Transdermal Drug Delivery Systems: A Focused Review of the Physical Methods of Permeation Enhancement.

The skin is the body's largest organ and serves as a site of administration for various medications. Transdermal drug delivery systems have several advantages over traditional delivery systems. It has both local and systemic therapeutic properties. Controlled plasma drug levels, reduced dosing frequency, and avoidance of hepatic first-pass metabolism are just a few of these systems' advantages. To achieve maximum efficacy, it is critical to understand the kinetics, physiochemical properties of the drug moiety, and drug transport route. This manuscript focused on the principles of various physical means to facilitate transdermal drug delivery. Some examples are iontophoresis, electrophoresis, photomechanical waves, ultrasound, needleless injections, and microneedles. Mechanical, chemical, magnetic, and electrical energy are all used in physical methods. A major advantage of physical methods is their capability to abbreviate pain, which can be used for effective disease management. Further investigation should be carried out at the clinical level to understand these methods for effective drug delivery.

Enhanced tissue distribution of ritonavir-loaded nanostructured lipid carriers-recommending its dose reduction.

Human immunodeficiency virus (HIV) mainly attacks lymphocytes of the human immune system. The untreated infection leads to acquired immune deficiency syndrome (AIDS). Ritonavir (RTV) belongs to protease inhibitors (PIs), the crucial contributors of the combination therapy used in the treatment of HIV that is called highly active antiretroviral therapy (HAART). Formulations targeting the lymphatic system (LS) play a key role in delivering and maintaining therapeutic drug concentrations in HIV reservoirs. In our previous study, we developed RTV-loaded nanostructured lipid carriers (NLCs), which contain the natural antioxidant alpha-tocopherol (AT). In the current study, the cytotoxicity of the formulation was studied in HepG2, MEK293, and H9C2 cell lines. The formulation efficacy to reach the LS was evaluated through a cycloheximide-injected chylomicron flow blockade model in Wistar rats. Biodistribution and toxicity studies were conducted in rodents to understand drug distribution patterns in various organs and to establish the safety profile of the optimized formulation (RTV-NLCs). From the MTT assay, it was found that the cell viability of the formulation is comparable with the pure drug (RTV-API). More than 2.5-folds difference in AUC was observed in animals treated with RTV-NLCs with and without cycloheximide injection. Biodistribution studies revealed higher drug exposure in the lymphoidal organs with the RTV-NLCs. No significant increase in serum biomarkers for hepatotoxicity was observed in rats dosed with the RTV-NLCs. The current study reveals the lymphatic uptake of the RTV-NLCs and their safety in rodents. As the tissue distribution of RTV-NLCs is high, hence re-adjusting the RTV-NLCs dose to get the response equivalent to RTV-API may be more beneficial with respect to its safety and efficacy.

Factors affecting the preparation of nanocrystals: characterization, surface modifications and toxicity aspects.

INTRODUCTION: The fabrication of well-defined nanocrystals in size and form is the focus of much investigation. In this work, we have critically reviewed several recent instances from the literature that shows how the production procedure affects the physicochemical properties of the nanocrystals. AREAS COVERED: Scopus, MedLine, PubMed, Web of Science, and Google Scholar were searched for peer-review articles published in the past few years using different key words. Authors chose relevant publications from their files for this review. This review focuses on the range of techniques available for producing nanocrystals. We draw attention to several recent instances demonstrating the impact of various process and formulation variables that affect the nanocrystals' physicochemical properties. Moreover, various developments in the characterization techniques explored for nanocrystals concerning their size, morphology, etc. have been discussed. Last but not least, recent applications, the effect of surface modifications, and the toxicological traits of nanocrystals have also been reviewed. EXPERT OPINION: The selection of an appropriate production method for the formation of nanocrystals, together with a deep understanding of the relationship between the drug's physicochemical properties, unique features of the various formulation alternatives, and anticipated in-vivo performance, would significantly reduce the risk of failure during human clinical trials that are inadequate.

