Degradation kinetics study of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) by a validated stability-indicating RP-HPLC method.

The chemical stability of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), a therapeutic agent for neutropenia, was investigated using a validated stability-indicating reversed phase high-performance liquid chromatographic (RP-HPLC) method. The forced degradation of PLAG was carried out under the stress conditions of hydrolysis (alkaline, acidic and various pH buffers), oxidation, photolysis and heat. A simple, sensitive, specific, robust, precise and accurate RP-HPLC method was developed and validated for evaluating the degradation kinetics of PLAG. The chromatographic validation of various parameters, such as system suitability, detection limit, quantification limit, linearity, accuracy, precision, specificity, robustness and stability, was achieved. The method was validated for linearity, accuracy and precision over the concentration range of 0.7813-100µg/mL (r2=0.9999). The proposed method provided excellent stability study of PLAG indicated by the resolution of degradation products from the drug. Degradation of PLAG provided first order kinetics under all experimental conditions. PLAG was catalysed more rapidly in alkaline and acidic conditions than in neutral conditions. PLAG was relatively stable in photolytic and oxidative conditions compared to hydrolysis and thermal conditions, although this drug was not also stable in these conditions. Exposed to high temperature, PLAG was more rapidly catalysed. The activation energy evaluated from the Arrhenius plot was about 110kJ/mol in the thermal conditions. Additionally, PLAG with a t1/2 of about 400h was very stable at room temperature. Therefore, PLAG was considerably influenced by alkaline and acidic hydrolysis, and thermal degradation.

Effect of inorganic mesoporous carriers on 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol-loaded solid self-emulsifying drug delivery system: Physicochemical characterization and bioavailability in rats.

The purpose of this study was to assess the impact of inorganic mesoporous carriers on the physicochemical properties and oral bioavailability of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG)-loaded solid self-emulsifying drug delivery system (solid SEDDS). Numerous PLAG-loaded solid SEDDS formulations were prepared by spray drying technique with sodium laurylsulfate (SLS), butylated hydroxyanisole (BHA) and inorganic mesoporous materials as a surfactant, antioxidant and solid carrier, respectively. The mesoporous materials, such as calcium silicate, silicon dioxide and magnesium aluminosilicate were used as the solid carriers. Their physicochemical properties, solubility, dissolution and pharmacokinetic studies in rats were performed compared with drug alone. Three solid SEDDSs composed of PLAG/BHA/SLS/mesopous carrier at the weight ratio of 1:0.0002:0.25:0.5 resulted in a small emulsion droplet and excellent drug loading efficiency. The solid SEDDS formulations prepared with calcium silicate and silicon dioxide showed a rough-surfaced irregular shape and rough-surfaced spheres, respectively. Magnesium aluminosilicate generated a sticky powder, due to its relatively low specific surface area, resulting in insufficient adsorption of PLAG. These solid SEDDSs improved the solubility, dissolution and oral bioavailability of PLAG. Ultimately, the solid SEDDS prepared with silicon dioxide resulted in the best drug loading efficiency, shape, solubility, dissolution and oral bioavailability due to its great specific surface area. Therefore, mesoporous carriers with different specific surface areas markedly influenced the physicochemical properties, solubility, dissolution and oral bioavailability of PLAG-loaded solid SEDDS.

A novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for improved stability and oral bioavailability of an oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol.

To develop a novel solid self-nanoemulsifying drug delivery system (S-SNEDDS) for a water-insoluble oily drug, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) with improved stability and oral bioavailability, numerous S-SNEDDS were prepared with surfactant, hydrophilic polymer, antioxidant, and calcium silicate (porous carrier) using the spray-drying method. Their physicochemical properties were evaluated using emulsion droplet size analysis, SEM and PXRD. Moreover, the solubility, dissolution, stability, and pharmacokinetics of the selected S-SNEDDS were assessed compared with the drug and a commercial soft capsule. Sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) with the highest drug solubility were selected as surfactant and hydrophilic polymer, respectively. Among the antioxidants tested, only butylated hydroxyanisole (BHA) could completely protect the drug from oxidative degradation. The S-SNEDDS composed of PLAG/SLS/HPMC/BHA/calcium silicate at a weight ratio of 1: 0.25: 0.1: 0.0002: 0.5 provided an emulsion droplet size of less than 300 nm. In this S-SNEDDS, the drug and other ingredients might exist in the pores of carrier and attach onto its surface. It considerably improved the drug stability (about 100 vs. 70%, 60 °C for 5 d) and dissolution (about 80 vs. 20% in 60 min) compared to the commercial soft capsule. Moreover, the S-SNEDDS gave higher AUC, Cmax, and Tmax values than the commercial soft capsule; in particular, the former improved the oral bioavailability of PLAG by about 3-fold. Our results suggested that this S-SNEDDS provided excellent stability and oral bioavailability of PLAG. Thus, this S-SNEDDS would be recommended as a powerful oral drug delivery system for an oily drug, PLAG.