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Triamcinolone acetonide (TAA), a long-acting synthetic glucocorticoid, is commonly used for the management of posterior uveitis (PU) because of its anti-inflammatory and immunosuppressive characteristics. The commercially available formulation is in the suspension form advised for intravitreal injection, which has a number of serious problems. In the present research work, we prepared TAA nanocrystals (TAA-NCs) using the principles of design of experiments (DoE). The optimized TAA-NCs had a particle size of 243.0 ± 6.5 nm and a yield (%) of 89.4 ± 4.3%. The optimized TAA-NCs were suspended in a dual-responsive in situ gelling system, which has been previously reported by our team. The TAA-NCs loaded in situ gel (TAA-NC-ISG) formulations were evaluated for rheology, stability, in vitro and in vivo characteristics. The ocular pharmacokinetic investigations revealed that TAA-NCs loaded in situ gel achieved higher concentrations (C max of TAA-NC-ISG = 854.9 ng/mL) of the drug in vitreous humor and sustained (MRT 0–∞ of TAA-NC-ISG = 11.2 h) the drug concentrations for longer duration compared to aqueous suspension of TAA-NCs (TAA-NC-Susp) and aqueous suspension of TAA with 20% hydroxypropyl β-cyclodextrin(TAA-HP-β-CD-Susp) reported in our previous work. This higher exposure of TAA by TAA-NC-ISG is due to the combined effect of the nanometric size of the TAA nanocrystals and the in situ gelling properties of the formulation. • Triamcinolone acetonide (TAA) nanocrystals were prepared for topical ocular administration. • Hybrid design of experiments (DoE) approach was employed to optimize the TAA nanocrystals. • Physicochemical characterization of the optimized nanocrystal was performed. • The optimized nanocrystals were loaded in a dual responsive in situ gelling system. • The TAA nanocrystals loaded in situ gel showed significantly higher vitreous humor concentrations compared to aqueous suspension of TAA with 20% hydroxypropyl β-cylcodextrin. [ABSTRACT FROM AUTHOR]

Objective: Design chitosan based nanoparticles for tenofovir disoproxil fumarate (TDF) with the purpose of enhancing its oral absorption. Significance: TDF is a prodrug that has limited intestinal absorption because of its susceptibility to gut wall esterases. Hence, design of chitosan based polymeric novel nanocarrier systems can protect TDF from getting metabolized and also enhance the oral absorption. Methods: The nanoparticles were prepared using the ionic gelation technique. The factors impacting the particle size and entrapment efficiency of the nanoparticles were evaluated using design of experiments approach. The optimized nanoparticles were characterized and evaluated for their ability to protect TDF from esterase metabolism. The nanoparticles were then studied for the involvement of active transport in their uptake during the oral absorption process. Further, in vivo pharmacokinetic studies were carried out for the designed nanoparticles. Results: The application of design of experiments in the optimization process was useful to determine the critical parameters and evaluate their interaction effects. The optimized nanoparticles had a particle size of 156 ± 5 nm with an entrapment efficiency of 48.2 ± 1%. The nanoparticles were well characterized and provided metabolic protection for TDF in the presence of intestinal esterases. The nanoparticles were able to increase the AUC of tenofovir by 380%. The active uptake mechanisms mainly involving clathrin-mediated uptake played a key role in increasing the oral absorption of tenofovir. Conclusions: These results show the ability of the designed chitosan based nanoparticles in enhancing the oral absorption of TDF along the oral route by utilizing the active endocytic uptake pathways. [ABSTRACT FROM AUTHOR]

Lopinavir (LPV)-loaded poly-ϵ-caprolactone (PCL) nanoparticles (NPs) were prepared by emulsion solvent evaporation technique. Effects of various critical factors in preparation of loaded NPs were investigated. Box-Behnken design (BBD) was employed to optimize particle size and entrapment efficiency (EE) of loaded NPs. Optimized LPV NPs exhibited nanometeric size (195.3 nm) with high EE (93.9%). In vitro drug release study showed bi-phasic sustained release behavior of LPV from NPs. Pharmacokinetic study results in male Wistar rats indicated an increase in oral bioavailability of LPV by 4-folds after incorporation into PCL NPs. From tissue distribution studies, significant accumulation of loaded NPs in tissues like liver and spleen indicated possible involvement of lymphatic route in absorption of NPs. Mechanistic studies using rat everted gut sac model revealed endocytosis as a principal mechanism of NPs uptake. In vitro rat microsomal metabolism studies demonstrated noticeable advantage of LPV NPs by affording metabolic protection to LPV. These studies indicate usefulness of PCL NPs in enhancing oral bioavailability and improving pharmacokinetic profile of LPV. [ABSTRACT FROM AUTHOR]

Raloxifene HCl (RLX), a selective oestrogen receptor modulator, has low oral bioavailability (<2%) in humans due to its poor aqueous solubility and extensive first-pass metabolism in gut. In this study, we optimised the method of preparation for poly (&varepsilon;-caprolactone) (PCL) based nanocapsules of RLX by double emulsion method (w/o/w). A hybrid design approach, Plackett-Burman design followed by rotatable central composite design, was used to arrive at the optimised formulation. The optimised formulation was subjected to in vitro and in vivo evaluation. RLX loaded nanocapsules were spherical in shape with particle size less than 200 nm and high encapsulation efficiency (>80%). RLX-loaded nanocapsules showed 2.1-fold increase in oral bioavailability compared to free RLX. IV pharmacokinetic studies indicated that RLX loaded into nanocapsule had significantly low clearance in comparison with free RLX. Designed nanocapsules showed promise as delivery systems to enhance oral bioavailability and in reducing clearance of raloxifene. [ABSTRACT FROM AUTHOR]

