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Alzheimer's disease (AD) is a neurodegenerative disorder affecting the central nervous system (CNS) characterized by the overproduction of amyloid beta proteins and its inability to clear from the brain resulting in its self-aggregation to form toxic oligomers, fibrils and plaques. Studies show that the incidence of AD would double in every 2 decade showing an increase from 66 million to 115 million by 2050. Currently therapies address systemic administration for treating Alzheimer's disease by appropriate manipulations in neutrophins, the neutrophic enhancing factors. In addition, therapeutic strategies using cholinesterase inhibitors, N-methyl-D-aspartate (NMDA) receptor blockage, or by drugs that remove amyloid plaques frombrain. Fluid biomarkers improve diagnostic accuracy in predementia phase as drugs would be effective only in initial stages. However, a major challenge in the CNS drug delivery being the blood brain barrier (BBB) and that nanotechnological approaches have been designed to facilitate drug delivery across this physiological barrier. This review addresses the current challenges and strategies as well as the significance of nanotechnology for a better understanding and delivery of drugs across the BBB to reach damaged areas of the CNS in patients.

Chaulmoogra oil based methotrexate loaded nanoemulsion was prepared via emulsification technique using tween 80 and ethanol as surfactants. The formulation was characterized by FTIR and TEM. The prepared nanoemulsion has an average particle size of 34 nm with negative surface charge and has pH compatible to skin. Rheological studies revealed the shear thinning non-Newtonian visco-elastic behavior of the formulation as explained by the Herschel Bulkley model. The formulation was cytocompatible towards mouse dermal fibroblast L929 cells when tested by MTT assay and was stable in refrigerator for the tested period of 3 months. The in-vitro release mechanism of methotrexate from formulation followed zero order release kinetics with non Fickian diffusion mechanism. The ex-vivo skin permeation studies done by Franz diffusion cell apparatus using porcine skin revealed the improved skin permeation and retention of drug in deep skin layers when compared with control drug solution. The in vivo anti-psoriatic studies done on imiquimod psoriatic model revealed superior anti-psoriatic efficacy, with effective skin retention and lesser serum and tissue accumulation when compared with orally administered methotrexate tablet.

Methotrexate loaded chitin nanogel (MCNG) was formulated for its topical use in psoriasis. MCNG was characterized by DLS, TEM and FTIR. The MCNG particles were spherical in shape with size of 196±14nm, having surface charge of +9.21±0.42 mv. MCNG exhibited greater swelling and drug release at acidic pH than neutral and alkaline conditions. The treatment with MCNG showed significant level of toxicity on HaCaT and THP-1 cells and was taken up well by HaCaT cells as revealed by fluorescent microscopy. MCNGs exhibited significant anti-inflammatory activity as revealed by the inhibitory effects observed on the activity of COX-2 and LOX-5 enzymes expressed in THP-1 cells. Skin permeation studies revealed an increased trasdermal flux of methotrexate from MCNG with loosened stratum corneum and other epidermal layers of skin in comparison with control methotrexate solution treated samples. Significant anti-psoriatic efficacy on imiquimod (IMQ) induced model of psoriasis without any dermal and systemic toxicities suggest that it as an ideal delivery platform for topical delivery of methotrexate in psoriasis. Thus it is expected to become a better alternative for the oral delivery of methotrexate in the selected disease.

The anti-psoriatic efficacy of orally administered methotrexate loaded chitin nanogel (MCNG) was evaluated (two doses- 2.715 mg/kg and 5.143 mg/kg) and compared against orally administered methotrexate tablet MTX (5.143 mg/kg). MCNG at both dose levels of 2.715 mg/kg and 5.143 mg/kg exhibited significant anti-psoriatic activity which is very much comparable with MTX, caused normalization of histological features and inflammatory score associated with induced psoriasis. Biodistribution studies revealed the presence of drug in serum and in vital organs at all the three cases with highest amount in MCNG at 5.143 mg/kg dose, followed by MTX tablet and are lowest in MCNG at 2.715 mg/kg dose. MCNG at the highest dose of 5.143 mg/kg caused liver, lung and kidney toxicities on sub acute toxicity studies and MTX tablet was found to be toxic on liver and lung on sub chronic toxicity studies. MCNG 2.715 mg/kg was found to be safe on both sub acute and sub chronic administrations, suggesting that it can provide sufficient serum and tissue level of methotrexate necessary to clear psoriatic lesions, without inducing systemic toxicity and expected to be a better alternative for orally administered conventional methotrexate tablet for patients who need systemic medications for psoriasis.

In the present study chitin nanogel loaded with anti-psoriatic drug clobetasol was developed (CLCNG) for its topical delivery in psoriasis. CLCNG had the particle size of 132±14nm, with gel like consistency, stability in refrigerator, having higher drug release properties at acidic pH. CLCNG exhibited significant toxicity towards HaCaT and THP-1cell lines by MTT assay. The uptake of nanogel by HaCaT cell lines was confirmed by fluorescent microscopy. CLCNG at 0.35mg/ml exhibited significant anti-inflammatory activity with an average of 65% and 70% inhibition in COX and LOX activities expressed in THP-1 cells. In vitro skin permeation studies revealed the increased transdermal flux with fragmented stratum corneum and loosened epidermal layers in CLCNG treated samples, compared with control drug solution. The in vivo anti-psoriatic studies done on imiquimod model confirmed the potential benefits of the nanogel for the topical delivery of clobetasol in psoriasis.

The present study focuses on the development of an effective topical nanogel formulation of two anti-psoriatic drugs; Acitretin (Act) and Aloe-emodin (AE) using natural polymer chitin. Simple regeneration chemistry was used to prepare Chitin Nanogel Systems (CNGs). The developed control chitin (CNGs) nanogels, acitretin loaded chitin nanogels (ActCNGs) and aloe-emodin loaded chitin nanogels (AECNGs) were characterized by DLS, SEM, FTIR, XRD and TG-DTA. The systems were found to be spherical in shape with a size range of 98±10, 138±8 and 238±6nm having zeta potential values of +28±3, +27±3 and +25±6mV for CNGs, ActCNGs and AECNGs respectively. The in vitro haemolysis assay revealed that all the nanogel systems are blood compatible. The systems exhibited higher swelling and release at acidic pH. The ex vivo skin permeation studies using porcine skin confirmed the higher deposition of the systems at epidermal and dermal layers, which was confirmed further by fluorescent imaging. The in vivo anti-psoriatic activity study using Perry's mouse tail model and skin safety studies confirmed the potential benefit of the system for topical delivery of acitretin and aloe-emodin in psoriasis.