Drug delivery to the brain: How can nanoencapsulated statins be used in the clinic?

© 2017 Future Science Ltd. Statins are used for the primary and secondary prevention of cardiovascular disease by inhibiting cholesterol synthesis in the liver. Statins have also noncholesterol-related effects, called pleiotropic effects, which arise from statins' anti-inflammatory, immunomodulatory and antioxidant properties. These effects are especially attractive for the treatment of various brain diseases ranging from stroke to neurodegenerative diseases. Still, low brain concentrations after oral drug administration hinder the clinical application of statins in these pathologies. Pharmaceutical nanotechnologies may offer a solution to this problem, as local or targeted delivery of nanoencapsulated statins may increase brain availability. This special report rapidly summarizes the potential of statins in the treatment of brain diseases and the pharmaceutical nanotechnologies that could provide a viable approach to enable these indications

Therapeutics and carriers: The dual role of proteins in nanoparticles for ocular delivery

© 2015 Bentham Science Publishers. Blindness and visual impairment affect millions of people worldwide and have a very important impact on patients quality of life. Proteins and peptides represent nowadays an important therapeutic tool for the treatment of ocular diseases but, despite their potential, have significant limitations, as the administration of protein-based pharmaceuticals represents a real challenge. Moreover, administration of ocular medications is difficult due to the peculiar structure of this organ and the presence of numerous barriers protecting the eye inner structure. Nanoencapsulation of peptides and proteins presents a number of advantages for their ocular delivery since it can protect the drug from metabolic activity, control and sustain the release and increase drug bioavailability after topical or intravitreal administration. In fact, nanoparticulate formulations are contributing to overcome ocular barriers, such as the corneal or the blood-retinal barrier, improve the residence time in the eye, increase local drug level, reduce the drug dosage and showing improved performance when compared to conventional formulations. Besides, proteins have also been proposed for the preparation of nanocarriers intended for ophthalmic administration, since they are highly biocompatible, biodegradable and easily modified to link surface ligands. The present review focuses the attention on the use of proteins in ocular drug delivery nanotechnology: their dual role as both therapeutics and carriers has been critically evaluated and discussed

Opportunities and challenges for the nasal administration of nanoemulsions

© 2015 Bentham Science Publishers. Nasal delivery has become a growing area of interest for drug administration as a consequence of several practical advantages, such as ease of administration and non-invasiveness. Moreover, the avoidance of hepatic first-pass metabolism and rapid and efficient absorption across the permeable nasal mucosa offer a promising alternative to other traditional administration routes, such as oral or parenteral delivery. In fact, nasal delivery has been proposed for a number of applications, including local, systemic, direct nose-to-brain and mucosal vaccine delivery. Nanoemulsions, due to their stability, small droplet size and optimal solubilization properties, represent a versatile formulation approach suitable for several administration routes. Nanoemulsions demonstrated great potential in nasal drug delivery, increasing the absorption and the bioavailability of many drugs for systemic and nose-tobrain delivery. Furthermore, they act as an active component, i.e. an adjuvant, in nasal mucosal vaccinations, displaying the ability to induce robust mucosal immunity, high serum antibodies titres and a cellular immune response avoiding inflammatory response. Interestingly, nanoemulsions have not been proposed for the treatment of local ailments of the nose. Despite the promising results in vitro and in vitro, the application of nanoemulsions for nasal delivery in humans appears mainly hindered by the lack of detailed toxicology studies to determine the effect of these formulations on the nasal mucosa and cilia and the lack of extensive clinical trials

Evolved gas analysis during thermal degradation of salbutamol sulphate

Crystalline salbutamol sulphate (SS) is a common β2-agonist used in dry powder inhalers for the treatment of asthma. The solid-state characteristics of SS are import since they govern the stability, and thus efficacy of the drug when incorporated in inhalation medicine. Previous studies have investigated the thermal properties of SS and the complex array of thermal events have been attributed a mixture of melting and/or degradation mechanisms. In order to ascertain the exact thermal transformation processes that SS undergoes, and we utilised a combination of differential scanning calorimetry coupled with quadrupole mass spectrometry and thermogravimetric analysis coupled with Fourier transform infrared spectroscopy over the temperature range 25-500 °C. Based on the coupled thermal analysis data, we proposed that SS undergoes a multi-step degradation mechanism in which the molecule dehydrates loosing water initially, followed by the break up of the secondary amine group and lastly formation of sulphur dioxide. When used in conjunction, the analytical techniques offered significant advantages over the use of thermal analysis alone, offering a better understanding of the transformations occurring to SS following heating

