Eutectic-based self-nanoemulsified drug delivery systems for solid oral dosage forms



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Texas Tech University


Commercially available nutraceutical preparations suffer from poor compliance with the regulatory guidelines for quality, strength, absorption characteristics, and safety. Preparation of Coenzyme Q[10] (C[0]Q[10]), presents an additional challenge in the development of an oral formulation because of its poor solubility. In recent years lipid-based and self-emulsified formulations gained more attention because of their ability to improve aqueous solubility and bioavailability of a variety of drugs. These formulations, however, suffer from large dosage size exceeding CFR limits for excipients, irreversible crystallization, and excipient interaction with the shell material of the capsules. Reversibly induced re-crystallized semisolid self-nanoemulsifying drug delivery system can be considered as an alternative delivery approach. In this method, the interaction between C0Q10 and a suitable eutectic agent allows the oil phase containing the drug to melt at body temperature from its semisolid consistency and disperse to form emulsion droplets in nanometer size range.

C0Q10 was found to form a eutectic mixture with menthol and essential oils, which was demonstrated using binary phase diagrams. This ability of C0Q10 to form eutectic mixture with essential oils was exploited in the development of eutectic-based delivery system for CoQ. At a ratio of 1:1, the mixture of C0Q10 and lemon oil melts at a temperature below 37°C and reversibly re-crystallizes at room temperature improving its shelf life. This was verified by FT-IR and thermal analysis. Upon consumption, C0Q10 blends with surfactant and cosurfactant re-melts and gently emulsifies into a dispersion with nanometer-sized particles. The quality and ease of emulsion formation was monitored by turbidimetiy and dissolution studies, which revealed the distinctive phases of the emulsion disruption process: lag time, pseudolinear phase, and the plateau. Within 15 minutes, eutectic-based formulations completely solubilize into the aqueous dissolution medium. Dissolution lag time was further cortelated with the formation of different liquid crystalline phases at the lipid-water interface during the early stages of the disruption process. Formulation ingredients, polyoxyl 35 castor oil (Cremophor EL), medium-chain mono- and diglycerides (Capmul MCM-C8), and lemon oil were subsequently optimized for release and emulsification rate by applying the Box-Behnken design of experiments. The quadratic interactions between the formulation ingredients were elucidated using contour and response surface plots.

Optimized formulation was then incorporated into a tablet dosage form. This was possible as the eutectic-based formulation of C0Q10 forms a wax-like paste when mixed with small quantities of copolyvidone (KoUidon VA 64). Copolyvidone paste ground with maltodextrin produced granules with good flow properties that are readily available for direct compression. When compressed, the above mixture produced soft compacts. Therefore, directly compressible microcrystalline cellulose (MCC) was added at 20% loading. Since Avicel® MCC comes in different grades, Avicel® particle size and moisture content were evaluated for their effect on compaction, surface roughness, and dissolution properties of the self-emulsified solid formulation. Heckel analysis, three point flexure test, and profilometry were applied in the study. Avicel PH-105 demonstrated a sustained release effect with minimum yield and tensile strength. Among the MCC grades, Avicel® PH-112, with an average diameter of 90 ^m and moisture content no more than 1.5%, was selected for the subsequent studies. Solid formulation ingredients, copolyvidone, maltodextrin, and MCC, were then optimized using the Box Behnken design to obtain a level of the ingredients with desired weight, dissolution rate, tensile strength, friability and disintegration. An optimized immediate release formulation was obtained that confined to the dissolution and disintegration limits set forth by USP guidelines. The formulation had a final weight of 867 mgs and a cumulative percent release of 92% in 45 minutes. For final production, process variables including applied compression pressure, amount of silicon dioxide added, and magnesium stearate mixing time were evaluated for their effect on the dissolution behavior of the self-emulsified tablet dosage form. Colloidal silicone dioxide and compression pressure induced a sustained release effect where the lipid formulation was delivered over a time span from 4 to 12 hrs. Process variables were therefore optimized using the face centered cubic design to obtain a final tablet dosage form that delivers the lipid-formulation over 8 hrs with a zero-order release kinetics. The final product had an improved flow ability and compaction properties with a flow index of 87 and a hardness of 5 kg. Optimized formulation was subjected to an accelerated stability study under various light, temperature, and humidity conditions. Low humidity conditions at 25°C and 30°C had an adverse effect on the extent and release rate of the eutectic lipid-based formulation. Dissolution profile was stable for 4 months when the preparations were refrigerated and stored under 60% relative humidity at 25°C and 30°C