Formulation, physicochemical characterization and stability study of lithium-loaded microemulsion system.

Lithium biocompatible microemulsion based on Peceol(®), lecithin, ethanol and water was studied in attempt to identify the optimal compositions in term of drug content, physicochemical properties and stability. Lithium solubilization in microemulsion was found to be compatible with a drug-surfactant binding model. Lithium ions were predominantly solubilized within lecithin head group altering significantly the interfacial properties of the system. Pseudo-ternary phase diagrams of drug free and drug loaded microemulsions were built at constant ethanol/lecithin weight ratio (40/60). Lithium loaded microemulsion has totally disappeared in the Peceol(®) rich part of phase diagram; critical fractions of lecithin and ethanol were required for the formation of stable microemulsion. The effect of lithium concentration on the properties and physical stability of microemulsions were studied using microscopy, Karl Fischer titrations, rheology analyses, conductivity measurements and centrifugation tests. The investigated microemulsions were found to be stable under accelerated storage conditions. The systems exhibited low viscosity and behaved as Newtonian fluid and no structural transition was shown.

Development of pharmaceutical clear gel based on Peceol®, lecithin, ethanol and water: Physicochemical characterization and stability study.

The phase behavior of the four-components Peceol®/lecithin/ethanol/water system has been studied in a part of the phase diagram poor in water and varying the lecithin/Peceol® ratio. Using several complementary techniques such as Karl Fischer titration, rheology, polarized microscopy and SAXS measurements several nanostructures of the complex systems were identified. W/O microemulsion (L2) as well as an inverted hexagonal (H2) liquid-crystal phase were studied. The analysis of the different phase transitions allows us to understand the effect of lecithin on the water solubilization efficiency of this clear gel and to show its pharmaceutical interest among lecithin organogels.

Water solubilization capacity of pharmaceutical microemulsions based on Peceol®, lecithin and ethanol.

Biocompatible microemulsions composed of Peceol(®), lecithin, ethanol and water developed for encapsulation of hydrophilic drugs were investigated. The binary mixture Peceol(®)/ethanol was studied first. It was shown that the addition of ethanol to pure Peceol(®) has a significant fluidifying and disordering effect on the Peceol(®) supramolecular structure with an enhancement in water solubilization. The water solubilization capacity was improved by adding lecithin as a third component. It was then demonstrated that the ethanol/lecithin weight ratio played an important role in determining the optimal composition in term of water solubilization efficiency, a necessary property for a nutraceutical or pharmaceutical application. The optimal ethanol/lecithin weight ratio in the Peceol(®) rich region was found to be 40/60. Combination different techniques such as SAXS, fluorimetry, rheology and conductivity, we analyzed the water uptake within the microemulsion taking into account the partitioning of ethanol between polar and apolar domains. This ethanol distribution quantified along a water dilution line has a major effect on microemulsion properties.

Systemic delivery of siRNA down regulates brain prion protein and ameliorates neuropathology in prion disorder.

One of the main challenges for neurodegenerative disorders that are principally incurable is the development of new therapeutic strategies, which raises important medical, scientific and societal issues. Creutzfeldt-Jakob diseases are rare neurodegenerative fatal disorders which today remain incurable. The objective of this study was to evaluate the efficacy of the down-regulation of the prion protein (PrP) expression using siRNA delivered by, a water-in-oil microemulsion, as a therapeutic candidate in a preclinical study. After 12 days rectal mucosa administration of Aonys/PrP-siRNA in mice, we observed a decrease of about 28% of the brain PrP(C) level. The effect of Aonys/PrP-siRNA was then evaluated on prion infected mice. Several mice presented a delay in the incubation and survival time compared to the control groups and a significant impact was observed on astrocyte reaction and neuronal survival in the PrP-siRNA treated groups. These results suggest that a new therapeutic scheme based an innovative delivery system of PrP-siRNA can be envisioned in prion disorders.

Phase behavior of reverse microemulsions based on Peceol(®).

The phase diagram of the four component system Peceol®/lecithin/ethanol/water was studied at 25°C and at a fixed fraction of ethanol. It shows an isotropic W/O microemulsion phase, biphasic liquid system and Liquid crystalline phases. The stabilizing effect of lecithin with the fluidifying effect of ethanol on the microemulsion based on long chain glycerides provides an effective combination to solubilize a large amount of water. Some structural transitions in the phase diagram were investigated as a function of water content using conductivity, rheology, Karl Fisher titration, optical microscopy and SAXS measurements. The results show no change in the microstructure of the isotropic liquid upon phase separation in the liquid biphasic area. However, in the water rich region, migration of ethanol to the external aqueous phase at the expense of the saturated microemulsion promotes the formation of liquid crystalline phases. As a function of water content, the structural change to the liquid crystalline phases follows: isotropic phase L2 → Inverted hexagonal phase H2 → Inverted hexagonal H2/lamellar Lα phases.

NP03, a novel low-dose lithium formulation, is neuroprotective in the YAC128 mouse model of Huntington disease.

Huntington disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene, remains without a treatment to modify the course of the illness. Lithium, a drug widely used for the treatment of bipolar disorder, has been shown to exert neuroprotective effects in a number of models of neurological disease but may have various toxic effects at conventional therapeutic doses. We examined whether NP03, a novel low-dose lithium microemulsion, would improve the disease phenotypes in the YAC128 mouse model of HD. We demonstrate that NP03 improves motor function, ameliorates the neuropathological deficits in striatal volume, neuronal counts, and DARPP-32 expression, and partially rescues testicular atrophy in YAC128 mice. These positive effects were accompanied by improvements in multiple biochemical endpoints associated with the pathogenesis of HD, including normalization of caspase-6 activation and amelioration of deficits in BDNF levels, and with no lithium-related toxicity. Our findings demonstrate that NP03 ameliorates the motor and neuropathological phenotypes in the YAC128 mouse model of HD, and represents a potential therapeutic approach for HD.