Anti-Inflammatory Properties of Statin-Loaded Biodegradable Lecithin/Chitosan Nanoparticles: A Step Toward Nose-to-Brain Treatment of Neurodegenerative Diseases

Nasal delivery has been indicated as one of the most interesting alternative routes for the brain delivery of neuroprotective drugs. Nanocarriers have emerged as a promising strategy for the delivery of neurotherapeutics across the nasal epithelia. In this work, hybrid lecithin/chitosan nanoparticles (LCNs) were proposed as a drug delivery platform for the nasal administration of simvastatin (SVT) for the treatment of neuroinflammatory diseases. The impact of SVT nanoencapsulation on its transport across the nasal epithelium was investigated, as well as the efficacy of SVT-LCNs in suppressing cytokines release in a cellular model of neuroinflammation. Drug release studies were performed in simulated nasal fluids to investigate SVT release from the nanoparticles under conditions mimicking the physiological environment present in the nasal cavity. It was observed that interaction of nanoparticles with a simulated nasal mucus decreased nanoparticle drug release and/or slowed drug diffusion. On the other hand, it was demonstrated that two antibacterial enzymes commonly present in the nasal secretions, lysozyme and phospholipase A2, promoted drug release from the nanocarrier. Indeed, an enzyme-triggered drug release was observed even in the presence of mucus, with a 5-fold increase in drug release from LCNs. Moreover, chitosan-coated nanoparticles enhanced SVT permeation across a human cell model of the nasal epithelium (×11). The nanoformulation pharmacological activity was assessed using an accepted model of microglia, obtained by activating the human macrophage cell line THP-1 with the Escherichia coli-derived lipopolysaccharide (LPS) as the pro-inflammatory stimulus. SVT-LCNs were demonstrated to suppress the pro-inflammatory signaling more efficiently than the simple drug solution (-75% for IL-6 and -27% for TNF-α vs. -47% and -15% at 10 µM concentration for SVT-LCNs and SVT solution, respectively). Moreover, neither cellular toxicity nor pro-inflammatory responses were evidenced for the treatment with the blank nanoparticles even after 36 h of incubation, indicating a good biocompatibility of the nanomedicine components in vitro. Due to their biocompatibility and ability to promote drug release and absorption at the biointerface, hybrid LCNs appear to be an ideal carrier for achieving nose-to-brain delivery of poorly water-soluble drugs such as SVT

Hybrid Nanoparticles as a Novel Tool for Regulating Psychosine-Induced Neuroinflammation and Demyelination In Vitro and Ex vivo

Polymeric nanoparticles are being extensively investigated as an approach for brain delivery of drugs, especially for their controlled release and targeting capacity. Nose-to-brain administration of nanoparticles, bypassing the blood brain barrier, offers a promising strategy to deliver drugs to the central nervous system. Here, we investigated the potential of hybrid nanoparticles as a therapeutic approach for demyelinating diseases, more specifically for Krabbe’s disease. This rare leukodystrophy is characterized by the lack of enzyme galactosylceramidase, leading to the accumulation of toxic psychosine in glial cells causing neuroinflammation, extensive demyelination and death. We present evidence that lecithin/chitosan nanoparticles prevent damage associated with psychosine by sequestering the neurotoxic sphingolipid via physicochemical hydrophobic interactions. We showed how nanoparticles prevented the cytotoxicity caused by psychosine in cultured human astrocytes in vitro, and how the nanoparticle size and PDI augmented while the electrostatic charges of the surface decreased, suggesting a direct interaction between psychosine and the nanoparticles. Moreover, we studied the effects of nanoparticles ex vivo using mouse cerebellar organotypic cultures, observing that nanoparticles prevented the demyelination and axonal damage caused by psychosine, as well as a moderate prevention of the astrocytic death. Taken together, these results suggest that lecithin-chitosan nanoparticles are a potential novel delivery system for drugs for certain demyelinating conditions such as Krabbe’s disease, due to their dual effect: not only are they an efficient platform for drug delivery, but they exert a protective effect themselves in tampering the levels of psychosine accumulation

