Polymeric amorphous dispersion as a carrier to enhance the in vitro dissolution in vivo pharmacokinetics and cytotoxicity of niclosamide

Abstract

AbstractAmorphous solid dispersion is one of the recent technologies that attracted the pharmaceutical industry to deliver poorly soluble drugs. However, the selection of polymeric carriers and characterization of drug‐polymer interactions need to be performed systemically to develop a stable amorphous delivery system. Solubility parameter analysis was used to screen the polymers. Hot melt extrusion (HME) was used to prepare the polymeric amorphous dispersion. Drug polymer interactions were identified by attenuated total reflection spectroscopy. Solid‐state transformations were characterized by differential scanning calorimetry and powder X‐ray diffraction. In vitro drug release was performed under non‐sink conditions. In vivo pharmacokinetic studies were performed on rats, and MCF‐7 and A‐549 cell lines were used to study the cytotoxicity. Polymer miscibility studies indicated polyvinylpyrrolidone (PVPK17) as a suitable polymer, and 180°C at 50 rpm was the ideal condition in the HME. The analytical tools confirmed the conversion of niclosamide (NCL) to an amorphous state and the existence of hydrogen bond interactions between the drug and the polymer. Prepared solid dispersions were stable for 3 months and showed about 214‐fold improvement in solubility and around 10‐fold improvement in dissolution over pure crystalline NCL. Pharmacokinetic studies showed a 4.04‐fold enhancement in Cmax and a 2.05‐fold enhancement in the area under the plasma concentration‐time curve (AUC0‐24h) compared to crystalline NCL. Cytotoxicity studies also showed a better toxicity profile with a reduction in the IC50 values of NCL in the amorphous solid dispersions. These encouraging findings indicate that polymeric amorphous solid dispersions could be a commercially feasible option to deliver poorly soluble drugs like NCL using HME.