Novel Luliconazole Spanlastic Nanocarriers: Development and Characterisation.

BACKGROUND: The formulation of spanlastic vesicles of luliconazole can be used to overcome its poor skin permeation and improve its antifungal efficacy. OBJECTIVE: In this study, we aimed to enhance the dermal delivery of luliconazole, an antifungal drug, through spanlastic vesicles. METHODS: A 23 regular factorial design was employed, using the Design Expert® software for optimization. The independent variables chosen were Span: Edge activator ratio, type of edge activator, and sonication intensity and their effect on the dependent variables, i.e., entrapment efficiency, particle size, and percentage of drug release after 8h were determined. Spanlastics were formulated by ethanol injection method using Tween 80 as an edge activator. RESULTS: Spanlastics were found to possess sizes in the nano range with entrapment efficiencies between 77 - 88% with optimum zeta potential and polydispersity index indicating a stable formulation. Differential scanning calorimetry, X-ray diffraction, and Fourier transform infrared studies revealed complete encapsulation of the drug within the elastic carriers. The optimized spanlastic formulation was further incorporated into a gel base and was found to be sufficiently viscous, spreadable, homogenous, showed a prolonged release for up to 8h and was also found to be non-irritant. The in-vitro permeation study revealed that the flux value obtained for luliconazole entrapped in the vesicular spanlastics (0.2292 mg/cm2.h) was also found to be higher than that of the marketed (0.1302 mg/cm2.h) and conventional gel (0.1122 mg/cm2.h). The optimized gel formulation was also evaluated for its antimycotic activity. Moreover, the optimized gel formulation also possessed a greater antimycotic activity against Candida albicans. The spanlastics loaded hydrogel formulation was found to have a greater zone of inhibition in comparison to the marketed formulation, thus proving to have optimum antifungal activity against Candida albicans. CONCLUSION: Collectively, the results revealed that spanlastics could be a potential nanocarrier for wellcontrolled delivery and for targeting deeper skin layers, thus providing new opportunities for dermal treatment.

Recent advances in nanoformulation development of Ritonavir, a key protease inhibitor used in the treatment of HIV-AIDS.

INTRODUCTION: AIDS is one of the world's most serious public health challenges. Protease inhibitors are key components of AIDS treatment regimen. Ritonavir is a well-known protease inhibitor with low aqueous solubility belonging to BCS class II category. Some of the severe adverse effects associated with this drug restricted its use in the treatment of AIDS. However, several attempts were made by researchers in the past to enhance the oral bioavailability of Ritonavir. AREAS COVERED: The current review mainly focuses on the adverse effects of Ritonavir and recent approaches followed by researchers on the development of nanoformulations of Ritonavir. Further, various patents filed on Ritonavir have also been discussed in the current review. EXPERT OPINION: Most research on nanoformulation development for Ritonavir is mainly focused on enhancing the solubility and oral bioavailability of the drug. Some of the researchers focused on the lymphatic targeting of the drug in order to bypass the hepatic metabolism of the drug. However, most of the research topics did not cover the toxicity evaluation of the developed formulation. Since the major issue of Ritonavir is not only oral bioavailability but also drug-induced toxicity, this area needs to be considered during the formulation development.

Exosomes as cell-derivative carriers in the diagnosis and treatment of central nervous system diseases.

Exosomes are extracellular vesicles with the diameter ranging from 50 to 100 nm and are found in different body fluids such as blood, cerebrospinal fluid (CSF), urine and saliva. Like in case of various diseases, based on the parent cells, the content of exosomes (protein, mRNA, miRNA, DNA, lipids and metabolites) varies and thus can be utilized as potential biomarker for diagnosis and prognosis of the brain diseases. Furthermore, utilizing the natural potential exosomes to cross the blood-brain barrier and by specifically decorating it with the ligand as per the desired brain sites therapeutics can be delivered to brain parenchyma. This review article conveys the importance of exosomes and their use in the treatment and diagnosis of brain/central nervous system diseases.