Proliposomes for enhanced oral bioavailability of BCS class II drugs

Abstract

Purpose. The aim of this study was to develop a simple preparation method of proliposomes (PLs) with a high lipid content, and to characterize and evaluate the BCS class II drug-loaded PLs (valsartan-loaded PLs (VSTPLs) and celecoxib-loaded PLs (CXBPLs)) in vitro and in vivo for their suitability for oral delivery. Methods. Rotary evaporator and freeze dryer were used to prepare PLs. Maximum lipid contents of PLs which can form liposomes after reconstitution were determined. After loading drugs, the solid state of PLs was also characterized by scanning electron microscopy (SEM), powder X-ray diffractometer (PXRD) and differential scanning calorimetry (DSC). PLs were reconstituted with distilled water, and then were characterized by measuring the particle size, zeta potential, entrapment efficiency (EE), and drug content. Particle morphology of reconstituted liposomes was determined by transmission electron microscopy (TEM). In vitro dissolution and in vivo pharmacokinetics of PLs in rats were also evaluated. Results. Phospholipid content of the PLs was increased up to 20% (w/w), thereby being able to enhance the drug loading content. Crystalline state of the drug was transformed to amorphous state during the preparation of PLs. Particle size of reconstituted VST-loaded liposomes and CXB-loaded liposomes were 369 ± 31 nm and 537 ± 10 nm with the zeta potential of -57.4 ± 0.4 mV and –64.2 ± 0.3 mV, respectively. The EE values of VST and CXB were 77.5 ± 2.8% and 84.7 ± 1.2% for VST-loaded liposomes and CXB-loaded liposomes, respectively. The rate and extent of dissolution of drugs from the PLs were higher than those of crude drug powder in various pHs. In pharmacokinetic studies after oral administration in rats, drugs in PLs showed higher Cmax values and 1.82-fold and 1.73-fold higher AUC values for VSTPLs and CXBPLs, respectively, than those from the drug powder. Shorter Tmax was shown in CXBPLs than that of crude drug powder. Conclusions. The preparation method of PLs developed in this study has the following advantages compared with conventional preparation methods: (a) the preparation method is simple and could be easily scaled up, (b) the solvent system used has no toxicity concern, (c) the PLs have a higher lipid content, which can enhance the incorporation of poorly water-soluble drugs, (d) the rapid formation of liposomes in aqueous media and the amorphous state of the drug in PLs can increase solubility and dissolution rate, thereby increase oral bioavailability of the drug.