A full factorial experimental design to study the effect of flavoring agents on the mechanical properties of curcumin chewing gum tablets with high solids content.

Objective: Developing chewing gum tablets (CGTs) with high drug loads is a challenge due to the loss of mastication properties. We postulated that poor mastication properties of such gums could be improved by adjusting the concentration of liquid flavors to serve as plasticizers and consequently increase the flexibility of the elastomer in the gum base. To test this hypothesis, the objective of this work was to evaluate the effects of flavor type and concentration, and storage conditions on the textural properties of CGTs loaded with 20% curcumin (CUR) by weight.Methods: CGTs were made by directly compressing Health in Gum® base with CUR. The resultant CGTs were characterized by single and two bites textural tests to measure their yield strength, post-bite failure rate, and compressibility.Results: Flavor concentration (X2) had a significant impact on the masticatory properties of the chewing gums, which could be ascribed to the plasticizing effect of peppermint oil. Addition of liquid flavors and storage at low temperature (X4) produced CGTs with the desirable properties of low yield strength (Y1) and post-bite structural failure rate (Y2), and high compressibility (Y3). The effect of flavors however was negated at high temperatures, especially when flavored gums were stored for extended time at 50 °C. Flavor type (X1) on the other hand had no effect on the masticatory properties of the chewing gums.Conclusions: This study concluded that it is feasible to formulate CGTs with high solids content without negatively impacting their mechanical properties by controlling the concentration of liquid flavors.

Effect of PEG surface conformation on anticancer activity and blood circulation of nanoemulsions loaded with tocotrienol-rich fraction of palm oil.

Tocotrienol-rich fraction of palm oil, which contains the isomers of vitamin E, was shown to possess potent anticancer activity against mammary adenocarcinoma cell lines. Its clinical use, however, is limited by poor oral bioavailability and short half-life. Previously, we developed tocotrienol-rich lipid nanoemulsions for intravenous administration. The objective of this study was to investigate the effect of surface grafted polyethylene glycol (PEG) on the properties of the nanoemulsions. PEGylation was achieved by the addition of equimolar PEG groups using poloxamer or 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)2000] (PEG2000-DSPE). The effect of PEG surface topography on the antiproliferative activity of nanoemulsions against mammary adenocarcinoma cells, their susceptibility to protein adsorption, and its effect on blood hemolysis and circulation time was investigated. Nanoemulsions PEGylated with poloxamer or PEG2000-DSPE were stable under physical stress. Poloxamer nanoemulsion, however, displayed higher uptake and potency against MCF-7 tumor cells in 2D and 3D culture and increased hemolytic effect and susceptibility to IgG adsorption, which was reflected in its rapid clearance and short circulation half-life (1.7 h). Conversely, PEGylation with PEG2000-DSPE led to a 7-fold increase in mean residence time (12.3 h) after IV injection in rats. Reduced activity in vitro and improved circulation time suggested strong shielding of plasma proteins from the droplets. Differences between the nanoemulsions were attributed to polymer imbibitions and the differences in PEG conformation and density on the surface of the droplets.

Molecular modelling and multisimplex optimization of tocotrienol-rich self emulsified drug delivery systems.

The objective of this study was to optimize a novel tocotrienol (TRF)-rich self emulsified drug delivery system (SEDDS). In the first part, an unusual phenomenon was investigated. It was observed that by substituting Tween 80 with Cremophor EL in the SEDDS it was possible to emulsify>55% TRF (by weight of the formulation) into submicron (<200 nm) emulsion. With Tween, only 17.5% of the loaded TRF could be emulsified into crude emulsion. The superiority of Cremophor was attributed to the special arrangement of the surfactant at the oil/water interface, which was confirmed by modelling and docking studies. In the second part of this study, the composition of the secondary ingredients in the TRF-rich SEDDS were optimized by the modified Multisimplex approach. SEDDS were manufactured at pre-defined step-size and tested for their dissolution behavior. Testing was performed sequentially until the optimum composition that can emulsify 50% of the loaded TRF into a stable<150 nm submicron emulsion was obtained. Optimization end-point was identified when the "membership value" approached 1, which was confirmed by a second Multisimplex run. Overall, this study demonstrated the utility of docking studies and the Multisimplex approach in product development when little is known about the experimental "design space".

