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Liquid crystal (LC) technology has attracted much interest for new injectable sustained-release (SR) formulations. In this study, an injectable liquid crystal-forming system (LCFS) including entecavir was prepared for the treatment of hepatitis B. In particular, an anchoring effect was introduced because LCFSs are relatively hydrophobic while entecavir is a slightly charged drug. The physicochemical properties of LCFSs were investigated by cryo-transmission electron microscopy (cryo-TEM), polarized optical microscopy, and small-angle X-ray scattering (SAXS), showing typical characteristics of the liquid crystalline phase, which was classified as the hexagonal phase. A pharmacokinetic study in rats showed sustained release of entecavir for 3–5 days with a basic LCFS formulation composed of sorbitan monooleate (SMO), phosphatidyl choline (PC), and tocopherol acetate (TA) as the main LC components. 1,2-Dipalmitoyl-sn-glycero-3-phosphatidic acid (DPPA), an anionic phospholipid, was added to increase the anchoring effect between the cationic entecavir and the anionic DPPA, which resulted in a 1.5-times increase in half-life in rats. In addition, anchoring was strengthened by optimizing the pH to 2.5–4.5, increasing the half-life in the rat and dog. Also, due to the increasing terminal half-life from rat to dog resulting from species differences, LCFS produced one week delivery of entecavir in rat and two weeks delivery in dog. Therefore, LCFS injection using the anchoring effect for entecavir can potentially be used to deliver the drug over more than 2 weeks or even 1 month for the treatment of hepatitis B. [ABSTRACT FROM AUTHOR]

Abstract: An injectable liquid crystal-forming system (LCFS) was prepared by using sorbitan monooleate (SMO) as a new liquid crystal-forming material for injections, and its potential use of clinically available sustained-release formulation was evaluated. LCFS was prepared using SMO mixed with phosphatidyl choline and tocopherol acetate, and contained 3.75mg of leuprolide acetate as a monthly dose in 90μl in liquid form. The semi-solid mesophase was formed from the liquid LCFS when it contacted water. The mesophase showed typical characteristics of the liquid crystalline phase, which was classified as the hexagonal phase. The safety of the LCFS was studied by an in vitro extraction colony assay and by examining the injection site in rats and white rabbits after an autopsy. Both in vitro release test and in vivo pharmacokinetic and pharmacodynamic studies showed a sustained release of leuprolide. When compared with a commercial depot formulation of leuprolide, the LCFS showed a similar AUClast value and significantly reduced initial burst with sufficient suppression of testosterone after subcutaneous injections in rats and dogs. The LCFS can serve as a new type of sustained-release injection formulation for its safety, ease of preparation, and sustained release properties. [Copyright &y& Elsevier]