Shailendra Kumar Singh

Supercritical fluid technology: a promising approach in pharmaceutical research

Supercritical fluids possess the unique properties of behaving like liquids and gases, above their critical point. Supercritical fluid technology has recently emerged as a green and novel technique for various processes such as solubility enhancement of poorly soluble drugs, plasticization of polymers, surface modification, nanosizing and nanocrystal modification, and chromatographic extraction. Research interest in this area has been fuelled because of the numerous advantages that the technology offers over the conventional methods. This work aims to review the merits, demerits, and various processes such as rapid expansion of supercritical solutions (RESS), particles from gas saturated solutions (PGSS), gas antisolvent process (GAS), supercritical antisolvent process (SAS) and polymerization induced phase separation (PIPS), that have enabled this technology to considerably raise the interest of researchers over the past two decades. An insight has been given into the numerous applications of this technology in pharmaceutical industry and the future challenges which must be appropriately dealt with to make it effective on a commercial scale.

Drug targeting to brain: a systematic approach to study the factors, parameters and approaches for prediction of permeability of drugs across BBB

Introduction: Drug targeting to brain by circumventing the physiological barriers is a prerequisite for drugs acting on central nervous system (CNS) and therapeutic potential of many drugs can be improved by effectively targeting the drug(s) to brain. Areas covered: Present review describes blood–brain barrier (BBB), drug transport mechanisms and factors affecting drug transportation across BBB along with in vitro BBB models; and the approaches for evaluation of permeability of drug across BBB. Expert opinion: The development of a still awaited perfect in vitro model to mimic BBB is a challenging task. System biologist, network biologist and computational technologist should come together to integrate the role of transporters, physiological and pathophysiological complexity of BBB to replicate vascular properties of the brain microcapillaries as a suitable model to facilitate the high-throughput screening of CNS acting biomolecules.

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.

Sumatriptan succinate loaded chitosan solid lipid nanoparticles for enhanced anti-migraine potential.

The objective of the present investigation was to prepare chitosan solid lipid nanoparticles (SLN), containing sumatriptan succinate using solvent injection method and to optimize the formulations for brain targeting potential. The formulation optimization was performed using three factor two level full factorial design so as to minimize the particle size and zeta potential, maximize the entrapment efficiency as well as maximize the concentration of drug in brain with maximized brain/plasma ratio of the drug. The particle size, zeta potential and entrapment efficiency for all the batches were in the range of 192-301.4nm, 30.2-51.4mV and 76.3-91.1% respectively. The optimized formulation showed a 4.54-fold increase in brain/blood ratio of drug after 2h of drug administration in male Wistar rats. The optimized nanoparticles were characterized by FT-IR spectroscopy, DSC, TGA, powder X-ray diffraction study and TEM analysis. It could be elucidated from the experimental in vivo and behavioral studies that the formulations successfully crossed the blood brain barrier and significantly exhibited its anti-migraine activity. Present investigation indicated that the hydrophilic drug sumatriptan succinate, loaded in chitosan SLN, can be successfully targeted to brain via oral delivery and thus present an effective approach for the therapeutic management of migraine.

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.

Development of zolmitriptan loaded PLGA/poloxamer nanoparticles for migraine using quality by design approach.

The purpose of this investigation was to develop Poly (D,L Lactide-co-Glycolide) (PLGA)/poloxamer nanoparticles (NPs) of the hydrophilic drug Zolmitriptan using quality-by-design approach for brain targeting. Randomized 2(4) full factorial design was employed to achieve the critical quality attributes of minimized particle size and maximized encapsulation efficiency. The PLGA/poloxamer NPs were fabricated using modified double emulsion solvent diffusion technique and particle size varied from 165.4-245.4 nm, encapsulation efficiency was in the range of 48.96-95.97% and percent cumulative drug release varied from 43.32 to 100%. The optimized nanoparticles were characterized by FTIR spectroscopy and powder X-ray diffraction technique which indicated the loading of drug in NPs without any chemical interactions between drug and the excipients. The uniform and spherical shape of the particles was affirmed from TEM analysis. The in-vivo studies for determination of brain uptake potential demonstrated a 14.13 fold increase in drug delivered to brain from the NPs as compared to the free drug. The pharmacodynamic studies involving Swiss albino mice further confirmed successful delivery of drug to brain circumventing the blood brain barrier, through significantly enhanced anti-migraine potential. This investigation thus presents the suitability of zolmitriptan loaded PLGA/poloxamer NPs in brain targeting for the efficient treatment of migraine.

Targeting silymarin for improved hepatoprotective activity through chitosan nanoparticles

Introduction: Silymarin is one of the best known hepatoprotective drugs, which is obtained from the seeds of Silybum marianum L., Family: Asteraceae or Compositae. The plant has traditionally been used for centuries as a natural remedy for liver and biliary tract diseases. The aim of the present investigation was to enhance the hepatoprotective activity of silymarin by incorporating it in chitosan (Ch) nanoparticles (NPs) for passive targeted delivery, thereby prolonging its retention time. Materials and Methods: Silymarin loaded NPs were prepared by ionic gelation technique, which were then optimized using a central composite design in order to minimize the particle size and maximize the drug entrapment efficiency. The optimized formulation was evaluated for in vitro drug release study and in vitro study on Swiss Albino mice using carbon tetrachloride (CCL4) induced hepatotoxicity model. Results: In vitro dissolution studies illustrated sustained, zero order drug release from optimized formulation; also its therapeutic potential was amplified during in vitro studies on Swiss Albino mice using CCL4 induced hepatotoxicity model. Conclusion: The results suggested that NPs of silymarin could successfully enhance its hepatoprotective effect by passive targeting and sustained release.

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.