Formulating Resveratrol and Melatonin Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) for Ocular Administration Using Design of Experiments.

Recent studies have demonstrated that Sirtuin-1 (SIRT-1)-activating molecules exert a protective role in degenerative ocular diseases. However, these molecules hardly reach the back of the eye due to poor solubility in aqueous environments and low bioavailability after topical application on the eye's surface. Such hindrances, combined with stability issues, call for the need for innovative delivery strategies. Within this context, the development of self-nanoemulsifying drug delivery systems (SNEDDS) for SIRT-1 delivery can represent a promising approach. The aim of the work was to design and optimize SNEDDS for the ocular delivery of two natural SIRT-1 agonists, resveratrol (RSV) and melatonin (MEL), with potential implications for treating diabetic retinopathy. Pre-formulation studies were performed by a Design of Experiment (DoE) approach to construct the ternary phase diagram. The optimization phase was carried out using Response Surface Methodology (RSM). Four types of SNEDDS consisting of different surfactants (Tween® 80, Tween® 20, Solutol® HS15, and Cremophor® EL) were optimized to achieve the best physico-chemical parameters for ocular application. Stability tests indicated that SNEDDS produced with Tween® 80 was the formulation that best preserved the stability of molecules, and so it was, therefore, selected for further technological studies. The optimized formulation was prepared with Capryol® PGMC, Tween® 80, and Transcutol® P and loaded with RSV or MEL. The SNEDDS were evaluated for other parameters, such as the mean size (found to be ˂50 nm), size homogeneity (PDI < 0.2), emulsion time (around 40 s), transparency, drug content (>90%), mucoadhesion strength, in vitro drug release, pH and osmolarity, stability to dilution, and cloud point. Finally, an in vitro evaluation was performed on a rabbit corneal epithelial cell line (SIRC) to assess their cytocompatibility. The overall results suggest that SNEDDS can be used as promising nanocarriers for the ocular drug delivery of RSV and MEL.

Development of Lyophilised Eudragit® Retard Nanoparticles for the Sustained Release of Clozapine via Intranasal Administration.

Clozapine (CZP) is the only effective drug in schizophrenia resistant to typical antipsychotics. However, existing dosage forms (oral or orodispersible tablets, suspensions or intramuscular injection) show challenging limitations. After oral administration, CZP has low bioavailability due to a large first-pass effect, while the i.m. route is often painful, with low patient compliance and requiring specialised personnel. Moreover, CZP has a very low aqueous solubility. This study proposes the intranasal route as an alternative route of administration for CZP, through its encapsulation in polymeric nanoparticles (NPs) based on Eudragit® RS100 and RL100 copolymers. Slow-release polymeric NPs with dimensions around 400-500 nm were formulated to reside and release CZP in the nasal cavity, where it can be absorbed through the nasal mucosa and reach the systemic circulation. CZP-EUD-NPs showed a controlled release of CZP for up to 8 h. Furthermore, to reduce mucociliary clearance and increase the residence time of NPs in the nasal cavity to improve drug bioavailability, mucoadhesive NPs were formulated. This study shows that the NPs already exhibited strong electrostatic interactions with mucin at time zero due to the presence of the positive charge of the used copolymers. Furthermore, to improve the solubility, diffusion and adsorption of CZPs and the storage stability of the formulation, it was lyophilised using 5% (w/v) HP-ß-CD as a cryoprotectant. It ensured the preservation of the NPs' size, PDI and charge upon reconstitution. Moreover, physicochemical characterisation studies of solid-state NPs were performed. Finally, toxicity studies were performed in vitro on MDCKII cells and primary human olfactory mucosa cells and in vivo on the nasal mucosa of CD-1 mice. The latter showed non-toxicity of B-EUD-NPs and mild CZP-EUD-NP-induced tissue abnormalities.

Nanonized carbamazepine for nose-to-brain delivery: pharmaceutical formulation development.

Epilepsy is one of the most common neurological disorders in the world. The therapeutic treatment is challenging since conventional drugs have limited efficacy and several side effects that impair patient management. Efforts are being made to find innovative strategies to control epileptic seizures. Intranasal administration provides a convenient route to deliver the drug to the brain. Carbamazepine (CBZ) is an anticonvulsant characterized by poor water solubility, nanonization can improve its bioavailability. Therefore, the design of CBZ nanocrystals (NCs) was assessed to obtain a formulation suitable for nose-to-brain delivery. CBZ NCs were prepared by sonoprecipitation following the Quality by Design approach identifying the impact of process and formulation variables on the critical quality attributes of the final product. The formulation was characterized by a technological point of view (thermotropic behavior, crystallinity, morphology, mucoadhesive strength). Response surface methodology was a reliable tool (error % 2.6) to optimize CBZ NCs with size ≤300 nm. Incubation of CBZ NCs in artificial cerebrospinal fluid at 37 °C did not promote aggregation and degradation phenomena. Preliminary biological studies revealed the biocompatibility of CBZ NCs towards Olfactory Ensheating Cells. The suspension was successfully converted into a powder. The highly concentrated formulation can be obtained, providing the possibility to administer the maximum dose of the drug in the lowest volume.

Nanotechnologies for intranasal drug delivery: an update of literature.

Scientific research has focused its attention on finding an alternative route to systemic oral and parenteral administration, to overcome their usual drawbacks, such as hepatic first-pass which decreases drug bioavailability after oral administration, off-target effects, low patient compliance and low speed of onset of the pharmacological action in first-aid cases. Innovative drug delivery systems (DDS), mainly based on polymer and lipid biocompatible materials, have given a great prompt in this direction in the last years. The intranasal (IN) route of administration is a valid non-invasive alternative. It is highly suitable for self-administration, the drug quickly reaches the bloodstream, largely avoiding the first pass effect, and can also reach directly the brain bypassing BBB. Association of IN route with DDS can thus become a winning strategy for the controlled delivery of drugs, especially when a very quick effect is desired or needed. This review aims at analyzing the scientific literature regarding IN-DDS and their different ways of administration (systemic, topical, pulmonary, nose-to-brain). In particular, attention was devoted to polymer- and lipid-based micro- and nanocarriers, being the topic of most published articles in the last decade, but the whole plethora of colloidal DDS investigated in recent years for IN administration was presented.