Impact of binary/ternary solid dispersion Utilizing poloxamer 188 and TPGS to improve pharmaceutical Attributes of Bedaquiline fumarate

Bedaquiline fumarate (BDQN) is approved in year 2012 to treat multidrug resistance tuberculosis (MDR-TB) through accelerated approval pathway by FDA. It belongs to class II of biopharmaceutical classification system (BCS) and shows poor aqueous solubility and dissolution rate which eventually leads to compromised bioavailability. In the present study, BDQN loaded binary solid dispersion (BSD) and ternary solid dispersion (TSD) were prepared with the aid of solvent evaporation technique wherein poloxamer 188 and tocopheryl polyethylene glycol 1000 succinate (TPGS) were used as dispersing matrix.

The prepared BSD and TSD were characterized by dynamic light scattering (DLS), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), hot stage microscopy (HSM), powder X-ray diffraction (PXRD), and evaluated for enhancement in saturated solubility, in vitro dissolution performance, and permeability through rat intestine. BSD and TSD showed 5.68-fold and 7.46-fold increment in saturation solubility respectively. In vitro dissolution data showed about 99.98 ± 1.48 % BDQN release from BSD within 15 min (t₁₅ min, %) and, 98.68 ± 1.98 % release from TSD within 30 min (t₃₀ min, %) which were significantly higher than that of BDQN plain drug and their respective physical mixtures at respective time points. However, BSD was unable to sustain the parachute effect of BDQN in dissolution medium and showed decreased concentrations whereas TSD maintained the same throughout experimental period.

Permeability of BDQN from BSD and TSD was found to be 1.86-fold and 3.53-fold, respectively, when compared to BDQN plain drug. TSD was found to be stable at accelerated condition for the period of 3 months when evaluated by PXRD, FTIR, DSC and in vitro dissolution. We may conclude from this study that solid dispersions of BDQN can be accepted as promising alternative formulation approach to enhance biopharmaceutical performance of BDQN in terms of solubility, dissolution rate and permeability for treatment of tuberculosis and may benefit the patients with MDR-TB for the emergency treatment with BDQN, which could ultimately lead to increase in bioavailability and reduced cost of final product.

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Article information: Vishwas P. Pardhi, Keerti Jain, Journal of Drug Delivery Science and Technology, 2021. https://doi.org/10.1016/j.jddst.2021.102349.