The value of tocotrienols in the prevention and treatment of cancer.

Tocopherols and tocotrienols represent the 2 subgroups that make up the vitamin E family of compounds, but only tocotrienols display potent anticancer activity. Although in vitro experimental evidence has been very promising, oral supplementation of tocotrienols in animal and human studies has produced inconsistent results. However, recent studies have now clarified the reasons for these discrepancies observed between in vitro and in vivo studies. Oral absorption of tocotrienols into the circulation is mediated in large part by carrier transporter systems that display saturation and apparently down-regulation when exposed to high concentrations of tocotrienols. To circumvent these limitations in oral absorption of tocotrienols, investigators have developed novel prodrug derivatives and nanoparticle delivery systems that greatly enhance tocotrienol bioavailability and therapeutic responsiveness. Additional studies have also demonstrated that combined treatment of tocotrienols with other traditional chemotherapeutic agents results in a synergistic anticancer response, and this synergistic response was further enhanced when these agents were encapsulated in a nanoparticle delivery system. Taken together, these findings clarify the limitations of oral tocotrienol administration and provide novel alternative drug-delivery systems that circumvent these limitations and greatly enhance the therapeutic effectiveness of tocotrienols in the prevention and treatment of cancer.

Effect of Eudragit RS 30D and talc powder on verapamil hydrochloride release from beads coated with drug layered matrices.

The aim of this study was to investigate the effect of Eudragit RS 30D, talc, and verapamil hydrochloride on dissolution and mechanical properties of beads coated with "drug-layered matrices". This was accomplished with the aid of a three-factor multiple-level factorial design using percent drug release in 1 and 2 h, T(50), tensile strength, brittleness, stiffness and toughness as the responses. Beads were coated in a fluidized-bed coating unit. Surface morphology and mechanical properties were evaluated by surface profilometry and texture analysis, respectively. No cracks, flaws and fissures were observed on the surfaces. The mechanical properties were dependent on the talc/polymer ratio. The release of verapamil from the beads was influenced by matrix components. Increasing the level of both talc and Eudragit decreased the percent drug released from 67% to 4.8% and from 80.7% to 6.7% in 1 and 2 h, respectively, and increased T(50) from 0.8 to 25.7 h. It was concluded that beads could be efficiently coated with "drug-layered matrices". The release of drug, however, depends on a balance between the levels of drug, talc, and polymer, whereby desired dissolution and mechanical properties could be controlled by the talc/polymer ratio and the level of drug loading.

Response surface methodology for the optimization of ubiquinone self-nanoemulsified drug delivery system.

The aim of the present study was to prepare and evaluate an optimized, self-nanoemulsified drug delivery system of ubiquinone. A 3-factor, 3-level Box-Behnken design was used for the optimization procedure with the amounts of Polyoxyl 35 castor oil (X1), medium-chain mono- and diglyceride (X2), and lemon oil (X3) as the independent variables. The response variable was the cumulative percentage of ubiquinone emulsified in 10 minutes. Different ubiquinone release rates were obtained. The amount released ranged from 11% to 102.3%. Turbidity profile revealed 3 regions that were used to describe the progress of emulsion formation: lag phase, pseudolinear phase, and plateau turbidity. An increase in the amount of surfactant decreased turbidity values and caused a delay in lag time. Addition of cosurfactant enhanced the release rates. Increasing the amount of the eutectic agent was necessary to overcome drug precipitation especially at higher loading of surfactants and cosurfactants. Mathematical equations and response surface plots were used to relate the dependent and independent variables. The regression equation generated for the cumulative percentage emulsified in 10 minutes was Y1 = 90.9 - 22.1X1 + 5.03X2 + 13.95X3 + 12.13X1X2 + 15.13X1X3 - 14.40X1(2) - 6.25X3(2). The optimization model predicted a 93.4% release with X1, X2, and X3 levels of 35, 35, and 30 respectively. The observed responses were in close agreement with the predicted values of the optimized formulation. This demonstrated the reliability of the optimization procedure in predicting the dissolution behavior of a self-emulsified drug delivery system.