Objectives To prepare stearic acid-based lopinavir ( LPV) loaded solid lipid nanoparticles ( SLNs) using a hybrid design and compare in-vivo performance of optimized formulation with marketed LPV/ritonavir (RTV) coformulation. Methods LPV SLNs were prepared by hot melt emulsion technique and optimized using Plackett- Burman design and Box- Behnken design. Physical characterization studies were conducted for the optimized SLNs. Comparative oral pharmacokinetic studies and tissue distribution studies of optimized SLNs and LPV/ RTV coformulation were done in Wistar rats. In-vitro metabolic stability and intestinal permeability studies for LPV SLNs were undertaken to elucidate the mechanism involved in the pharmacokinetic improvement of LPV. Key findings Optimized SLNs exhibited nanometeric size (223 nm) with high entrapment efficiency (83%). In-vitro drug release study of SLNs showed biphasic sustained release behaviour. Significant increase in oral bioavailability of LPV from LPV SLNs (5 folds) and LPV/ RTV coformulation (3.7 folds) was observed as compared with free LPV. LPV SLNs showed better tissue distribution of LPV in HIV reservoirs than LPV/ RTV coformulation. In-vitro studies demonstrated that SLNs provided metabolic protection of LPV and were endocytosized during absorption. Conclusions SLNs enhanced oral bioavailability and improved distribution profile of LPV to HIV reservoirs and hence could be better alternative to LPV/ RTV coformulation. [ABSTRACT FROM AUTHOR]

Abstract: Raloxifene HCl (RLX) shows low oral bioavailability (<2%) in humans due to poor aqueous solubility and extensive (>90%) metabolism in gut. Lipid nanoparticles (SLN) with glyceryl tribehenate were designed to enhance drug’s oral bioavailability. Box–Bhenken design was used to optimize manufacturing conditions. Optimized SLN had particle size of 167±3nm and high encapsulation efficiency (>92%). Oral bioavailability of RLX from SLN was improved by 3.24 folds compared to free RLX in female Wistar rats. Both clathrin and caveolae mediated endocytosis pathways were involved in the uptake of SLN. Lymphatic transport inhibitor, cycloheximide significantly reduced oral bioavailability of SLN. [Copyright &y& Elsevier]

Piribedil (PBD) is a compound that has shown efficacy in clinical trials to treat motor and non-motor symptoms of Parkinson's disease. However, drug delivery issues like low oral bioavailability, high dosing frequency (3–5 tablets/day), gastrointestinal side-effects reduced the clinical use of PBD. In this work, we have developed lecithin-chitosan hybrid nanoparticles (PBD-LCNs) to improve the direct nose to brain uptake of PBD. PBD-LCNs were optimized using hybrid design approach based on DoE. The mean particle size and drug loading of PBD-LCNs were 147 nm, and 12%, respectively. The PBD-LCNs showed good stability and were found to be nearly spherical in shape. Further, the optimized LCNs were loaded in methylcellulose thermo-responsive in situ gel (PBD-LCN-ISG) to overcome rapid mucociliary clearance upon intranasal administration. Plasma and brain pharmacokinetic studies in rats showed that PBD-LCN-ISG increased the relative bioavailability of PBD in brain (AUC brain) by about 6.4-folds and reduced the (C max) plasma by 3.7-folds when compared to plain intranasal suspension of PBD (PBD-Susp). Further, PBD-Susp showed limited direct nose to brain uptake with DTP values less than 0, while the optimized PBD-LCNs showed DTP value of 56% indicating efficient direct nose to brain uptake. Overall, the development of nanoformulations significantly improved the direct nose to brain uptake of PBD. • PBD has unique pharmacological advantages but is limited by issues with oral dosing. • Nose to brain uptake avoids issues of oral route while increasing the brain availability. • LCNs were developed for intranasal delivery of PBD to improve direct brain uptake. • In situ gel loaded LCNs were found to be superior over plain piribedil suspension. • Direct nose to brain transport with in situ gel loaded LCNs of Piribedil was 56%. [ABSTRACT FROM AUTHOR]

[Display omitted] • Piribedil is an anti-Parkinson's drug with unique pharmacological advantages. • Its clinical use is limited due to high dosing frequency of the oral tablets. • SLNs were developed for intranasal delivery of PBD to improve direct brain uptake. • In situ gel loaded SLNs were found to be superior over plain piribedil suspension. • Direct nose to brain transport with in situ gel loaded SLNs of Piribedil was 27%. Piribedil (PBD) is an anti-Parkinson's drug that gained interest recently due to its unique pharmacological profile. But its clinical use is severely limited by drug delivery issues like high dosing frequency (up to 5 tablets/day), low oral bioavailability (<10%), severe GI side-effects, etc. In this work, we have developed solid lipid nanoparticles (PBD-SLNs) to access the nose to brain pathways for direct uptake of PBD. PBD-SLNs were optimized using design of experiments approach to a mean particle size of 358 nm, and drug loading of 15%. The optimized PBD-SLNs were found to be nearly spherical in shape and showed good stability. Further, the SLNs were loaded in thermoresponsive Methyl Cellulose in situ gel (PBD-SLN-ISG) to delay mucociliary clearance upon intranasal administration in rats. Intranasal administration at the olfactory region was achieved with a cannula-microtip setup. In vivo pharmacokinetic studies showed that PBD-SLN-ISG increased the PBD (AUC) brain by about 4-folds and reduced the (C max) plasma by 2.3-folds when compared to plain intranasal suspension of PBD (PBD-Susp). Further, PBD-Susp showed limited direct nose to brain uptake with direct transport percentage (DTP) values less than 0, while the optimized PBD-SLN-ISG showed DTP value of 27% indicating efficient direct nose to brain uptake. [ABSTRACT FROM AUTHOR]