
2) The mathematical theories developed so far will be extended in order to take also the in vivo fate of the drug(s) into account. In particular, the drug elimination from the site of action will be considered in a quantitative manner.
3) The physico-chemical characterization of the thin films, cylindrical extrudates, miniaturized implants, liposomes and hydrogels will be continued and extended, using for instance Raman imaging and scanning electron microscopy.
4) Changes in the key properties of the different types of advanced drug delivery systems upon exposure to appropriate release media will be studied. This includes for example critical device properties such a potential swelling of the miniaturized implants as well as their mechanical stability.
5) Theoretical predictions concerning the impact of the key formulation and processing parameters of the miniaturized implants and liposome-containing gels on the resulting drug release kinetics will be made and compared with independent experimental results. These comparisons will allow to optimize the mathematical theories in order to take into account all the dominant mass transport phenomena controlling drug release.
6) The manufacturing procedures of the novel drug-loaded implants, liposomes and hydrogels as well as their compositions will be optimized, based on the obtained experimental and theoretical results.
7) In the long run, the results obtained in this project are intended to serve as the basis for the development and introduction of innovative drug products to the market, allowing for a facilitated and more effective treatment of diseases and disorders of the inner ear.

So far, the results of this project have been published in the following journal articles (A), oral (O) and poster (P) presentations at international scientific meetings:

A1) Gehrke, M. et al. Ear Cubes for local controlled drug delivery to the inner ear. Int. J. Pharm. 509, 85-94, 2016.
A2) El Kechai, N.; et al. Mixtures of hyaluronic acid and liposomes for drug delivery: Phase behavior, microstructure and mobility of liposomes. Int. J. Pharm. 523, 246-259, 2017.

P1) El Kechai, N. et al. Hyaluronic acid gels containing liposomes… Formula VIII Int. Conf., Barcelona, 2016.
P2) El Kechai, N. et al. Injectable hyaluronic acid gels ... ECIS 2016, 30th Conf. Eur. Colloid and Interface Society, Rome, 2016.
P3) Gehrke, M. et al. Hybrid Ear Cubes for controlled dexamethasone delivery ... 10th World Meeting on Pharmaceutics, Glasgow, 2016.
P4) Gehrke, M. et al. Ear Cubes: A new approach for local controlled drug delivery ... 10th World Meeting on Pharmaceutics, Glasgow, 2016.
P5) Gehrke, M. et al. Characterization of Ear Cubes ... 4th Conf. Innovation in Drug Delivery, Antibes, 2016.
P6) Gehrke, M. et al. Characterization of Hybrid Ear Cubes .... 4th Conf. Innovation in Drug Delivery, Antibes, 2016.
P7) Gehrke, M. et al. Ear Cubes loaded with gentamicin ... 4th Conf. Innovation in Drug Delivery, Antibes, 2016.
P8) Sircoglou, J. et al. In-situ forming trans-oval-window implants ... 10th World Meeting on Pharmaceutics, Glasgow, 2016.

O1) Siepmann, J. Drug delivery to the inner ear. 4th Conf. Innovation in Drug Delivery, Antibes, 2016.
O2) Siepmann, J. Mathematical Modeling of Diffusion Controlled Release Dosage Forms. AAPS Annual Meeting, Denver, 2016.
O3) Oliveira, PFM. et al. Solid state transformations of dexamethasone induced by milling. 2nd Eur. Conf. on Pharmaceutics, Cracovie, 2017.
O4) Oliveira, PFM. et al. Transformations of dexamethasone drug induced by mechanical milling. 9th Int. Conf. on Mechanochemistry and Mechanical Alloying, Kosice, 2017.

The aim of this project is to open up new horizons for innovative medical treatments of the cochlear of the inner ear. New therapeutic strategies will be developed for ear ailments, in particular hearing loss. Despite the availability of highly potent drugs, which could be of great benefit for the patients, most treatments are nowadays not possible because the drug cannot reach its target site: the inner ear. This is due to the blood-cochlear barrier, which effectively hinders drug transport from the systemic circulation into the inner ear. Thus, upon administration via conventional routes (e.g. oral, i.m., i.v.) the drug does not reach its site of action. Direct injection into the inner ear presents an effective means to overcome the blood-cochlear barrier, but frequent administrations would be required due to drug elimination. This is not possible because of the risk of infections and the sensitivity of the very small fluid volume in the cochlear to fluctuations. Advanced drug delivery systems allowing for local and time-controlled drug release offer the potential to overcome these crucial hurdles. However, up to date most approaches in this domain show significant variability, since the residence times of the proposed systems at the administration site generally significantly vary in vivo, due to their more or less rapid elimination. This results in high uncertainty with respect to the drug amount reaching the inner ear and the time period during which the drug is delivered. This uncertainty leads to unreliable therapeutic efficacy and safety concerns for the patient. The aim of this project is to overcome this fundamental bottleneck and to assure reliable local controlled drug delivery to the inner ear. Two types of advanced drug delivery systems will be developed: (i) bioadhesive, liposome-loaded gels, administered onto the round window membrane and releasing the drug during several hours, days or weeks, and (ii) intracochlear implants, inserted directly into the inner ear and releasing the drug at the site of action during several months or years. The two types of devices are complementary and can be expected to allow for a much more reproducible control of the drug concentrations at the site of action and, thus, improved therapeutic efficacy and treatment safety. The drug will be embedded within biocompatible polymeric matrices (optionally containing liposomes), which will prohibit instantaneous release upon administration and assure controlled drug release over pre-programmed time periods. Intratympanic gels and intracochlear implants loaded with different drugs will be prepared by polymer rehydration with liposome suspensions and injection molding, respectively. Their performance will be tested in vitro and in vivo (animals). Variation of the manufacturing processes and compositions of the systems will allow for the optimization of the resulting drug release kinetics. A thorough physical characterization of the implants and gels and mechanistically realistic mathematical modeling will allow for understanding how the devices work. Furthermore, the mechanical key properties of the systems will be monitored to assure convenient handling by the surgeon. The expected results of this project include: (1) Prototypes (implants and gels) and know-how to prepare innovative drug delivery systems allowing to overcome the blood-cochlear barrier, (2) Knowledge of the key features of these new types of devices, (3) Possibility to allow for new therapeutic strategies to treat inner ear ailments, and (4) Comprehensive data bases on the in vitro and in vivo performance of the systems, serving as a starting point for clinical trials envisaged as follow-up studies. As an industrial company specialized on high-tech intracochlear electrodes (commercializing drug-free implants) is part of the consortium, also the economic exploitation of the new findings is foreseen in the long run.