Preparation, characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting.

OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder manifested by cognitive, memory deterioration and variety of neuropsychiatric symptoms. Donepezil is a reversible cholinesterase inhibitor used for the treatment of AD. The purpose of this work is to prepare a nanoparticulate drug delivery system of donepezil using poly(lactic-co-glycolic acid) (PLGA) for sustained release and efficient brain targeting. MATERIALS AND METHODS: PLGA nanoparticles (NPs) were prepared by the solvent emulsification diffusion-evaporation technique and characterized for particle size, particle-size distribution, zeta potential, entrapment efficiency, drug loading and interaction studies and in vivo studies using gamma scintigraphy techniques. RESULTS AND DISCUSSION: The size of drug-loaded NPs (drug polymer ratio 1:1) was found to be 89.67 ± 6.43 nm. The TEM and SEM images of the formulation suggested that particle size was within 20-100 nm and spherical in shape, smooth morphology and coating of Tween-80 on the NPs was clearly observed. The release behavior of donepezil exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous sustained release. The biodistribution studies of donepezil-loaded PLGA NPs and drug solution via intravenous route revealed higher percentage of radioactivity per gram in the brain for the nanoparticulate formulation as compared with the drug solution (p < 0.05). CONCLUSION: The high concentrations of donepezil uptake in brain due to coated NPs may help in a significant improvement for treating AD. But further, more extensive clinical studies are needed to check and confirm the efficacy of the prepared drug delivery system.

Nanosizing of valsartan by high pressure homogenization to produce dissolution enhanced nanosuspension: pharmacokinetics and pharmacodyanamic study.

PURPOSE: The purpose of the present study was to formulate and evaluate nanosuspension of Valsartan (VAL), a poorly water soluble and low bioavailable drug (solubility of 0.18 mg mL(-1); 23% of oral bioavailability) with the aim of improving the aqueous solubility thus the bioavailability and consequently better anti-hypertensive activity. METHODS: Valsartan nanosuspension (VAL-NS) was prepared using high-pressure homogenization followed by lyophilisation. The screening of homogenization factors influencing nanosuspension was done by 3-factorial, 3-level Box-Behnken statistical design. Model suggested the influential role of homogenization pressure and cycles on drug nanosizing. The optimized formulation containing Poloxamer(-1)88 (PXM 188) was homogenized for 2 cycles at 500 and 1000 bar, followed by 5 cycles at 1500 bars. RESULTS: The size analysis and transmission electron microscopy showed nanometric size range and uniform shape of the nanosuspension. The in vitro dissolution showed an enhanced release of VAL from nanosuspension (VAL-NS) compared to physical mixture with PXM 188. Pharmacodynamic results showed that, oral administration of VAL-NS significantly lowered (p ≤ 0.001) blood pressure in comparison to non-homogenized VAL (VAL-Susp) in Wistar rat. The level of VAL in rat plasma treated with VAL-NS showed significant difference (p ≤ 0.005) in Cmax (1627.47 ± 112.05 ng mL(-1)), Tmax (2.00 h) and AUC0→24 (13279.2 ± 589.426 ng h mL(-1)) compared to VAL-Susp that was found to be 1384.73 ± 98.76 ng mL(-1), 3.00 h and 9416.24 ± 218.48 ng h mL(-1) respectively. The lower Tmax value, proved the enhanced dissolution rate of VAL. CONCLUSION: The overall results proved that newly developed VAL-NS increased the plasma bioavailability and pharmacodyanamic potential over the reference formulation containing crude VAL.

Development and evaluation of brain targeted intranasal alginate nanoparticles for treatment of depression.

The purpose of the present study was to investigate the potential of Venlafaxine loaded alginate nanoparticles (VLF AG-NPs) for treatment of depression via intranasal (i.n.) nose to brain delivery route. The VLF AG-NPs were prepared and optimized on the basis of various physio-chemical characteristics. Pharmacodynamic studies of the VLF AG-NPs for antidepressant activity were carried in-vivo by forced swimming test and locomotor activity test on albino Wistar rats. VLF AG-NPsi.n. treatment significantly improved the behavioural analysis parameters i.e. swimming, climbing, and immobility in comparison to the VLF solutioni.n. and VLF tabletoral. The intranasal VLF AG-NPs also improved locomotor activity when compared with VLF solutioni.n. and VLF tabletoral. Confocal laser scanning fluorescence microscopy studies were performed on isolated organs of rats after intravenous and intranasal administrations of Rodamine-123 loaded alginate nanoparticles to determine its efficacy for nose to brain delivery and also for its qualitative distribution to other organs. Brain uptake and pharmacokinetic studies were performed by determination of VLF concentration in blood and brain respectively for VLF AG-NPsi.n., VLF solutioni.n. and VLF solutioni.v. The greater brain/blood ratios for VLF AG-NPsi.n. in comparison to VLF solutioni.n. and VLF solutioni.v. respectively at 30 min are indicative of superiority of alginate nanoparticles for direct nose to brain transport of VLF. Thus, VLF AG-NPsi.n. delivered greater VLF to the brain in comparison to VLF solution which indicates that VLF AG-NPs could be a promising approach for the treatment of depression.

