Silicone matrices for controlled dexamethasone release: toward a better understanding of the underlying mass transport mechanisms.

Dexamethasone-loaded silicone matrices offer an interesting potential as innovative drug delivery systems, e.g. for the treatment of inner ear diseases or for pacemakers. Generally, very long drug release periods are targeted: several years/decades. This renders the development and optimization of novel drug products cumbersome: experimental feedback on the impact of the device design is obtained very slowly. A better understanding of the underlying mass transport mechanisms can help facilitating research in this field. A variety of silicone films were prepared in this study, loaded with amorphous or crystalline dexamethasone. Different polymorphic drug forms were investigated, the film thickness was altered and the drug optionally partially/completely exchanged by much more water-soluble dexamethasone 'phosphate'. Drug release studies in artificial perilymph, scanning electron microscopy, optical microscopy, differential scanning calorimetry, X-ray diffraction and Raman imaging were used to elucidate the physical states of the drugs and polymer, and of the systems' structure as well as dynamic changes thereof upon exposure to the release medium. Dexamethasone particles were initially homogeneously distributed throughout the systems. The hydrophobicity of the matrix former very much limits the amounts of water penetrating into the system, resulting in only partial drug dissolution. The mobile drug molecules diffuse out into the surrounding environment, due to concentration gradients. Interestingly, Raman imaging revealed that even very thin silicone layers (<20 µm) can effectively trap the drug for prolonged periods of time. The physical state of the drug (amorphous, crystalline) did not affect the resulting drug release kinetics to a noteworthy extent.

Hybrid systems combining liposomes and entangled hyaluronic acid chains: Influence of liposome surface and drug encapsulation on the microstructure.

Mixtures of hyaluronic acid (HA) with liposomes lead to hybrid colloid-polymer systems with a great interest in drug delivery. However, little is known about their microstructure. Small angle neutron scattering (SANS) is a valuable tool to characterize these systems in the semi-dilute entangled regime (1.5% HA) at high liposome concentration (80 mM lipids). The objective was to elucidate the influence of liposome surface (neutral, cationic, anionic or anionic PEGylated), drug encapsulation and HA concentration in a buffer mimicking biological fluids (37 °C). First, liposomes were characterized by SANS, cryo-electron microscopy, and dynamic light scattering and HA by SANS, size exclusion chromatography, and rheology. Secondly, HA-liposome mixtures were studied by SANS. In HA, liposomes kept their integrity. Anionic and PEGylated liposomes were in close contact within dense clusters with an amorphous organization. The center-to-center distance between liposomes corresponded to twice their diameter. A depletion mechanism could explain these findings. Encapsulation of a corticoid did not modify this organization. Cationic liposomes formed less dense aggregates and were better dispersed due to their complexation with HA. Liposome surface governed the interactions and microstructure of these hybrid systems.

Transtympanic injection of a liposomal gel loaded with N-acetyl-L-cysteine: A relevant strategy to prevent damage induced by cochlear implantation in guinea pigs?

Patients with residual hearing can benefit from cochlear implantation. However, insertion can damage cochlear structures and generate oxidative stress harmful to auditory cells. The antioxidant N-acetyl-L-cysteine (NAC) is a precursor of glutathione (GSH), a powerful endogenous antioxidant. NAC local delivery to the inner ear appeared promising to prevent damage after cochlear implantation in animals. NAC-loaded liposomal gel was specifically designed for transtympanic injection, performed both 3 days before and on the day of surgery. Hearing thresholds were recorded over 30 days in implanted guinea pigs with and without NAC. NAC, GSH, and their degradation products, N,N'-diacetyl-L-cystine (DiNAC) and oxidized glutathione (GSSG) were simultaneously quantified in the perilymph over 15 days in non-implanted guinea pigs. For the first time, endogenous concentrations of GSH and GSSG were determined in the perilymph. Although NAC-loaded liposomal gel sustained NAC release in the perilymph over 15 days, it induced hearing loss in both implanted and non-implanted groups with no perilymphatic GSH increase. Under physiological conditions, NAC appeared poorly stable within liposomes. As DiNAC was quantified at concentrations which were twice as high as NAC in the perilymph, it was hypothesized that DiNAC could be responsible for the adverse effects on hearing.

Trans-Oval-Window Implants, A New Approach for Drug Delivery to the Inner Ear: Extended Dexamethasone Release From Silicone-based Implants.

HYPOTHESIS: The purpose of this study was to develop a new strategy to deliver drugs to the inner ear from dexamethasone (DXM)-loaded silicone implants and to evaluate the distribution of the drug in the cochlea with confocal microscopy. BACKGROUND: Systemic drug administration for the treatment of inner ear disorders is tricky because of the blood-cochlear barrier, a difficult anatomical access, the small size of the cochlea, and can cause significant adverse effects. An effective way to overcome these obstacles is to administer drugs locally. METHODS: In vitro, the drug release from DXM-loaded silicone-based thin films and tiny implants into artificial perilymph was thoroughly analyzed by high-performance liquid chromatography. In vivo, a silicone implant loaded with 10% DXM and 5% polyethylene glycol 400 was implanted next to the stapes's footplate of gerbils. Delivery of DXM into the inner ear was proved by confocal microscopy imaging of the whole cochlea and the organ of Corti. RESULTS: The study showed a continuous and prolonged release during 90 days in vitro. This was confirmed by confocal microscopy that allowed detection of DXM by fluorescence labeling in the cell body of the hair cells for at least 30 days. Interestingly, fluorescence was already observed after 20 minutes of implantation, reached a climax at day 7, and could still be detected 30 days after implantation. CONCLUSIONS: Thus, we developed a new device for local corticosteroids delivery into the oval window with an extended drug release of DXM to the inner ear.