Dinanath Mishra

Optimization of brain targeted chitosan nanoparticles of Rivastigmine for improved efficacy and safety

The study aims at formulation and optimization brain targeted nanoparticles (NP) of Rivastigmine (RT) to improve its therapeutic potential and to verify its safety profile. The NP were optimized using a two factor three level (3(2)) central composite design aiming to minimize particle size; maximize zeta potential and drug entrapment efficiency of NP. The optimized formulation (cRTNP) was evaluated using in vitro drug release study; in vivo behavioral, and biochemical and maximum tolerated dose (MTD) study. The optimized formulation evidenced a significant reversal of scopolamine-induced amnesia by Tween 80(®) coated nanoparticles as compared to both pure RT as well as uncoated nanoparticles. The MTD of RT was increased by 10% by formulating them as cRTNP. Thus, formulation of RT as cRTNP improved the therapeutic and safety profile of RT.

Evaluation of safety and efficacy of brain targeted chitosan nanoparticles of minocycline.

The aim of present study was to evaluate the antidepressant-like effects of minocycline hydrochloride (MH); enhance this effect using nanoparticulate drug delivery system; and further evaluate their safety by determining maximum tolerated dose (MTD). Pure drug MH, MH loaded nanoparticles (MHNP) and Tween 80(®) coated MH encapsulated nanoparticles (cMHNP) were explored for antidepressant-like activity in terms of immobility period using despair swim test (DST) and tail suspension test (TST) in mice (dose equivalent to 100mg/kg MH, i.p.). For MTD determination, Wistar rats were treated with gradual increasing doses of MH and cMHNP orally for 28 consecutive days and observed for body weight, weight indices (WI), behavioral, biochemical and histopathological changes until MTD was found. In mice, MH treatment showed antidepressant-like activity and cMHNP treatment significantly improved this effect. On the other hand, no significant effect was observed for MHNP treated group. However, administration of MH in any case did not produce locomotor activation, suggesting that the antidepressant-like effects of MH may not be attributed to the enhanced locomotion. The MTD was found to be 319mg/kg for MH and 350mg/kg for cMHNP (350mg/kg). Thus surface modified nanoparticles (cMHNP) improved the therapeutic efficacy as well as safety of MH.

Nanoparticle mediated brain targeted delivery of gallic acid: in vivo behavioral and biochemical studies for protection against scopolamine-induced amnesia

Abstract Context: Gallic acid (GA) has well-documented antioxidant and CNS effects affecting glutathione, catalase and malonaldehyde levels in brain. Objective: This study was designed to evaluate the anti-amnesic activity of pure GA in scopolamine (SC)-induced amnesic models and to enhance its effects using Tween 80®-coated nanoparticles. Methods: GA-loaded chitosan nanoparticles (GANP) and corresponding Tween 80®-coated batch (cGANP) were formulated. Amnesia was induced by using SC (0.4 mg/kg, i.v.). GA, GANP, cGANP (dose equivalent to GA 10 mg/kg, i.p.) and positive control Piracetam (400 mg/kg, i.p.) were administered for successive 7 days to male Swiss albino mice. The in vivo pharmacodynamic study was performed using Morris water maze (MWM) and elevated plus maze (EPM) models; locomotor activity using photoactometer and brain acetyl cholinesterase (AChE) activity was also studied. Key findings: GA-treated mice exhibited significant decrease in transfer latency in the EPM test; increase in time spent in target quadrant in MWM and reduced AChE activity. GA significantly reversed SC-induced amnesic activity. There was no significant change in locomotor activity of the mice by GA and its nanoparticle formulations. These effects were significantly increased by the administration of cGANP compared with pure GA administration but no significant change was observed for GANP. Conclusion: GA possesses anti-amnesic activity by reversing the SC-induced amnesia which may be attributed to its anti-cholinesterase activity. Tween 80®-coated nanoparticle approach with improved brain targeting may serve as an effective approach to enhance its anti-amnesic effect.

