Design and development of bioinspired calcium phosphate nanoparticles of MTX: pharmacodynamic and pharmacokinetic evaluation.

The aim of this investigation is the management of rheumatoid arthritis (RA) by developing methotrexate-loaded calcium phosphate nanoparticles (MTX-CAP-NP) and to evaluate pharmacokinetic and pharmacodynamic behavior in adjuvant induced arthritis model. The nanoparticles were synthesized by wet precipitation method and optimized by Box-Behnken experimental design. MTX-CAP-NPs were characterized by TEM, FTIR, DSC and XRD studies. The particle size, zeta potential and entrapment efficiency of the optimized nanoparticles were found to be 204.90 ± 64 nm, -11.58 ± 4.80 mV, and 88.33 ± 3.74%, respectively. TEM, FTIR, DSC and XRD studies revealed that the developed nanoparticles were nearly spherical in shape and the crystalline structure of CAP-NP was not changed after MTX loading. The pharmacokinetic studies revealed that MTX-CAP-NP enhanced bioavailability of MTX by 2.6-fold when compared to marketed formulation (FOLITRAX-10). Under pharmacodynamic evaluation, arthritic assessment, radiography and histopathology studies revealed that CAP has ability to regenerate cartilage and bone therefore, together with MTX, MTX-CAP-NPs have shown significant reduction in disease progression. The overall work demonstrated that the developed nanodelivery system was well tolerated and more effective than the marketed formulation.

Improvement of oral efficacy of Irinotecan through biodegradable polymeric nanoparticles through in vitro and in vivo investigations.

BACKGROUND: Irinotecan (IRN) (CPT-11) is a camptothecin derivative with low oral bioavailability due to active efflux by intestinal P-glycoprotein (p-gp) receptors. Hence, no oral formulation is marketed for IRN till date and its oral ingestion continues to remain a challenge. AIM OF STUDY: The study aims to develop a nanoformulation i.e. Chitosan (CS)-coated-IRN-loaded-poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) (CS-IRN-PLGA-NPs)in order to enhance oral bioavailability of IRN. RESULTS: Developed formulation revealed particle size, 166.9 ± 13.63 nm, zeta potential, 14.67 ± 1.08 mV and drug content (42.69 ± 1.97 µg/mg), with spherical shape and smooth surface. Cytotoxicity studies, performed against human breast adenocarcinoma cell lines (MCF-7), confirmed the superiority of IRN-CS-PLGA-NPs over free IRN solution (IRN-S). Cellular transport conducted on human colon adenocarcinoma cell line (Caco-2) exhibited a higher permeability of 1.33 folds for IRN through CS-IRN-PLGA-NPs as compared to IRN-S (p < 0.01) whereas the permeability for IRN was found to be higher at a rate of 4.32 folds, across rat ileum. Furthermore, pharmacokinetic studies demonstrated marked improvement of 3.53 fold and 8.03 fold in Wistar rat's plasma as well as brain higher oral bioavailability through IRN-CS-PLGA-NPs when compared with IRN-S. A simple, rapid UPLC-ESI-Q-TOF-MS/MS method for the determination of IRN (CPT-11) and SN-38 in both plasma and brain (over a range: 1.00-25000.00 ng/ml) was also developed and successfully applied for pharmacokinetic study. DISCUSSION: CS-IRN-PLGA-NPs approach may be effectively utilised, to replace pre-existing intravenous therapy thus providing 'patient care at home.

Experimental design-based optimization of lipid nanocarrier as delivery system against Mycobacterium species: in vitro and in vivo evaluation.

The study aimed to optimize self-nanoemulsifying drug delivery system using experimental design using excipients holding innate anti-mycobacterium activities followed with characterizations for responses such as optical clarity (Y1), zone of inhibition (ZOI) against Mycobacterium smegmatis strains (Y2, Y3), and globular size (Y4). The optimized formulations (OF1-OF3) were further characterized for responses and evaluated for zeta potential, minimum inhibition concentration (MIC) against non-pathogenic and tubercular strains, morphological (electron microscopy and atomic force microscopy), and confocal laser scanning microscopy (CLSM) studies. The desirability analysis suggested that the predicted values of the OF1 for the responses Y1, Y2, Y3, and Y4 were 0.137, 22.77 mm, 21.9 mm, and 191.11 nm, respectively. The morphological assessment confirmed the in vitro studies and established the inhibition mechanism as evidenced with oozing, ablation, and cell-wall fragmentation followed with cell disruption. The OF1, OF2, and OF3 showed an MIC value at 8.8 ± 0.56 mg/ml, 12.5 ± 0.22 mg/ml, and 15.0 ± 0.4 mg/ml, respectively, corroborating effectiveness against tubercular strain. CLSM studies revealed 75.1, 80.3, and 88.7% as an intense fluorescence intensity of OF1, OF2, and OF3, respectively, as compared with dye solution (∼53%). Conclusively, it can be inferred that the delivery of anti-tubercular drugs might be reassessed using excipients with inherent anti-mycobacterium activities.

Formulation and development of novel lipid-based combinatorial advanced nanoformulation for effective treatment of non-melanoma skin cancer.

Non-melanoma skin cancer is one of the most common malignancies reported with high number of morbidities, demanding an advanced treatment option with superior chemotherapeutic effects. Due to high degree of drug resistance, conventional therapy fails to meet the desired therapeutic efficacy. To break the bottleneck, nanoparticles have been used as next generation vehicles that facilitate the efficient interaction with the cancer cells. Here, we developed combined therapy of 5-fluorouracil (5-FU) and cannabidiol (CBD)-loaded nanostructured lipid carrier gel (FU-CBD-NLCs gel). The NLCs were optimized using central composite design that showed an average particle size of 206 nm and a zeta potential of -34 mV. In addition, in vitro and ex vivo drug permeations studies demonstrated the effective delivery of both drugs in the skin layers via lipid structured nanocarriers. Also, the prepared FU-CBD-NLCs showed promising effect in-vitro cell studies including MTT assays, wound healing and cell cycle as compared to the conventional formulation. Moreover, dermatokinetic studies shows there was superior deposition of drugs at epidermal and the dermal layer when treated with FU-CBD-NLCs. In the end, overall study offered a novel combinatorial chemotherapy that could be an option for the treatment of non-melanoma skin cancer.

Comparative efficacy of liposome-entrapped amiloride and free amiloride in animal models of seizures and serum potassium in mice.

The present study was aimed to evaluate a liposomal formulation of amiloride on experimental seizure models including the increasing current electroshock seizure threshold test (ICES), pentylenetetrazole (PTZ)-induced seizures and PTZ-induced status epilepticus in mice. Further, the effect of liposomal amiloride on serum K(+) levels was also investigated using flame photometry. We found an improved anticonvulsant action with liposome-entrapped amiloride as compared to free amiloride. Further, free amiloride showed an increase in serum K(+) levels, however the latter was unaffected with liposomal formulation treatment. These results, together with previously published data, suggest that as drug delivery vehicles, liposomes can enhance the effectiveness of drugs in the CNS without producing peripheral toxicity (hyperkalemia).