Expanding the therapeutic potential of Statins by means of nanotechnology enabled drug delivery systems

Statins are effective lipid lowering agents traditionally used for the primary and secondary prevention of cardiovascular disease. Statins also exert a range of pleiotropic effects that make them attractive candidates for use in a wide range of disorders, in particular inflammatory and immune mediated conditions. However, the exploitation of such pleiotropic effects has been greatly hindered by poor bioavailability and adverse effects on muscles and the liver at higher doses. Nanotechnology is often suggested as the solution to this problem, as it enables an increased bioavailability of statins. Moreover, colloidal carriers can offer targeted drug delivery approaches that enable localised biological effects of statins, further reducing their potential for unwanted toxicity and adverse effects. This article reviews the available evidences for the increased potential of statin therapy when administered in nano-formulations such as nanocrystals, nanoparticles, liposomes, micelles and various nano-enabled devices. © 2014 Bentham Science Publishers

Respicelltm: An innovative dissolution apparatus for inhaled products

To overcome some of the shortfalls of the types of dissolution testing currently used for pulmonary products, a new custom-built dissolution apparatus has been developed. For inhalation products, the main in vitro characterisation required by pharmacopoeias is the deposition of the active pharmaceutical ingredient in an impactor to estimate the dose delivered to the target site, i.e., the lung. Hence, the collection of the respirable dose (<5 µm) also appears to be an essential requirement for the study of the dissolution rate of particles, because it results as being a relevant parameter for the pharmacological action of the powder. In this sense, dissolution studies could become a complementary test to the routine testing of inhaled formulation delivered dose and aerodynamic performance, providing a set of data significant for product quality, efficacy and/or equivalence. In order to achieve the above-mentioned objectives, an innovative dissolution apparatus (RespiCell™) suitable for the dissolution of the respirable fraction of API deposited on the filter of a fast screening impactor (FSI) (but also of the entire formulation if desirable) was designed at the University of Parma and tested. The purpose of the present work was to use the RespiCell dissolution apparatus to compare and discriminate the dissolution behaviour after aerosolisation of various APIs characterised by different physico-chemical properties (hydrophilic/lipophilic) and formulation strategies (excipients, mixing technology)

Optimization of RPMI 2650 Cells as a Model for Nasal Mucosa

In the past few years, a human nasal epithelial cell line derived from septum carcinoma (RPMI 2650) has been proposed as a potential in vitro model for screening nasally delivered drugs. However, these studies have left some unanswered questions in terms of the validation of the in vitro model. In particular, no clear agreement was found with respect to several parameters, such as the seeding density, the time for switching cell culture from liquid covered culture (LCC) to air liquid interface (ALI) conditions, or the day at which cell cultures have to be used for transport experiments, when these cells are cultured in vitro. Hence, the aim of this study was to expand on the previous in vitro cell models to better define the fundamental parameters to be used as a tool for studying drug deposition and transport through the nasal mucosa

The vaginal-PVPA: A vaginal mucosa-mimicking in vitro permeation tool for evaluation of mucoadhesive formulations

Drug administration to the vaginal site has gained increasing attention in past decades, highlighting the need for reliable in vitro methods to assess the performance of novel formulations. To optimize formulations destined for the vaginal site, it is important to evaluate the drug retention within the vagina as well as its permeation across the mucosa, particularly in the presence of vaginal fluids. Herewith, the vaginal-PVPA (Phospholipid Vesicle-based Permeation Assay) in vitro permeability model was validated as a tool to evaluate the permeation of the anti-inflammatory drug ibuprofen from liposomal formulations (i.e., plain and chitosan-coated liposomes). Drug permeation was assessed in the presence and absence of mucus and simulated vaginal fluid (SVF) at pH conditions mimicking both the healthy vaginal premenopausal conditions and vaginal infection/pre-puberty/post-menopause state. The permeation of ibuprofen proved to depend on the type of formulation (i.e., chitosan-coated liposomes exhibited lower drug permeation), the mucoadhesive formulation properties and pH condition. This study highlights both the importance of mucus and SVF in the vaginal model to better understand and predict the in vivo performance of formulations destined for vaginal administration, and the suitability of the vaginal-PVPA model for such investigations