The aim of this study was to develop a proliposomal formulation of lipopeptide antibiotic drug daptomycin (DAP) for oral delivery. Thin film hydration was the selected method for preparation of proliposomes. Different phospholipids including soy-phosphatidylcholine (SPC), hydrogenated egg-phosphatidylcholine (HEPC), and distearoyl-phosphatidylcholine (DSPC) were evaluated in combination with cholesterol. The inclusion of surface charge modifiers in the formulation such as dicetyl phosphate (DCP) and stearylamine (SA) to enhance drug encapsulation was also evaluated. Particle size, surface charge, and encapsulation efficiency were performed on daptomycin-hydrated proliposomes as part of physical characterization. USP type II dissolution apparatus with phosphate buffer (pH 6.8) was used for in vitro drug release studies. Optimized formulation was evaluated for in vivo pharmacokinetics after oral administration to Sprague-Dawley rats. Proliposomes composed of SPC exhibited higher entrapment efficiency than those containing HEPC or DSPC. The highest entrapment efficiency was achieved by positively charged SPC-SA proliposomes, showing an encapsulation efficiency of 92% and a zeta potential of + 28 mV. In vitro drug release of optimized formulation demonstrated efficient drug retention totaling for less than 20% drug release within the first 60 min and only 42% drug release after 2 h. Pharmacokinetic parameters after single oral administration of optimized proliposomal formulation indicated a significant increase in oral bioavailability of DAP administered as SPC-SA proliposomes when compared to drug solution. Based on these results, incorporation of charge modifiers into proliposomes may increase drug loading and proliposomes an attractive carrier for oral delivery of daptomycin.

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Celastrol (CL), a bioactive compound isolated from Tripterygium wilfordii, has demonstrated bioactivities against a variety of diseases including cancer and obesity. However, its poor water solubility and rapid in vivo clearance limit its clinical applications. To overcome these limitations, nanotechnology has been employed to improve its pharmacokinetic properties. Nanoparticles made of biological materials offer minimal adverse effects while maintaining the efficacy of encapsulated therapeutics. Silk fibroin (SF) solution was prepared successfully by extraction from the cocoons of silkworms, and a final concentration of 2 mg/mL SF solution was used for the preparation of CL-loaded SF nanoparticles (CL-SFNP) by the desolvation method. A stirring speed of 750 rpm and storage time of 20 h at −20 °C resulted in optimized product yield. A high-performance liquid chromatography (HPLC) method was developed and validated for the analysis of CL in rat plasma in terms of selectivity, linearity, intra-/inter-day precision and accuracy, and recovery. No interference was observed in rat plasma. Linearity in the concentration range of 0.05–5 µg/mL was observed with R2 of 0.999. Precision and accuracy values were below the limit of acceptance criteria, i.e., 15% for quality control (QC) samples and 20% for lower limit of quantification (LLOQ) samples. Rats were given intravenous (IV) administration of 1 mg/kg of pure CL in PEG 300 solution or CL-SFNP. The pharmacokinetic profile was improved with CL-SFNP compared to pure CL. Pure CL resulted in a maximum concentration (Cmax) value of 0.17 µg mL−1 at 5 min following administration, whereas that for CL-SFNP was 0.87 µg mL−1 and the extrapolated initial concentrations (C0) were 0.25 and 1.09 µg mL−1, respectively, for pure CL and CL-SFNP. A 2.4-fold increase in total area under the curve (AUC0-inf) (µg h mL−1) was observed with CL-SFNP when compared with pure CL. CL-SFNP demonstrated longer mean residence time (MRT; 0.67 h) than pure CL (0.26 h). In conclusion, the preparation of CL-SFNP was optimized and the formulation demonstrated improved pharmacokinetic properties compared to CL in solution following IV administration.

An accurate, highly sensitive, and precise method for quantitative analysis of tramadol (TMD) and gabapentin (GBP) by high performance liquid chromatography and tandem mass spectrometry in human plasma was proposed and validated successfully using venlafaxine and pregabalin as internal standards (ISTDs), respectively. An aliquot of 200 μL of plasma was mixed with internal standard dilution and extraction was performed by using solid phase extraction (SPE) technique. Peak resolution was achieved on Phenomenex PFP column (50×4.6 mm, 2.6 μm). The total analytical run time was 3.8 min. Both analytes were monitored using multiple reaction monitoring (MRM) scan and the mass spectrometer was operated in positive polarity mode. The method was validated for specificity, sensitivity, precision, accuracy, and other analytical parameters. The results found were satisfactory over the linear calibration range of 1-500 ng/mL and 10-6000 ng/mL for TMD and GBP, respectively. The developed method can be ready to use by scientific community for quantification of analytes in plasma samples from various clinical studies of different dose strengths.

Abstract:The objective of this paper was to describe the development and validation of a novel liquid chromatography / tandem mass spectrometry (LC-MS/MS) method for the determination of Febuxostat in human plasma using febuxostat-d9 as internal standard (IS). An API-4000 triple quadrupole mass spectrometer operated in MRM mode was used for the selective quantification of Febuxostat in human plasma. Sample extraction utilizes protein precipitation (PP), followed by analyte and the IS were chromatographed on a C18 column using an isocratic mobile phase composed of 5mM ammonium formate and acetonitrile (20:80, v/v) pumped at a flow rate of 1.0 mL/min. Precision and accuracy of the method was determined using five analytical batches in the concentration range of 15.0-8000 ng/mL. All the validation experiments were carried out as per the US FDA guidelines and results met the acceptance criteria. The developed method was rapid with a total chromatographic run time of 2.0 min.