Intranasal administration of dextran-pramlintide polyelectrolyte complex-coated nanoemulsions improves cognitive impairments in a mouse model of Alzheimer's disease.

Nasal delivery has emerged as a non-invasive route to administer drugs for brain delivery. In particular, polyelectrolyte complexes-based nanocarriers have been demonstrated to be advantageous for nasal delivery of peptide drugs and vaccines. Pramlintide (Pram) is a peptide that emerges as a novel neuroprotective strategy to modify the pathogenesis of Alzheimer's disease (AD). In this study, we examined the effects of the intranasal administration of dextran-pramlintide polyelectrolyte complex-coated nanoemulsions (PEC-NEDexS/Pram) in an experimental model of AD induced by intracerebroventricular (i.c.v.) infusion of amyloid-beta (Aß1-42) peptide in mice. PEC-NEDexS/Pram displayed droplet size lower than 200 nm and a negatively charged surface. The locomotor activity of the animals was not affected by the i.c.v. Aß1-42 injection or Pram treatment. On the other hand, the intranasal administration of PEC-NEDexS/Pram at a dose of 100 µg/day for 14 consecutive days restored the impairment induced by Aß1-42 injection in the discriminative learning and the short-term spatial reference memory of mice. However, Pram treatment did not alter the Aß1-42-induced anhedonic behavior, oxidative stress parameters, or the pre-synaptic SNAP-25 and post-synaptic PSD-95 levels in the hippocampus and prefrontal cortex. These findings indicate cognitive-enhancing properties of intranasal Pram administration in an animal model of AD.

Nasal Model Experiments Show That a Collimated Fluid Delivers Precise Doses to the Human Olfactory Cavity in the Side-Laying Position.

The nasal administration of therapeutic fluids and vaccines is used to treat allergic rhinitis, sinusitis, congestion, coronaviruses and even Alzheimer's disease. In the latter, the drug must reach the olfactory region, so it finds its way into the central nervous system. Effective administration techniques able to reach the olfactory region are challenging due to the tortuous anatomy of the nasal cavity, and are frequently evaluated in vitro using transparent anatomical models. Here, the liquid distribution inside a 3D printed human nasal cavity is quantified for model fluids resulting from the discharge of a 1-mL syringe with either a spray-generating nozzle, and a straight tip emitting a collimated fluid stream. Experiments using two model fluids with different viscosities suggest that a simple, correctly positioned straight tip attached to a syringe is able to efficiently deliver most of a therapeutic fluid in the human olfactory region in the side-laying position, avoiding the adoption of head-back and head-down positions that can be difficult for patients in the age range typical of Alzheimer's disease. Furthermore, we demonstrate by computer simulations that the conclusion is valid within a wide range of parameters.

Hydroxyethylcellulose-Based Hydrogels Containing Liposomes Functionalized with Cell-Penetrating Peptides for Nasal Delivery of Insulin in the Treatment of Diabetes.

Liposomes functionalized with cell-penetrating peptides are a promising strategy to deliver insulin through the nasal route. A hydrogel based on hydroxyethylcellulose (HEC) aqueous solution was prepared, followed by a subsequent addition of liposomes containing insulin solution functionalized with trans-activator of transcription protein of HIV-1 (TAT) or Penetratin (PNT). The formulations were characterized for rheological behavior, mucoadhesion, syringeability, in vitro release and in vivo efficacy. Rheological tests revealed non-Newtonian fluids with pseudoplastic behavior, and the incorporation of liposomes (HLI, HLITAT and HLIPNT) in hydrogels did not alter the behavior original pseudoplastic characteristic of the HEC hydrogel. Pseudoplastic flow behavior is a desirable property for formulations intended for the administration of drugs via the nasal route. The results of syringeability and mucoadhesive strength from HEC hydrogels suggest a viable vehicle for nasal delivery. Comparing the insulin release profile, it is observed that HI was the system that released the greatest amount while the liposomal gel promoted greater drug retention, since the liposomal system provides an extra barrier for the release through the hydrogel. Additionally, it is observed that both peptides tested had an impact on the insulin release profile, promoting a slower release, due to complexation with insulin. The in vitro release kinetics of insulin from all formulations followed Weibull's mathematical model, reaching approximately 90% of release in the formulation prepared with HEC-based hydrogels. Serum insulin levels and the antihyperglycemic effects suggested that formulations HI and HLI have potential as carriers for insulin delivery by the nasal pathway, a profile not observed when insulin was administered by subcutaneous injection or by the nasal route in saline. Furthermore, formulations functionalized with TAT and PNT can be considered promoters of late and early absorption, respectively.

Nasal Drug Delivery of Anticancer Drugs for the Treatment of Glioblastoma: Preclinical and Clinical Trials.

Glioblastoma (GBM) is the most lethal form of brain tumor, being characterized by the rapid growth and invasion of the surrounding tissue. The current standard treatment for glioblastoma is surgery, followed by radiotherapy and concurrent chemotherapy, typically with temozolomide. Although extensive research has been carried out over the past years to develop a more effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in terms of the overall survival of patients. Consequently, new therapeutic approaches are urgently needed. Overcoming the blood-brain barrier (BBB) is a major challenge in the development of therapies for central nervous system (CNS) disorders. In this context, the intranasal route of drug administration has been proposed as a non-invasive alternative route for directly targeting the CNS. This route of drug administration bypasses the BBB and reduces the systemic side effects. Recently, several formulations have been developed for further enhancing nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review is to provide an overview of the strategies that have been developed for delivering anticancer compounds for the treatment of GBM while using nasal administration. In particular, the specific properties of nanomedicines proposed for nose-to-brain delivery will be critically evaluated. The preclinical and clinical data considered supporting the idea that nasal delivery of anticancer drugs may represent a breakthrough advancement in the fight against GBM.

Box-Behnken design optimization of mucoadhesive chitosan-coated nanoemulsions for rosmarinic acid nasal delivery-In vitro studies.

Mucoadhesive chitosan-coated nanoemulsions for rosmarinic acid (RA) nasal delivery were optimized. The optimum ratio between the formulation components that led to minimum droplet size and PDI, and maximal ζ-potential and RA content was obtained using Box-Behnken design (BBD). Optimized conditions were 8.5% oil phase (w/v), 3:10 lecithin to oil phase ratio (w/w), and 0.1% chitosan final concentration (w/v). Physicochemical characterization, mucoadhesion measurement, in vitro release and permeation/retention were performed. Optimized chitosan-coated RA nanoemulsions presented adequate physicochemical characteristics, high mucoadhesive potential, prolonged drug release, and long-lasting permeation time with a higher RA penetration/retention through porcine nasal mucosa. Cell viability and death by necrosis in fibroblasts cells were also evaluated to investigate the formulations safety. Formulations did not induce cytotoxicity following 24 h (3.125-50 µM) or 48 h (3.125-25 µM) of treatments. Overall results demonstrated that optimized chitosan-coated nanoemulsion showed to be a suitable carrier for RA nasal delivery aiming neuroprotective therapies.