Preparation and characterization of solid lipid nanoparticles containing silibinin.

The study describes the development of stealth solid lipid nanoparticles (SLNs) as colloidal carriers for silibinin, a drug with very low solubility. Stealth SLNs were constituted mainly of bioacceptable and biodegradable lipids, such as stearic acid and surfactant Brij 78 (polyoxyethylene 20 stearyl ether) and can incorporate amounts of silibinin up to 7.55%. Stealth-loaded SLNs were in the nanometer size range. Thermal analysis (differential scanning calorimetry) showed that silibinin was dispersed in the stealth SLNs at an amorphous state. Release of silibinin from stealth SLNs was very slow. Stealth SLNs were stable without precipitation of silibinin on storage conditions and can be proposed for their parenteral administration.

High-performance liquid chromatographic method for the estimation of the novel investigational anti-cancer agent SR271425 and its metabolites in mouse plasma.

A simple and reliable HPLC method was developed for the estimation of a new anti-cancer agent that belongs to the thioxanthone class, SR271425 in mouse plasma. SR271425, it's metabolites and internal standard (SR233377) were separated from plasma by liquid-liquid extraction using dichloromethane after quenching the plasma proteins with acetonitrile. Chromatography was performed on a reversed-phase C18 column using methanol-10 mM phosphate buffer, pH 3.5 (45:55) as mobile phase at a flow-rate of 0.8 ml/min for first 10 min and 1.4 ml/min for the next 15 min with UV-Vis detection at 264 nm and SR233377 as internal standard. The retention times of SR271425 and internal standard were 18.6 and 14.8 min, respectively. The limit of detection was 40 ng/ml and the limit of quantification was 78 ng/ml. This method was also able to detect the three metabolites of SR271425. The intra- and inter-day relative standard deviations were less than 13% at all concentrations. This analytical method was precise and reproducible for pharmacokinetics and metabolism studies of the drug in mice. SR271425 is proceeding to phase I clinical trials in 2001.

Permeability of antisense oligonucleotide through porcine buccal mucosa.

Antisense oligonucleotides (AONs) that can modulate malfunctioning genes have a great potential to become future therapeutic agents. In this study, we investigated the feasibility of buccal delivery of AONs using ISIS 3082 as a model compound. An isocratic HPLC method was developed to quantify ISIS 3082. The permeability coefficient of this AON at 37 degrees C, determined by using side-by-side diffusion cells, was 1.05x10(-9) (cm/s). The flux of ISIS 3082 across buccal mucosa was dependent upon its concentration in the donor chamber. The permeation of ISIS 3082 was increased when 100 mM of sodium glycocholate was used as a permeation enhancer. The potential of delivering AONs via buccal route with the aid of permeation enhancers is explored in this study.

Taxanes: an overview of the pharmacokinetics and pharmacodynamics.

Paclitaxel and docetaxel have emerged in the last two decades as effective antitumor agents in a variety of malignancies. Paclitaxel is a semisynthetic taxane isolated from bark of the Pacific yew tree. Docetaxel is a semisynthetic taxane derived from the needles of the European yew (Taxus baccata). These compounds bind to tubulin, leading to microtubule stabilization, mitotic arrest and, subsequently, cell death. Plasma clearance of paclitaxel exhibits nonlinear kinetics, which results in a disproportionate change in plasma concentration and area under the curve (AUC) with dose alterations. In contrast, docetaxel has a linear disposition over the dose ranges used clinically, so its concentration changes linearly with changes in the dosage. Premedicating with corticosteroids and histamine H1 and H2 receptor antagonists is advocated prior to paclitaxel administration; prior to docetaxel administration, premedication with corticosteroids is suggested. The taxanes are metabolized in the liver by the cytochrome P-450 enzymes and are eliminated in the bile. The known metabolites are either inactive or less potent than the parent compounds. The toxic effects associated with paclitaxel therapy are mainly neutropenia, peripheral neuropathy, and, rarely, cardiotoxicity. Docetaxel toxicity produces mainly myelosuppression and a cumulative dose fluid retention syndrome. Paclitaxel demonstrates sequence-dependent interactions with cisplatin, cyclophosphamide, and doxorubicin. Docetaxel has shown increased myelosuppression with preceding ifosfamide in a preliminary study. The future holds increasing indications for taxanes in newer combination regimens; consideration of their pharmacologic characteristics is an important aspect of designing and applying new taxane-based treatment regimens.

Fluorescence spectroscopic investigation of effect of excipients on epidermal barrier and transdermal systems.

Excipients are often used in transdermal formulations to overcome the formidable barrier offered by the epidermis in order to achieve the target flux. In this study we describe the use of frequency-domain fluorescence spectroscopy to characterize the effect of two commonly used excipients, propyleneglycol monolaurate (PGML) and oleic acid on stratum corneum and in a silicone-based transdermal delivery system. Fluorescence lifetime and limiting anisotropy for the probe 1,6-diphenyl-1,3,5-hexatriene in isolated human epidermis were measured as a function of formulation treatment. The drop in lifetime ranged from 0.5 to 2.3 ns, indicative of an increased dielectric constant of the lipophilic barrier exposed to all formulations. This increase is due to increased partitioning of the polar excipients from the delivery system into the stratum corneum. The limiting anisotropy showed a drop of 0.1 in the case of the epidermis exposed to oleic acid formulation and not the PGML formulations, indicative of the different modes of action for these two excipients. The fluorescence data suggested fluidization of the silicone matrix by both oleic acid and PGML. The dynamic fluorescence measurements described in this study are a powerful way to screen formulations while gaining valuable mechanistic insight into the mode of flux enhancement in transdermal formulations.