Nanocarriers for drug targeting and improved bioavailability

CORRIAS, FRANCESCO

2014-04-14

---

Abstract

This PhD thesis debates, mostly, on two main topics: - Drug delivery to brain - Nanosuspensions for different applications The objective of the first topic was the development of liposomes to which anti-TfR-monoclonal antibodies (Ox26) or lactoferrin was bounded to transport the selective NK3 receptor agonist senktide to CNS across the BBB. NK3 receptors are widely expressed in the CNS and their stimulation by senktide (ICV) increase extracellular DA. Liposomes were prepared using the film hydration method. In vivo microdialysis studies were performed to estimate the responsiveness of NAc shell DA to senktide as a consequence of its CNS delivery. Senktide given ICV or loaded into Ox26/lactoferrin-liposome (0.5 μg/kg iv) elicited a significant increase of dialysate DA in the NAc shell of rats whilst senktide given iv (0.1 mg/kg) or loaded in control stealth liposomes did not affect NAc shell DA. Liposomes formulation here described represent an effective way of CNS delivering of senktide following intravenous administration the TfR-transport system. On the other hand, three different types of nanosuspensions were formulated and studied: - Tretinoin nanosuspensions for topical delivery - Piroxicam nanosuspensions loaded in oral disintegrating tablet (ODT) for oral delivery - Quercetin nanosuspensions loaded in fast dissolving films for oral delivery The aims of the first work were to improve cutaneous targeting and photostability of tretinoin by using nanosuspension formulation. Tretinoin is a drug widely used in the topical treatment of various dermatological diseases. The tretinoin nanosuspension was prepared by precipitation method and then characterized by photo correlation spectroscopy for mean size and size distribution, and by transmission electron microscopy for morphological studies. An oil in water tretinoin nanoemulsion was also prepared and used as a control. Dermal and transdermal delivery of both tretinoin nanosuspension and nanoemulsion were tested in vitro by using Franz diffusion cells and newborn pig skin. Photodegradation studies were carried out by UV irradiation (1 h, λ=366 nm) of the tretinoin nanosuspension in comparison with the nanoemulsion and a methanolic solution of the drug. During 8 h percutaneous experiments, no permeation of tretinoin through the whole skin thickness was detected but the drug was deposited into the skin layers, mainly in the stratum corneum, similarly to the nanoemulsion. UV irradiation of the nanosuspension showed a great improvement of tretinoin stability in comparison with both controls. Overall results show that nanosuspension might be a useful formulation for improving tretinoin dermal delivery and stability. Piroxicam (PRX) is a non-steroidal anti-inflammatory drug characterized by a poorly water solubility and consequently by a low oral bioavailability. Different nanocrystals orally disintegrating tablets (ODT) were prepared to enhance piroxicam dissolution velocity and saturation solubility. Nanosuspensions were prepared using high pressure homogenization technique. Different ODT formulations were prepared using the same nanosuspension but changing different excipients in order to optimize dissolution properties. PRX nanocrystals size and zeta potential were determined by photon correlation spectroscopy (PCS). Characterization of PRX nanocrystals ODT was carried out by infrared spectroscopy (FTIR), X-ray powder diffractometry (XRPD), differential scanning calorimetry. Dissolution study of PRX ODT was performed in distilled water (pH 5.5) and was compared with PRX coarse suspension ODT, PRX/poloxamer 188 physical mixture, bulk PRX samples and a piroxicam commercial ODT (Feldene). All PRX nanocrystals ODT formulations showed a higher drug dissolution rate than coarse PRX ODT. PRX nanocrystals ODT prepared using gelatin or croscaramellose as excipient showed a higher PRX dissolution rate compared with the commercial formulation and with ODT prepared using xanthan gum. The improvement in PRX dissolution rate is mainly caused by the increased surface-to-volume ratio due to the submicron dimension of the drug nanocrystal, however, also the presence of the correct excipients (as disgregant) seem to play an essential role. Finally, quercetin nanosuspensions loaded fast dissolving films were formulated and studied. The aim of this work was to investigate the possible use of maltodextrin IT6 (MDX) to prepare fast-dissolving films, loaded by quercetin nanocrystals. Quercetin nanosuspensions were prepared using an high pressure homogenizer, meanwhile drug loaded films were obtained drying in a siliconized polyester sheet quercetin nanosuspensions with the others compounds in a oven at 60 °C. Films were finally cut and packed within sealed aluminium pouches. Quercetin nanocrystals were characterized by photo correlation spectroscopy for mean size and size distribution and by transmission electron microscopy for morphological studies. On the other hand, quercetin nanosuspensions loaded films were characterized in term of flexibility, tensile strength and thickness. Finally, dissolution studies in distilled water were performed, comparing release profiles of quercetin loaded films, quercetin raw material and quercetin nanosuspensions.