Novel Self-Assembled Ibrutinib-Phospholipid Complex for Potently Peroral Delivery of Poorly Soluble Drugs with pH-Dependent Solubility
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As an irreversible small-molecule kinase inhibitor, ibrutinib (IBR) exhibits excellent tumor suppression in various tumor cells. However, IBR is insoluble at neutral pH and can dissolve only at low pH: thus, commercial IBR products present poor bioavailability and weakened in vivo antitumor activity. Therefore, we aimed to develop a stable IBR-phospholipid complex (IBR-PC) using egg phosphatidylglycerol (EPG) as excipients to improve the bioavailability of IBR and further enhance its antitumor effects. IBR-PC was characterized by transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray powder diffraction (XPRD), and molecular docking and simulation test, which all explained the interactions of two components. Solubility tests demonstrate that the novel formulation can maintain excellent solubility (above 5 mg/mL) at various pH levels. Storage stability tests show that no change in particle size or content of IBR-PC was observed during the experimental period. In vivo pharmacokinetic results demonstrated that the relative bioavailability of IBR-PC was a 9.14-fold improvement relative to that of IBR suspension (IBR-susp). Furthermore, IBR-PC was associated with enhanced cytotoxic activity in vitro and superior tumor growth suppression in vivo compared to that resulting from the free IBR. Thus, the proposed IBR-PC system is a promising drug delivery system that enhances the oral bioavailability of IBR, resulting in its improved in vivo antitumor effect.
KEY WORDSibrutinib phospholipid complex egg phosphatidylglycerol bioavailability antitumor activity
This research was supported by the National Natural Science Foundation of China (No. 81373334 and No. 81573375).
Compliance with Ethical Standards
All animal experiments were performed in accordance with the guidelines of the Animal Welfare Committee of Shenyang Pharmaceutical University. The protocol numbers of the animal studies were SYPU-IACUC-C2018-1-24-201 and SYPU-IACUC- C2018-4-4-101.
Conflict of Interest
The authors declare that they have no conflict of interest.
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