Neuronal uptake and neuroprotective effect of curcumin-loaded PLGA nanoparticles on the human SK-N-SH cell line.

Curcumin, a natural polyphenolic pigment present in the spice turmeric (Curcuma longa), is known to possess a pleiotropic activity such as antioxidant, anti-inflammatory, and anti-amyloid-ß activities. However, these benefits of curcumin are limited by its poor aqueous solubility and oral bioavailability. In the present study, a polymer-based nanoparticle approach has been utilized to deliver drugs to neuronal cells. Curcumin was encapsulated in biodegradable poly (lactide-co-glycolide) (PLGA) based-nanoparticulate formulation (Nps-Cur). Dynamic laser light scattering and transmission electronic microscopy analysis indicated a particle diameter ranging from 80 to 120 nm. The entrapment efficiency was 31% with 15% drug-loading. In vitro release kinetics of curcumin from Nps-Cur revealed a biphasic pattern with an initial exponential phase followed by a slow release phase. Cellular internalization of Nps-Cur was confirmed by fluorescence and confocal microscopy with a wide distribution of the fluorescence in the cytoplasm and within the nucleus. The prepared nanoformulation was characterized for cellular toxicity and biological activity. Cytotoxicity assays showed that void PLGA-nanoparticles (Nps) and curcumin-loaded PLGA nanoparticles (Nps-Cur) were nontoxic to human neuroblastoma SK-N-SH cells. Moreover, Nps-Cur was able to protect SK-N-SH cells against H2O2 and prevent the elevation of reactive oxygen species and the consumption of glutathione induced by H2O2. Interestingly, Nps-Cur was also able to prevent the induction of the redox-sensitive transcription factor Nrf2 in the presence of H2O2. Taken together, these results suggest that Nps-Cur could be a promising drug delivery strategy to protect neurons against oxidative damage as observed in Alzheimer's disease.

Nanostructured lipid carriers system: recent advances in drug delivery.

Nanostructured lipid carrier (NLC) is second generation smarter drug carrier system having solid matrix at room temperature. This carrier system is made up of physiological, biodegradable and biocompatible lipid materials and surfactants and is accepted by regulatory authorities for application in different drug delivery systems. The availability of many products in the market in short span of time reveals the success story of this delivery system. Since the introduction of the first product, around 30 NLC preparations are commercially available. NLC exhibit superior advantages over other colloidal carriers viz., nanoemulsions, polymeric nanoparticles, liposomes, SLN etc. and thus, have been explored to more extent in pharmaceutical technology. The whole set of unique advantages such as enhanced drug loading capacity, prevention of drug expulsion, leads to more flexibility for modulation of drug release and makes NLC versatile delivery system for various routes of administration. The present review gives insights on the definitions and characterization of NLC as colloidal carriers including the production techniques and suitable formulations. This review paper also highlights the importance of NLC in pharmaceutical applications for the various routes of drug delivery viz., topical, oral, pulmonary, ocular and parenteral administration and its future perspective as a pharmaceutical carrier.

Development and evaluation of rivastigmine loaded chitosan nanoparticles for brain targeting.

