Ear Cubes for local controlled drug delivery to the inner ear

https://doi.org/10.1016/j.ijpharm.2016.04.003Get rights and content

Abstract

A new type of advanced drug delivery systems is proposed: Miniaturized implants, which can be placed into tiny holes drilled into (or close to) the oval window. They consist of two parts: 1) A cylinder, which is inserted into the hole crossing the oval window. The cylinder (being longer than the depth of the hole) is partly located within the inner ear and surrounded by perilymph. This provides direct access to the target site, and at the same time assures implant fixation. 2) A cuboid, which is located in the middle ear, serving as a drug reservoir. One side of the cuboid is in direct contact with the oval window. Drug release into the cochlea occurs by diffusion through the cylindrical part of the Ear Cubes and by diffusion from the cuboid into and through the oval window. High precision molds were used to prepare two differently sized Ear Cubes by injection molding. The miniaturized implants were based on silicone and loaded with different amounts of dexamethasone (10 to 30 % w/w). The systems were thoroughly characterized before and upon exposure to artificial perilymph at 37 °C. Importantly, drug release can effectively be controlled and sustained during long time periods (up to several years). Furthermore, the implants did not swell or erode to a noteworthy extent during the observation period. Drug diffusion through the polymeric matrix, together with limited dexamethasone solubility effects, seem to control the resulting drug release kinetics, which can roughly be estimated using mathematical equations derived from Fick’s second law. Importantly, the proposed Ear Cubes are likely to provide much more reliable local long term drug delivery to the inner ear compared to liquid or semi-solid dosage forms administered into the middle ear, due to a more secured fixation. Furthermore, they require less invasive surgeries and can accommodate higher drug amounts compared to intracochlear implants. Thus, they offer the potential to open up new horizons for innovative therapeutic strategies to treat inner ear diseases and disorders.

Introduction

Drug delivery to the inner ear is highly challenging due to the blood-cochlea-barrier, which is similar to the blood-brain-barrier and effectively prevents the transport of drugs from the systemic circulation into the cochlea (El Kechai et al., 2015a, Juhn, 1988). Consequently, the resulting drug concentrations at the site of action remain low upon administration using standard routes, e.g. oral, i.v., i.m., i.p., etc. This leads to poor therapeutic efficacies. At the same time, the drug concentrations in the rest of the human body are high, resulting in potentially severe side effects. An interesting strategy to overcome this bottleneck is to administer the drug directly into the inner ear (Salt and Plontke, 2005, Salt and Plontke, 2009). However, the cochlea is very small and highly sensitive. Furthermore, each direct drug administration into the inner ear can cause infections and tissue damage. In practice, therapeutic drug concentrations often need to be provided during long time periods, requiring repeated administrations (due to drug elimination). But frequent cochlear surgeries are not feasible.

To overcome these hurdles, local controlled drug delivery systems might be used. Different types of advanced drug delivery systems have been proposed, including pumps delivering the drug into the middle ear (El Kechai et al., 2015a, Borkholder et al., 2014), as well as semi-solid formulations, which are placed onto the round window (Engleder et al., 2014, Al-mahallawi et al., 2014, El Kechai et al., 2015b). Once the drug is in contact with the latter, it can potentially partition into this membrane and cross it by diffusion. Unfortunately, the residence times of such semi-solid formulations in the middle ear are uncertain, since liquids may or may not be present in this cavity and eliminate the systems more or less rapidly from the administration site. Also, pumps might get blocked or displaced and provide a permanent risk of introducing infections. Miniaturized implants, which are directly inserted into the inner ear can assure reliable long term delivery to the target site (Arsiwala et al., 2014, Krenzlin et al., 2012, Farahmand Ghavi et al., 2010, Douchement et al., 2015, Liu et al., 2015), since they remain in place. But their administration is invasive and can cause tissue damage. The aim of this study was to propose a new type of advanced drug delivery systems allowing for reliable local long term delivery of drugs into the cochlea using a less invasive placement technique.

The basic idea is to drill a tiny hole into (or close to) the oval window and to insert a miniaturized implant into this hole. The geometry of these systems, called “Ear Cubes”, is illustrated in Fig. 1 (the dimensions are indicated in mm). The schemes on the left hand side and in the middle show two differently sized Ear Cubes. They consist of two parts: 1) A cylinder, which is to be placed into the hole crossing the oval window (scheme on the right hand side of the figure), and 2) A “cuboid”, which is located in the middle ear. The cylinder is longer than the depth of the hole, thus, one end of it is placed in the inner ear and is surrounded by perilymph. This allows for direct drug release at the target site. The cylinder also provides the “anchorage” of the implant at the administration site. If needed, eventually a drop of rapidly hardening silicone might be added, surrounding the cuboid and fixing it to the oval window. The cuboid serves as a drug reservoir and participates in the drug delivery. Drug transport into the cochlea can occur via: a) drug diffusion through the cylindrical part of the Ear Cubes, and b) drug partitioning from the cuboid into the oval window, followed by diffusion across this membrane into the inner ear. Note that the presence of these Ear Cubes might eventually affect the hearing function of the patient. The extent of such a potential impact will essentially depend on the dimensions and position of the hole drilled into (or close to) the oval window and on the dimensions and composition of the Ear Cubes. In vivo studies are envisaged to investigate this aspect in the future. The rationale in humans is to drill the footplate of the oval window in a similar way that is done for a stapedotomy in the surgical management of otosclerosis. A stapedotomy approach has a well-known low morbidity on hearing, but should be adapted for Ear Cube placement.

