A PEGylated Nanocarrier for Oral Delivery of Immunomodulator Thymopentin

Abstract

The oral delivery of drugs is the most popular route of administration for patients. However, thymopentin (TP5) is only available in the market in forms for parenteral administration as an immunomodulator. Predominantly, this is because of extensive peptidolytic degradation in the gastrointestinal tract (GIT), which decreases the amount of TP5 available for absorption. PEGylated niosomal drug delivery systems are in nanoscale with lipid and surfactant surround, which can provide a lipid based carrier for oral delivery of TP5, while PEGylation is able to reduce the kidney clearance and prolong systemic circulation time for TP5 reaching to the target site. The aim of this thesis is to develop a PEGylated niosome to enhance the physicochemical stability of TP5, improve its oral bioavailability, and investigate this nanocarrier for in vitro and ex vivo parameters. A rapid, simple, and reliable HPLC analytical method for TP5 was developed and validated. The preformulation studies showed that TP5 displays a poor physicochemical and enzymatical stability. TP5 with the effective inhibitors were loaded into PEGylated nanocarriers using the thin film hydration method and optimised by central composite designs with following recipe: 2 μmoL of DCP; 30 μmol cholesterol (including 22.5 μmol PEG600-cholesterol); 120 μmol Span 60; 10mg EDTA in 10 mL water containing 10 of TP5 with 0.2 mg SBTCI; and 60 minutes for 60°C hydration. The TP5-PEG-nanocarriers were characterised in terms of morphology, particle size, zeta potential, entrapment efficacy (EE%), in vitro drug release, cytotoxicity, cellular uptake, cellular transport, and ex vivo protection studies. Notably, TP5-PEG-Niosomes was based on active endocytosis, and time-, energy- and concentration- dependent in Caco-2 and HT29 co-cultured cell lines. Cellular transport of TP5-PEG-Niosomes were through adsorptive- and clathrin- mediated endocytosis with energy participated. It also displayed superior protection under ex vivo intestinal luminal and mucosal extracts for 6 hours compared with the pure drug. These findings suggest that using PEGylated niosomes can decrease peptide degradation, enhance drug absorption in the intestine, and improve the drug oral bioavailability. Future work will focus on in vivo assays to assess the pharmacokinetic and pharmacodynamic activities of this formulation in rats. This delivery system of TP5 shows promise as an immunomodulating formulation and may serve as an oral delivery platform for other peptides or immunomodulators.