The histone deacetylase inhibitor suberoylanilide hydroxamic acid, known as vorinostat, is a promising anti-cancer drug with a unique mode of action; however, it is plagued by low water solubility, low permeability, and suboptimal pharmacokinetics. In this study, poly(ethylene glycol)-b-poly(DL-lactic acid) (PEG-b-PLA) micelles of vorinostat were developed. Vorinostat’s pharmacokinetics in rats were investigated after intravenous (i.v.) (10 mg/kg) and oral (50 mg/kg) micellar administrations and compared to a conventional PEG400 solution and methylcellulose suspension. The micelles increased the aqueous solubility of vorinostat from 0.2 mg/ml to 8.15 ± 0.60 mg/ml and 10.24 ± 0.92 mg/ml at drug to nanocarrier ratios of 1:10 and 1:15, respectively. Micelles had nanoscopic mean diameters of 75.67 ± 7.57 nm and 87.33 ± 8.62 nm for 1:10 and 1:15 micelles, respectively, with drug loading capacities of 9.93 ± 0.21% and 6.91 ± 1.19 %, and encapsulation efficiencies of 42.74 ± 1.67% and 73.29 ± 4.78%, respectively. The micelles provided sustained exposure and improved pharmacokinetics characterized by a significant increase in serum half-life, area under curve, and mean residence time. The micelles reduced vorinostat clearance particularly after i.v. dosing. Thus, PEG-b-PLA micelles significantly improved the oral and intravenous pharmacokinetics and bioavailability of vorinostat, which warrants further investigation.

Abstract. Effects of tromethamine (Tris), polyvinylpyrrolidone (PVP-K25), and low molecular weight chitosan (LM-CH) on dissolution and therapeutic efficacy of glimepiride (Gmp) were investigated using physical mixtures (PMs), coground mixtures, coprecipitates (Coppts) or kneaded mixtures (KMs), and compared with drug alone. Fourier transform infrared spectroscopy, differential scanning colorimetry, and X-ray diffractometry were performed to identify any physicochemical interaction with Gmp. Surface morphology was examined via scanning electron microscopy. The results of Gmp in vitro dissolution revealed that it was greatly enhanced by Coppt with Tris or PVP-K25 and KM with LM-CH at a drug to carrier ratio of 1:8. Gmp amorphization by PVP-K25 and LM-CH was a major factor in increasing Gmp dissolution. Being basic, Tris might increase the pH of the microdiffusion layer around Gmp particles improving its dissolution. Formation of water-soluble complexes suggested by solubility study may also explain the enhanced dissolution. Capsules were prepared from Coppts and KM 1:8 drug to carrier binary systems and also with Tris PMs. In vivo, the hypoglycemic efficacy of Gmp capsules in rabbits increased by 1.63-, 1.50-, and 1.46-fold for 1:8 Coppts with Tris or PVP-K25 and KM with LM-CH respectively, compared with Gmp alone. Surprisingly, the response to Tris PM 1:20 capsules was 1.52-fold revealing statistically insignificant difference to that of Tris Coppt 1:8 (1.63 fold). As a conclusion, dissolution enhancement and hypoglycemic potentiation by 1:20 PM of Gmp/Tris, being simple and easy to prepare, may enable development of a reduced-dose and fast-release oral dosage form of Gmp.

The utility of currently reported liquid chromatography mass spectrometry methods for quantitation of vorinostat in plasma or serum may be limited. These methods employ time consuming and expensive procedures such as solid phase extraction or limited-access techniques such as high turbulence liquid chromatography coupled with column switching. This study offers a simple isocratic LC/MS method validated for determination of vorinostat in both rat serum and urine. Proteins were precipitated from serum using ice-cold acetonitrile and daidzein was used as internal standard. Separation was achieved using a Phenomenex ® Luna ® C 18 (2) (5 µm, 250 x 4.60 mm) column and isocratic elution with a mobile phase consisting of acetonitrile, water, and formic acid (30:70:0.1, v/v/v). Mass spectrometry detection using electrospray positive-mode ionization with selected ion monitoring detection was employed. The calibration curves were linear ranging from 0.05 to 50 µg/ml in serum and from 0.5 to 25 µg/ml in urine. In both biological matrices, assay precision was <15% (RSD) and the intra-and inter-run bias were within acceptable range (-15% to 15%). No degradation of vorinostat in either matrix was found following three freeze-thaw cycles and 24 h storage in the auto-injector. The lower limit of quantitation in rat serum and urine were 0.05 and 0.5 µg/ml, respectively. The upper limit of quantitation in rat serum and urine were 50 and 25 µg/ml, respectively. This assay was applied successfully to a pre-clinical study of vorinostat pharmacokinetics in rats.

No abstract