Optimization of brain targeted gallic acid nanoparticles for improved antianxiety-like activity

Ligand coated nanoparticles may improve brain uptake of drugs. To formulate brain targeted nanoparticles of gallic acid (GA) for improving its antianxiety-like activity. The nanoparticles were prepared and optimized to minimize particle size and maximize percent drug entrapment efficiency using two factor three level (3(2)) central composite design. Pure GA, optimized ligand coated nanoparticles of GA (cGANP) and corresponding uncoated nanoparticles (GANP) were administered to Swiss albino mice for seven consecutive days and evaluated in vivo for their antianxiety-like activity. Behavioral studies revealed that cGANP significantly improved antianxiety-like activity in mice. The plasma nitrite level decreased with GA, GANP and cGANP (most pronounced for cGANP) treated group as compared to saline treated control group while no change in plasma corticosterone levels was observed in any treatment. The treatments (except alprazolam) did not show any significant effect on locomotor activity of mice. The antianxiety-like activity may be attributed to decreased plasma nitrite level and effect was improved by enhanced brain uptake of GA via ligand coated nanoparticles. Thus antianxiety-like activity of GA was significantly improved formulating it as ligand coated nanoparticles. On the other hand, no significant difference was observed between antianxiety-like activity by administration of pure GA and GANP.

Dissolution enhancement of glimepiride using modified gum karaya as a carrier.

Objective: The aim of present investigation is to enhance in vitro dissolution of poorly soluble drug glimepiride by preparing solid dispersions using modified gum karaya. Materials and Methods: Solid dispersions of drug were prepared by solvent evaporation method using modified gum karaya as carrier. Four batches of solid dispersion (SD1, SD4, SD9, and SD14) and physical mixture (PM1, PM4, PM9, and PM14) were prepared and characterized by differential scanning colorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, powder X-Ray diffraction (X-RD), and scanning electron microscopy (SEM) studies. Equilibrium solubility studies were carried out in shaker incubator for 24 h and in vitro drug release was determined using USP Dissolution Apparatus-II. Results: Maximum solubility and in vitro dissolution were observed with Batch SD4. No significant enhancement of dissolution characteristics were observed in the corresponding physical mixture PM4. Low viscosity with comparable swelling characteristics as compared to GK of modified form of gum karaya may lead to improvement in dissolution behavior of solid dispersion batches. Also, the conversion of crystalline form of drug to amorphous form may be a responsible factor, which was further confirmed by DSC, FTIR studies, and X-RD studies. SEM photographs of batch SD4 revealed porous nature of particle surface. Conclusion: Modified forms of natural carriers prove beneficial in dissolution enhancement of poorly soluble drugs and exhibited a great potential in novel drug delivery systems.

Influence of the formulation on the maximum tolerated doses of brain targeted nanoparticles of gallic acid by oral administration in Wistar rats

The objective of the present investigation was to study the effect of pure gallic acid (GA) and its Tween 80 coated chitosan nanoparticles (cGANP) on the maximum tolerated dose (MTD) using Wistar rats.

Minocycline encapsulated chitosan nanoparticles for central antinociceptive activity.

The purpose of the study is to explore the central anti-nociceptive activity of brain targeted nanoparticles (NP) of minocycline hydrochloride (MH). The NP were formulated using the modified ionotropic gelation method (MHNP) and were coated with Tween 80 (T80) to target them to brain (cMHNP). The formulated nanoparticles have already been characterized for particle size, zeta potential, drug entrapment efficiency and in vitro drug release. The nanoparticles were then evaluated for pharmacodynamic activity using thermal methods. The pure drug and the formulation, MHNP were not able to show a statistically significant central analgesic activity. cMHNP on the other hand evidenced a significant central analgesic activity. Animal models evidenced that brain targeted nanoparticles may be utilized for effective delivery of central anti-nociceptive effect of MH. Further clinical studies are required to explore the activity for mankind.