Assessment of the efficacy of a local steroid rescue treatment administered 2 days after a moderate noise-induced trauma in guinea pig.

OBJECTIVES: Intratympanic injection of corticosteroids membrane after noise-induced hearing loss is an accepted alternative to general administration. We investigated the effect on hearing of a hyaluronic acid gel with liposomes loaded with dexamethasone (DexP) administered into the middle ear. METHODS: An acute acoustic trauma was performed to 13 guinea pigs for a period of 1 h on Day -2. Two 2 days after the noise trauma, the animals were then assigned randomly to four experimental groups: control without gel, gel injection, gel-containing free DexP, gel-containing DexP loaded into liposomes. Auditory thresholds were measured with Auditory Brainstem Response before Day -2 and at Day 0, Day 7 and Day 30 after noise trauma. RESULTS: Seven days after, a complete hearing recovery was observed in the control group at all frequencies apart from 8 kHz, and no recovery was observed in the three groups receiving a gel injection. Thirty days after trauma, all of the animals had recovered normal hearing, apart from at the 8-kHz frequency, with similar auditory thresholds. CONCLUSIONS: Local DexP administration 48 h after a mild acoustic trauma did not improve hearing recovery, even with a sustained release in a specific gel formulation designed for inner ear therapy.

Mixtures of hyaluronic acid and liposomes for drug delivery: Phase behavior, microstructure and mobility of liposomes.

Hyaluronic acid liposomal gels have previously demonstrated in vivo their great potential for drug delivery. Elucidating their phase behavior and structure would provide a better understanding of their use properties. This work evaluates the microstructure and the phase behavior of mixtures of hyaluronic acid (HA) and liposomes and their impact on the vesicle mobility. HA concentration and surface properties of liposomes (positively or negatively charged, neutral, with a polyethylene glycol corona) are varied while the liposome concentration remains constant. Below the entanglement concentration of HA (0.4%), the mixtures exhibit a depletion phase separation except for positively charged liposomes that interact with anionic HA through attractive electrostatic interactions. At high HA concentration, no macroscopic phase separation is observed, except a slight syneresis with cationic liposomes. The microstructure shows aggregates of liposomes homogeneously distributed into a HA network except for PEGylated liposomes, which seem to form bicontinuous interpenetrating networks. The diffusion of liposomes is controlled by HA concentration and their surface properties. Finally, PEGylated liposomes display the highest mobility at high HA concentration (2.28%) both macro- and microscopically. The microstructure of HA-liposomes mixtures and the diffusion of liposomes are key parameters that must be taken into account for drug delivery.

Hyaluronic acid liposomal gel sustains delivery of a corticoid to the inner ear.

The inner ear is one of the most challenging organs for drug delivery, mainly because of the blood-perilymph barrier. Therefore, local rather than systemic drug delivery methods are being developed for inner ear therapy. In this work, we have evaluated the benefit of a hyaluronic acid liposomal gel for sustained delivery of a corticoid to the inner ear after local injection into the middle ear in a guinea pig model. The liposomal gel was easily injectable as a result of the shear-thinning behavior of hyaluronic acid. A prolonged residence time at the site of injection as well as in the round window were achieved without any negative effect on the hearing thresholds of the animals. The presence of liposomes in the formulation resulted in sustained release of the drug in the perilymph for 30days and promoted the conversion of the prodrug loaded within the liposomes (dexamethasone phosphate) into its active form (dexamethasone). In this way, therapeutic doses were attained in the perilymph. A small amount of intact liposomes was visualized in the perilymph, whereas the main proportion of liposomes seemed to be trapped in the round window resulting in a reservoir effect. Thus, the administration of hyaluronic acid liposomal gel to the middle ear is an efficient strategy for delivering corticoids to the inner ear in a sustained manner.

Recent advances in local drug delivery to the inner ear.

Inner ear diseases are not adequately treated by systemic drug administration mainly because of the blood-perilymph barrier that reduces exchanges between plasma and inner ear fluids. Local drug delivery methods including intratympanic and intracochlear administrations are currently developed to treat inner ear disorders more efficiently. Intratympanic administration is minimally invasive but relies on diffusion through middle ear barriers for drug entry into the cochlea, whereas intracochlear administration offers direct access to the colchlea but is rather invasive. A wide range of drug delivery systems or devices were evaluated in research and clinic over the last decade for inner ear applications. In this review, different strategies including medical devices, hydrogels and nanoparticulate systems for intratympanic administration, and cochlear implant coating or advanced medical devices for intracoclear administration were explored with special attention to in vivo studies. This review highlights the promising systems for future clinical applications as well as the current hurdles that remain to be overcome for efficient inner ear therapy.

Effect of liposomes on rheological and syringeability properties of hyaluronic acid hydrogels intended for local injection of drugs.

The aim of this work was to thoroughly study the effect of liposomes on the rheological and the syringeability properties of hyaluronic acid (HA) hydrogels intended for the local administration of drugs by injection. Whatever the characteristics of the liposomes added (neutral, positively or negatively charged, with a corona of polyethylene glycol chains, size), the viscosity and the elasticity of HA gels increased in a lipid concentration-dependent manner. Indeed, liposomes strengthened the network formed by HA chains due to their interactions with this polymer. The nature and the resulting effects of these interactions depended on liposome composition and concentration. The highest viscosity and elasticity were observed with liposomes covered by polyethylene glycol chains while neutral liposomes displayed the lowest effect. Despite their high viscosity at rest, all the formulations remained easily injectable through needles commonly used for local injections thanks to the shear-thinning behavior of HA gels. The present study demonstrates that rheological and syringeability tests are both necessary to elucidate the behavior of such systems during and post injection. In conclusion, HA liposomal gels appear to be a promising and versatile formulation platform for a wide range of applications in local drug delivery when an injection is required.