Nanosuspensions of hesperetin: preparation and characterization.

Nanosuspensions are a smart formulation principle for dermal applications, as they increase the penetration of poorly soluble substances into the skin. Because microbial stability is a pre-requisite for dermal formulations, water containing formulations need to be preserved. Preservatives are known to possibly impair the physical stability of disperse systems, i.e. by causing agglomeration. These aggregation phenomena might occur during storage of the final product, but can already occur during the production process itself. Therefore, in this study the influence of six different preservatives on the diminution efficiency during the production of hesperetin nanocrystals was investigated. Particles with and without the addition of preservatives were produced by high pressure homogenization (HPH) and the final particle size was analysed and compared to the non-preserved suspension. All preservatives influenced the diminution progress during production and the final particle sizes obtained. The non-preserved suspension yielded a particle size of about 300 nm. Preservation with Hydrolite, Euxyl PE9010, Rokonsal and Phenonip led to sizes of about 400 nm. Preservation with Caprylyl glycol and MultiEx did not lead to nanoparticles (size > 1 microm) and caused a slight agglomeration of the nanosuspensions. Based on zeta potential measurements it was found that the impairment is related to the lipophilicity of the presverative, i.e. the lower the lipophilicity, the less is the impairment. In conclusion, preservatives impair the diminution efficacy during the production of nanosuspensions. Therefore, if possible, preservatives should be added to nanosuspensions after the production process. If preservatives are required during production, highly hydrophilic preservatives, e.g. Hydrolite E, should be used.

SiRNA delivery: challenges and role of carrier systems.

Gene silencing by RNA interference is a rapidly growing therapeutic area for managing diseases. Despite research advances in this direction, the poor cellular uptake of synthetic small interfering RNAs is a major impediment to their clinical applications. Polymer and lipid-based systems are attractive carrier systems for delivery of siRNA and provide options for desirable engineering of carrier particles. In this review, there is a detailed discussion of RNAi delivery systems and recent advances in the field.

Preserving hesperetin nanosuspensions for dermal application.

Nanosuspensions as aqueous formulations need to be preserved. However, preservatives could vitiate the physical stability of suspensions and to a greater extent nanosuspensions. The impact of six varied preservatives on the physical stability of previously prepared nanosuspensions was studied. The hesperetin nanosuspensions were stabilized using plantacare 2000.30 cycles of high pressure homogenization (HPH) led to a mean photon correlation spectroscopy (PCS) diameter of 335 nm. The preservatives were, caprylyl glycol, Euxyl PE9010, Hydrolite-5, MultiEx naturotics, Phenonip and Rokonsal PB5. On one hand, aggregations were noticed after adding caprylyl glycol, MultiEx naturotics and Phenonip reaching PCS mean diameters of about 500, 1070, 800 nm, respectively. While on the other hand Euxyl PE9010, Hydrolite-5 and Rokonsal PB5 have not significantly affected the physical stability of the nanosuspensions with mean PCS diameters of about 365, 332, 350 nm, respectively. The obtained nanosuspensions were further characterized by measuring zeta potential. From the obtained data it was found that the lipophilicity of the used preservatives demonstrates major influence on the stability of the nanosuspensions, i.e. the higher lipophilicity of the preservative, the stronger the destabilizing effect. Briefly, highly hydrophilic preservatives are recommended to preserve hesperetin nanosuspensions in order to maintain their physical stability during storage.

smartCrystal combination technology--scale up from lab to pilot scale and long term stability.

The production of nanocrystals was scaled up from lab scale (20 g) to pilot scale (3 kg), scale up factor 150. The flavonoid apigenin was used as model compound, with potential for pharma, cosmetic and nutraceutical products. Lab scale production was performed by high pressure homogenization (HPH), pilot scale by applying the smartCrystal combination technology (CT), combining pearl milling and a subsequent HPH (1 cycle, 300 bar). The obtained particle sizes were compared on the basis of photon correlation spectroscopy (PCS), laser diffractometry (LD) and light microscopy. The results showed, that assessment of successful scale up depends on the characterization method used, e.g., PCS covering only a part of the particle size range (3 nm-3 microm) of the population, or LD the full size distribution. Long-term stability was predicted on zeta potential (ZP) measurements. Lab and pilot scale possessed sufficiently high ZP values (> 30 mV) for a stable dispersion, but the ZP values were different (5-7 mV). This was explained by differences in the Stern/Nernst potential of the nanocrystals, potentially due to different levels in the crystals where they break in a high energy process (HPH) versus a low energy size reduction (pearl mill). Independent on the production method and batch size, the nanosuspensions proved to be physically stable for 6 months at storage temperatures 4 degrees C, room temperature and 40 degrees C.