'Transfersome-embedded-gel' for dual-mechanistic delivery of anti-psoriatic drugs to dermal lymphocytes.

AIM: Develop a platform for co-delivering clobetasol propionate (CP) and cyclosporine (CyA) to the epidermis and dermis to treat psoriasis. METHODS: The transfersomes were prepared by thin-film hydration method. Transfersomes were characterised by dynamic light scattering and transmission electron microscope (TEM). Then, the gel stability, viscosity, pH, and spreadability were measured. Cytotoxicity of the CyA-loaded transfersome embedded in CP-dispersed gel (TEG-CyA-CP) was assessed on both human keratinocyte cell line (HaCaT) and Jurkat cells. In vitro cellular uptake and ex vivo dermal distribution was measured. The expression of inflammatory markers was assessed by reverse-transcription PCR (RT-PCR). RESULTS: Nanoscale (<150 nm) transferosomes with high CyA encapsulation efficiency (>86%) were made. TEG-CyA-CP demonstrated higher viscosity (4808.8 ± 12.01 mPas), which may help control dual drug release. Ex vivo results showed TEG-CyA-CP ability to deliver CyA in the dermis and CP in the epidermis. RT-PCR studies showed the optimised formulation helps reduce the tumour necrosis factor (TNF-α) and interleukin-1 (IL-1) levels to relieve psoriasis symptoms. CONCLUSION: The developed TEG-CyA-CP represents a promising fit-to-purpose delivery platform for the dual-site co-delivery of CyA and CP in treating psoriasis.

In-silico approach as a tool for selection of excipients for safer amphotericin B nanoformulations.

Safer and efficacious Amphotericin B (AmB) nanoformulations can be designed by augmenting AmB in the monomeric or super-aggregated state, and restricting the aggregated state, by choosing the appropriate excipient, which can be facilitated by employing in-silico prediction as a tool. Excipients selected for the study included linear fatty acids from caprylic (C8) to stearic(C18) and the stearate based amphiphilic surfactants polyoxyl-15-hydroxystearate (PS15) and polyoxyl-40-stearate (PS40). Blend module was employed to determine the two miscibility parameters mixing energy (Emix) and interaction parameter (χ). AmB-excipient interactions were modelled using molecular docking software. The fatty acids revealed a decrease in Emix and χ values with increase in carbon chain length, suggesting enhanced affinity with increase in fatty acid hydrophobicity. Significantly higher affinity was observed with amphiphilic surfactants, in particular PS40 which exhibited negative values of Emix and χ proposing very high degree of miscibility. Molecular docking study confirmed extensive interaction of all the excipients with the AmB polyene chain. PS15 and PS40 displayed in addition hydrophilic interactions with the mycosamine and polyol moieties with PS40 exhibiting complete wrapping of the AmB molecule. PS15 demonstrated only partial wrapping, attributed to the shorter ethylene oxide chain. AmB nanosuspensions (NS) were prepared by in situ nanoprecipitation using the excipients and the AmB state identified by UV scanning between 300-500 nm. AmB NS with fatty acids and PS15-AmB NS revealed a high intensity peak between 330-350 nm of aggregated AmB and low intensity monomeric peaks between 405-415 nm reflecting predominance of the aggregated state. PS40-AmB NS on the other hand revealed complete absence of aggregated state and a high intensity peak between 321-325 nm which corresponded to the super-aggregated state. Also, the super-aggregated state slowly released the safe monomeric form without aggregate formation. Furthermore, very low hemolysis seen with PS40-AmB NS confirmed low toxicity attributed to the safer super-aggregated state and while higher hemolysis as anticipated was seen with PS15-AmB NS (aggregated state). The basis for selection of the appropriate excipient for design of safer AmB nanoformulations would be those excipients that exhibit negative values of miscibility parameters Emix and χ, exhibit interaction with the hydrophobic and hydrophilic regions of AmB and demonstrate complete wrapping of AmB in the molecular docking study. Our study thus demonstrates feasibility of in-silico prediction as a practical tool for excipient selection for safer AmB nanoformulations.

Psoriasis: implication to disease and therapeutic strategies, with an emphasis on drug delivery approaches.

Skin is the most visible and vulnerable organ of the integumentary system. Psoriasis is a chronic inflammatory skin disorder with an equal prevalence rate in males and females globally. Psoriasis is seen today beyond a cosmetic turmoil as it significantly impacts the socioeconomic life of the patients. Patients with severe psoriasis report feeling denounced and isolated. Despite detailed understanding of the molecular mechanisms and pathogenesis of psoriasis, issues like the autoimmune cause of inflammation and role of external, genetic, cutaneous, and systemic factors on initiation, progression, and treatment of psoriasis are still ambiguous. The present review summarizes immunogenic pathophysiology of psoriasis with a cascade of events from stimuli-based release of self-nucleotides to the hyperproliferation of keratinocytes leading to psoriasis. The review emphasizes challenges and hurdles toward the efficient treatment of psoriasis. The review also provides a detailed understanding of conventional and novel treatment strategies including drug delivery approaches and patented technologies for therapeutic and preventive approaches leading to improved outcome for psoriasis patients. The review summarizes a brief insight on biologics and gene therapy that has resulted in a paradigm shift in the treatment strategies for psoriasis management.