In vitro and in vivo evaluation ofanovel self-assembled oral delivery system for hydrophobic drugs

Abstract

Objective To design and synthesize a new hydrophilic aspartic acid peptide derivative, poly(isopropyl-D, L-aspartamide) (PIPAA), and investigate its efficiency to self-assemble with carboxy-containing therapeutics into pH-sensitive microspheres to enhance the dissolution and oral bioavailability of hydrophobic drugs. Methods With phosphoric acid as the catalyst, D, L-aspartic acid was polymerized into polysuccinimide (PSI) at 180 ℃ followed by ring-opening reaction with isopropylamine to form PIPAA. The successful synthesis of PSI and PIPAA was characterized by Fourier transform infrared spectroscopy (FT-IR) and 1H NMR spectroscopy. The morphology, size, drug loading content and loading efficiency of IND/PIPAA microspheres were characterized. FT-IR and 1H NMR spectroscopy were used to determine non-covalent forces between IND and PIPAA in IND/PIPAA microspheres, and the existence form of IND in IND/PIPAA microspheres was examined by differential scanning calorimetry (DSC) and Xray diffraction (XRD) measurement. We carried out in vitro tests to investigate pH-responsive release profiles of IND/PIPAA microspheres. We also examined plasma concentrations of IND using high-performance liquid chromatogrpahy (HPLC) in rats after oral administration of IND/PIPAA microspheres, and evaluated the anti-inflammatory efficacy of IND/PIPAA microspheres in rats with carrageen-induced paw edema. Results FT-IR and 1H NMR spectra demonstrated successful synthsis of PSI and PIPAA. Morphological observation and size determination revealed a spherical shape and uniform particle size of the IND/PIPAA microspheres, which were self-assembled through electrostatic force, hydrogen bonding, and hydrophobic interactions between IND and PIPAA as confimred by FT-IR and 1H NMR spectra. DSC and XRD measurements indicated that IND molecules entrapped in the microspheres were essentially amorphous. While drug release was almost completely suppressed at a gastric pH level, rapid IND release from the microspheres in vitro was observed at pH 7.4. After oral administration in rats, IND/PIPAA microspheres, as compard with raw IND, obviously enhanced plasma concentrations of IND with a 2.4-fold higher AUC. In rats with carrageen-induced acute inflammation in the paws, IND/PIPAA microspheres exhibited much stronger anti-inflammatory activity than saline (P=0.046) and raw IND (P=0.002). Conclusion The carboxyl-containing hydrophobic drug IND and the hydrophilic aspartic acid peptide derivative PIPAA can self-assemble into well-defined microspheres with a uniform size to serve as an efficient drug delivery system that increases intestinal dissolution of IND to enhance its oral bioavailability and efficacy.

Keywords

• poly(isopropyl-d
• l-aspartamide)
• self-assembly
• intestinal targeting
• insoluble drugs
• ph-sensitivity