Development of novel docetaxel-loaded double-reverse thermoreversible system for intramuscular treatment

Abstract

The primary aim of this study was to develop novel solid lipid nanoparticle (SLN)-loaded dual-reverse thermoreversible system (DRTS) for intramuscular administration of docetaxel (DCT) with sustained release. The DCT-loaded SLN was prepared by homogenization and membrane emulsification technique, after optimizing the amounts of lipid mixture (tricaprin and tricaprylin), drug and surfactant. The DCT-loaded thermosensitive SLN composed of drug, lipid mixture and surfactant at a weight ratio of 0.3/1.4/0.6 was a solid at room temperature, and changed to liquid form at physiological temperature due to its melting point of about 32 °C. This SLN gave the mean particle size of about 157 nm and entrapment efficiency of around 93%. The DRTSs were prepared by adding various amounts of poloxamer mixtures in the DCT-loaded thermosensitive SLN dispersion, and their rheological characterizations were investigated. The mixture of poloxamer 188 (P 188) and poloxamer 407 (P 407) decreased the gelation temperature and gelation time, but increased the viscosity at 25 °C and gel strength of DRTS. In particular, the DRTS composed of [SLN/P 188/P 407 (2.3/7.5/6.5%)] with the gelation temperature of about 33 °C existed as liquid at room temperature, but gelled at 30-36 oC, leading to opposite reversible property of SLN. Thus, it was easy to administer intramuscularly, and it gelled rapidly inside the body. After evaluation of its gel properties, release test and pharmacokinetic study of this DRTS were performed after its intramuscular administration to rats compared with the suspension and hydrogel. The DRTS gave a significantly increased dissolution rate of the drug as compared to the suspension, but significantly retarded as compared to the hydrogel in the release test. In animal experiments, this DRTS gave significantly higher plasma concentration and 3.2-fold AUC values compared to the suspension, but lower initial plasma concentration and Cmax value compared to the hydrogel due to reduced initial burst effect. Therefore, it can be concluded that the DCT-DRTS was successfully developed as a prospective intramuscular formulation of docetaxel with particles in nano size, excellent double reverse thermosensitive effect and diminished burst effect.