Purpose: Ternary mixture formulations are free-flowing powders used for the delivery of the poorly water-soluble drug substance which increases the solubility and bioavailability. The prepared powder formulations show uniform dispersed particles when added to the aqueous phase. The aim of the present study was to develop ternary mixture formulations to enhance the dissolution of dronedarone HCl by improving solubility, dissolution and the permeability. In vitro transport across the membrane was evaluated using parallel artificial membrane permeability assay (PAMPA).
Methods: To optimize the composition of dronedarone HCl- ternary mixture formulations, solubility tests, dispersibility properties, droplet size and zeta potential were performed. Ternary mixture formulations were prepared with varying concentrations of lipid, surfactant, and organic phase to aqueous phase ratios. Lipids such as DSPC, DMPG, Phospholipon 90H and Soy Phosphatidyl Choline were used and Gelucire, Poloxamer and Tween 80 were used as surfactants. Lipid, drug, and surfactant were dissolved in organic solvent and described as a solvent solution. Filler or diluents were dissolved in water to which another organic solvent was added slowly and called as a second aqueous solution. The solvent solution and the second aqueous solution were mixed to form a clear homogeneous solution, which was subsequently spray dried (LabPlant spray dryer) to yield a free-flowing powder. In vitro dissolutions and drug transport studies of pure drug and ternary mixture formulations were carried out. Dissolution profiles were tested using pH 6.8 phosphate buffer with 0.25% SLS of 900 mL at 75 rpm. As per the dissolution profiles, dronedarone HCl API (pure drug), DTM F2 (DSPC: Drug: Surfactant) and DTM F4 (Phospholipon 90H: Drug: Surfactant) formulations were tested for flux (J) (μg/cm2/h) using artificial PAMPA membrane.
In vitro transport across the membrane was evaluated using parallel artificial membrane permeability assay (PAMPA). Along with the pure drug, all the finalized formulations (DTM F2 and DTM F4) were taken for PAMPA studies. All the compositions were taken at a concentration of 100 µg/ mL in pH 6.8 phosphate buffer into the donor well plate. In the receptor compartment, 300 µL of pH 6.8 phosphate buffer was added. Samples were collected at 1, 2, 3, 4, 6, and 8 hours. The drug levels were quantified by HPLC with PDA detector at 290 nm.
Results: All the ternary mixtures after spray drying exhibited an increased solubility compared to pure drug. The prepared powder formulations had shown uniform dispersed particles when added to the aqueous phase. The particle size of the powder mixtures, when redispersed in water, was observed to be in the range of 1100- 1650 nm. Ternary mixtures optimized formulations have shown a significantly higher rate of dissolution than pure drug. The percent drug release of the pure drug was observed to be 35.20% by the end of 240 minutes. In case of optimized formulations, about 70% of the drug was released at 60 minutes time point. From the results of PAMPA studies, ternary mixtures prepared with DSPC and Phospholipon 90H at a drug to lipid ratio of 1:2 had shown a 7.85 and 9.11 fold increase of flux respectively when compared with dronedarone HCl pure drug (Table 2).
Conclusion: Apparent permeability values from PAMPA revealed that the ternary mixture formulations were successful in enhancing the permeation of dronedarone HCl. Therefore the ternary mixture formulations of dronedarone could provide improved oral bioavailability and further reduction in dose due to enhanced solubility, permeability and hence absorption.
Vanaja Kenchappa– Post Doctoral Research Scholar, Western University of Health Sciences, Pomona
Rohit Joshi– Western University of Health Sciences
Milan Prabhu– Western University of Health Sciences, California
Guru Betageri– Western University of Health Sciences, California