The rivastigmine (RHT) loaded chitosan nanoparticles (CS-RHT NPs) were prepared by ionic gelation method to improve the bioavailability and enhance the uptake of RHT to the brain via intranasal (i.n.) delivery. CS-RHT NPs were characterized for particles size, particle size distribution (PDI), encapsulation efficiency, zeta potential and in vitro release study. Nose-to-brain delivery of placebo nanoparticles (CS-NPs) was investigated by confocal laser scanning microscopy technique using rhodamine-123 as a marker. The brain/blood ratio of RHT for different formulations were 0.235, 0.790 and 1.712 of RHT (i.v.), RHT (i.n.), and CS-RHT NPs (i.n.) respectively at 30 min are indicative of direct nose to brain transport bypassing the BBB. The brain concentration achieved from i.n. administration of CS-NPs (966 ± 20.66 ng ml(-1); t(max) 60 min) was significantly higher than those achieved after i.v. administration of RHT sol (387 ± 29.51 ngml(-1); t(max) 30 min), and i.n. administration of RHT solution (508.66 ± 22.50 ng ml(-1); t(max) 60 min). The higher drug transport efficiency (355 ± 13.52%) and direct transport percentage (71.80 ± 6.71%) were found with CS-RHT NPs as compared to other formulation. These results suggest that CS-RHT NPs have better brain targeting efficiency and are a promising approach for i.n. delivery of RHT for the treatment and prevention of Alzheimer's disease (AD).

Venlafaxine loaded chitosan NPs for brain targeting: pharmacokinetic and pharmacodynamic evaluation.

The purpose of the present investigation was to prepare venlafaxine (VLF) loaded chitosan nanoparticles (NPs) to enhance the uptake of VLF to brain via intranasal (i.n.) delivery. VLF loaded chitosan NPs were prepared and characterized for particle size, size distribution, zeta potential, encapsulation efficiency and in vitro drug release. In order to investigate the localization of chitosan NPs in brain and other organs qualitatively confocal laser scanning microscopy technique was carried out using rhodamine-123 (ROD-123) as marker. The levels of VLF in plasma and brain tissues were also determined, the brain/blood ratios of VLF for VLF (i.v.), VLF (i.n.), VLF chitosan NPs (i.n.) were 0.0293, 0.0700 and 0.1612, respectively, at 0.5h, indicative of better brain uptake of VLF chitosan NPs. The higher drug transport efficiency (508.59) and direct transport percentage (80.34) of VLF chitosan NPs as compared to other formulations suggest its better efficacy in treatment of depression.

Neurotherapeutic applications of nanoparticles in Alzheimer's disease.

A rapid increase in incidence of neurodegenerative disorders has been observed with the aging of the population. Alzheimer's disease (AD) is the most common neurodegenerative disorder among the elderly. It is characterized by memory dysfunction, loss of lexical access, spatial and temporal disorientation and impairment of judgement clinically. Unfortunately, clinical development of drugs for the symptomatic and disease-modifying treatment of AD has resulted in both promise and disappointment. Indeed, a large number of drugs with differing targets and mechanisms of action were investigated with only a few of them being clinically available. The targeted drug delivery to the central nervous system (CNS), for the diagnosis and treatment of neurodegenerative disorders such as AD, is restricted due to the limitations posed by the blood-brain barrier (BBB) as well as due to opsonization by plasma proteins in the systemic circulation and peripheral side-effects. Over the last decade, nanoparticle-mediated drug delivery represents one promising strategy to successfully increase the CNS penetration of several therapeutic moieties. Different nanocarriers are being investigated to treat and diagnose AD by delivering at a constant rate a host of therapeutics over times extending up to days, weeks or even months. This review provides a concise incursion on the current pharmacotherapies for AD besides reviewing and discussing the literature on the different drug molecules that have been successfully encapsulated in nanoparticles (NPs). Some of them have been shown to cross the BBB and have been tested either for diagnosis or treatment of AD. Finally, the route of NPs administration and the future prospects will be discussed.

New non-oral drug delivery systems for Parkinson's disease treatment.

INTRODUCTION: Parkinson's disease (PD) remains the only neurodegenerative disorder for which there are highly effective symptomatic therapies, but still unmet needs regarding its long-term management. Levodopa (LD) remains the most effective treatment; however, chronic use is associated with potentially disabling motor complications. AREAS COVERED: This review highlights a variety of new non-oral drug delivery strategies for non-invasive and invasive routes of drug administration for the treatment of PD. It also includes current and future trends of liposomes, solid lipid nanoparticles and biocompatible microparticles as new non-oral drug delivery systems. EXPERT OPINION: The long-term complications and limitations of LD treatment might be improved by changing therapy from the present pulsatile stimulation to a more constant stimulation of central dopamine receptors. Stimulation of these receptors may be possible with a new non-oral drug delivery system, with the aim of achieving long-lasting and less fluctuating drug levels, minimization of peak levels and thereby reduction of side effects.