Development of a floating drug delivery system with superior buoyancy in gastric fluid using hot-melt extrusion coupled with pressurized CO2.

The present study aimed to develop a continuous single-step manufacturing platform to prepare a porous, low-density, and floating multi-particulate system (mini-tablet, 4 mm size). This process involves injecting inert, non-toxic pressurized CO2gas (P-CO2) in zone 4 of a 16-mm hot-melt extruder (HME) to continuously generate pores throughout the carrier matrix. Unlike conventional methods for preparing floating drug delivery systems, additional chemical excipients and additives are not needed in this approach to create minute openings on the surface of the matrices. The buoyancy efficiency of the prepared floating system (injection of P-CO2) in terms of lag time (0 s) significantly improved (P < 0.05), compared to the formulation prepared by adding the excipient sodium bicarbonate (lag time 120 s). The main advantages of this novel manufacturing technique include: (i) no additional chemical excipients need to be incorporated in the formulation, (ii) few manufacturing steps are required, (iii) high buoyancy efficiency is attained, and (iv) the extrudate is free of toxic solvent residues. Floating mini-tablets containing acetaminophen (APAP) as a model drug within the matrix-forming carrier (Eudragit® RL PO) have been successfully processed via this combined technique (P-CO2/HME). Desired controlled release profile of APAP from the polymer Eudragit® RL PO is attained in the optimized formulation, which remains buoyant on the surface of gastric fluids prior to gastric emptying time (average each 4 h).

Anti-proliferative effects of γ-tocotrienol are associated with suppression of c-Myc expression in mammary tumour cells.

OBJECTIVES: Aberrant c-Myc activity plays a central role in cancer transformation. γ-tocotrienol is a member of the vitamin E family that displays potent anti-cancer activity. Here, studies were conducted to determine the role of c-Myc in mediating anti-proliferative effects of γ-tocotrienol in mammary cancer cells. MATERIALS AND METHODS: Treatment effects on mouse +SA and human MCF-7 mammary cancer cell proliferation were determined by MTT assay and Ki-67 staining. Protein expression was determined by western blot analysis. Immunofluorescence staining and qRT-PCR were used to characterize cellular c-Myc and MYC levels respectively. RESULTS: Anti-proliferative effects of γ-tocotrienol were associated with reduction in total c-Myc and phosphorylated-c-Myc-serine 62, and increase in phosphorylated-c-Myc-threonine 58 levels. γ-tocotrienol also reduced PI3K/Akt/mTOR and Ras/MEK/Erk mitogenic signalling, cyclin D1 and cyclin-dependent kinase 4 levels, and increased p27 levels. However, γ-tocotrienol had no effect on MYC mRNA levels. γ-tocotrienol also increased levels of FBW7 (E3 ligase that initiates ubiquitination of c-Myc), but had no effect on serine/threonine phosphatase PP2A or isomerase Pin 1 levels. Combined treatment with GSK3α/ß inhibitor LiCl or proteasome inhibitor MG132 blocked γ-tocotrienol-induced reductions in c-Myc. CONCLUSIONS: These findings indicate that anti-proliferative effects of γ-tocotrienol are associated with reduction in c-Myc that results from increase in GSK-3α/ß-dependent ubiquitination and degradation, rather than from reduction in c-Myc synthesis in +SA and MCF-7 mammary cancer cells.