The development of folate-PAMAM dendrimer conjugates for targeted delivery of anti-arthritic drugs and their pharmacokinetics and biodistribution in arthritic rats.

The aim of this study was to synthesize folate-dendrimer conjugates as suitable vehicle for site specific delivery of anti-arthritic drug (indomethacin) to inflammatory regions and to determine its targeting efficiency, biodistribution in adjuvant induced arthritic rats. Folic acid was coupled to the surface amino groups of G4-PAMAM dendrimer (G4D) via a carbodiimide reaction and loaded with indomethacin. The conjugates were characterized by (1)H-NMR and IR spectroscopy. The drug content and percent encapsulation efficiency increased with increasing folate content for the dendrimer conjugates. The in vitro release rate was decreased for the folate conjugates when compared with unconjugated dendrimer (DNI). The plasma concentration profile showed a biphasic curve indicating rapid distribution followed by slow elimination. The AUC(0-infinity), half-life and residence time of indomethacin in inflamed paw was higher for folate-dendrimer conjugates. The time-averaged relative drug exposure (r(e)) of the drug in paw and overall drug targeting efficiency (T(e)) were higher for folate conjugate with 21 folate moieties (4.1 and 2.78, respectively) when compared with DNI (1.91 and 1.88, respectively). This study demonstrated the superiority of active targeting over dendrimer mediated passive targeting and also for the first time, folate-mediated targeting of an anti-arthritic drug to the inflammatory tissues.

Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery.

Folate receptor is overexpressed on the activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring rheumatoid arthritis. The aim of this study was to prepare folate targeted poly(ethylene glycol) (PEG) conjugates of anionic dendrimer (G3.5 PAMAM) as targeted drug delivery systems to inflammation and to investigate its biodistribution pattern in arthritic rats. Folate-PEG-PAMAM conjugates, with different degrees of substitution were synthesized by a two-step reaction through a carbodiimide-mediated coupling reaction and loaded with indomethacin. Folate-PEG conjugation increased the drug loading efficiency by 10- to 20-fold and the in vitro release profile indicated controlled release of drug. The plasma pharmacokinetic parameters indicated an increased AUC, circulatory half-life and mean residence time for the folate-PEG conjugates. The tissue distribution studies revealed significantly lesser uptake by stomach for the folate-PEG conjugates, thereby limiting gastric-related side effect. The time-averaged relative drug exposure (r(e)) of the drug in paw for the folate-PEG conjugates ranged from 1.81 to 2.37. The overall drug targeting efficiency (T(e)) was highest for folate-PEG conjugate (3.44) when compared to native dendrimer (1.72). The folate-PEG-PAMAM conjugates are the ideal choice for targeted delivery of antiarthritic drugs to inflammation with reduced side-effects and higher targeting efficiency.

Development and evaluation of nitrendipine loaded solid lipid nanoparticles: influence of wax and glyceride lipids on plasma pharmacokinetics.

Nitrendipine is an antihypertensive drug with poor oral bioavailability ranging from 10 to 20% due to the first pass metabolism. For improving the oral bioavailability of nitrendipine, nitrendipine loaded solid lipid nanoparticles have been developed using triglyceride (tripalmitin), monoglyceride (glyceryl monostearate) and wax (cetyl palmitate). Poloxamer 188 was used as surfactant. Hot homogenization of melted lipids and aqueous phase followed by ultrasonication at temperature above the melting point of lipid was used to prepare SLN dispersions. SLN were characterized for particle size, zeta potential, entrapment efficiency and crystallinity of lipid and drug. In vitro release studies were performed in phosphate buffer of pH 6.8 using Franz diffusion cell. Pharmacokinetics of nitrendipine loaded solid lipid nanoparticles after intraduodenal administration to conscious male Wistar rats was studied. Bioavailability of nitrendipine was increased three- to four-fold after intraduodenal administration compared to that of nitrendipine suspension. The obtained results are indicative of solid lipid nanoparticles as carriers for improving the bioavailability of lipophilic drugs such as nitrendipine by minimizing first pass metabolism.

Novel approach for delivery of insulin loaded poly(lactide-co-glycolide) nanoparticles using a combination of stabilizers.

Insulin stability during microencapsulation and subsequent release is essential for retaining its biological activity. The successful delivery of insulin relies on the proper selection of stabilizers in addition to other parameters. Attempts were made to address the problem with a few combination of stabilizers for maintaining the integrity of insulin during formulation and delivery. Insulin loaded nanoparticles with different stabilizers such as pluronic F68, trehalose, and sodium bicarbonate were prepared by the double emulsion evaporation method using two different copolymer ratios of poly(DL-lactide-co-glycolide) (50:50 and 85:15). The presence of stabilizers in the nanoparticles resulted in an increase in the particle size but a reduction of encapsulation efficiency. Insulin release rate was comparatively higher for the batches containing stabilizers when compared with controls for both the copolymer ratios. Also the presence of stabilizers resulted in sustained release of insulin resulting in prolonged reduction of blood glucose levels in streptozotocin induced diabetic rats. From the in vitro and in vivo studies, we concluded that a combination of stabilizers results in beneficial effects without compromising the advantages of delivery systems.

A rapid, sensitive and validated method for the determination of ondansetron in human plasma by reversed-phase high-pressure liquid chromatography.

A simple and sensitive method for the determination of ondansetron (CAS 116002-70-1) in human plasma was developed using high-pressure liquid chromatography (HPLC). The procedure involves extraction of human plasma with tertiary butyl methyl ether containing 2 mol/l sodium hydroxide, followed by reversed-phase HPLC using a LiChrospher 100 RP-18e 5 microm column and UV detection at 305 nm. The retention times of ondansetron and internal standard (propranolol hydrochloride, CAS 318-98-9) were 9.38 and 13.40 min, respectively. The calibration curves were linear over the range of 10 ng/ml (lower limit of quantitation, LOQ) and 380 ng/ml for ondansetron. The intra- and inter-assay coefficients of variation for all the criteria of validation were less than 15% over the linearity range. Ondansetron was stable upon storage in human plasma. The sensitivity and precision of the method were within the accepted limits (< 15 %) throughout the validation period. The present method is useful for determination of plasma concentrations of ondansetron during human pharmacokinetic studies.