The Ear Cubes in this study were based on silicone, since this polymer is well-known for a variety of medical applications, including implants remaining during many years in the human body (Mond and Stokes, 1996). Silicones can also provide the required mechanical properties for this type of application, and their permeability for drugs can be adjusted by altering different formulation parameters (Di Colo et al., 1986, Malcolm et al., 2003, Gehrke et al., 2016). Dexamethasone has been chosen as drug in this study, because it can be expected to limit tissue inflammation and prolong the life time expectancy of hair cells in case of hearing loss (Krenzlin et al., 2012).

Due to the inherent risk of tissue damage and induction of infections during the insertion of a local controlled drug delivery system for the inner ear, ideally drug release should be controlled over very long time periods, e.g. several years. Unfortunately, this implies highly cumbersome, cost-intensive and time-consuming product development: Experimental feedback is obtained only extremely slowly. In addition, if the underlying drug release mechanisms are not understood, the impact of the variation of formulation and processing parameters on the systems’ key properties can be surprising and numerous series of trial-and-error experiments are required. In the case of miniaturized implants, an additional challenge is faced: The production of new prototypes is not straightforward, requiring the manufacturing of high precision molds. Importantly, a better understanding of the mass transport mechanisms controlling drug release, together with mathematical modeling, can substantially simplify and accelerate research and development in this field (Siepmann, 2013, Siepmann and Goepferich, 2001, Siepmann and Siepmann, 2012, Siepmann and Siepmann, 2013, Siepmann et al., 2006, Kaunisto et al., 2011). Ideally, the impact of the geometry and composition of the implants on their key features (e.g., drug release kinetics) can be theoretically predicted within a few seconds (Siepmann and Peppas, 2001, Siepmann and Siepmann, 2008, Siepmann et al., 2010, Frenning et al., 2005, Siepmann and Siepmann, 2011). For these reasons, another aim of this study was to provide simple tools allowing for an − at least very rough − estimation of the resulting drug release kinetics from the newly proposed Ear Cubes.

Section snippets

Materials

Kits for the preparation of silicone elastomers: LSR 5 (Applied Silicone, Santa Paula, USA); Kwik‐Sil (World Precision Instruments, Sarasota, USA); dexamethasone (Discovery Fine Chemicals, Dorset, UK); calcium chloride dihydrate, magnesium sulfate tetrahydrate, potassium chloride, sodium chloride and 4-(2-hydroxyethyl) piperazine-1-ethanesulfonic acid (HEPES, HEPES Pufferan) (Carl Roth, Lauterbourg, France); acetonitrile and tetrahydrofuran (HPLC grade; Fisher Scientific, Illkirch, France).

Preparation of drug-loaded silicone matrices

Ten

Results and discussion

Fig. 1 shows schematically the design of the novel Ear Cube implants: On the left hand side, a “smaller” Ear Cube is shown, in the middle a “larger” one. The dimensions are indicated in mm. The cartoon on the right hand side illustrates how an Ear Cube can be placed into a hole drilled into (or close to) the oval window. The cylindrical part of the Ear Cube assures its fixation in (or close to) the oval window and is partially surrounded by perilymph. The cuboid is located in the middle ear.

Conclusion

The newly proposed Ear Cubes offer an interesting potential for local controlled drug delivery to the inner ear: They can control drug release during long periods of time, can be securely fixed at (or close to) the oval window and their placement is less invasive compared to intracochlear implants. They could also be placed into tiny holes drilled into the round window. Future studies should address their in vivo efficacy and suitability to delivery other types of drugs than dexamethasone.

Acknowledgments

The authors are very grateful to the ANR (The French National Research Agency) for their financial support (N° ANR-15-CE19-0014-01), and to Dr. M. Hamoudi (INSERM U1008) as well as Mr. A. Addad and Mrs. A.M. Blanchenet from the “Centre Commun de Microscopie” of the University of Lille (“Plateau technique de le Federation Chevreul CNRS FR 2638”) for their valuable technical help.

References (29)

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