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

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Title: Eutectic-based self-nanoemulsified drug delivery systems for solid oral dosage forms
Author: Nazzal, Sami Mahmoud
Abstract: 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
URI: http : / /hdl .handle .net /2346 /17066
Date: 2002-08

Citation

Eutectic-based self-nanoemulsified drug delivery systems for solid oral dosage forms. Doctoral dissertation, Texas Tech University. Available electronically from http : / /hdl .handle .net /2346 /17066 .

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