Engineering Lipid Spherulites for the Sustained Release of Highly Dosed Small Hydrophilic Compounds

Abstract

Currently, there is a lack of parenteral sustained release formulations for the delivery of highly dosed small hydrophilic drugs. Therefore, parenteral lipid spherulites are engineered capable of entrapping large amounts of such compounds and spontaneously releasing them in a sustained fashion. A library of spherulites is prepared with a simple green process, using phosphatidylcholine (PC) and/or phosphatidylethanolamine (PE), nonionic surfactants and water. The vesicle formulations exhibiting appropriate size distribution and morphology are selected and loaded with 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), ((OEG 2 ) 2 -IP4), an inositol phosphate derivative currently under clinical evaluation for the treatment of aortic valve stenosis. The loading efficiency of spherulites is up to 12.5-fold higher than that of liposomes produced with the same materials. While the PC-containing vesicles showed high stability, the PE spherulites gradually lost their multilayer organization upon dilution, triggering the active pharmaceutical ingredient (API) release over time. In vitro experiments and pharmacokinetic studies in rats demonstrated the ability of PE spherulites to increase the systemic exposure of (OEG 2 ) 2 -IP4 up to 3.1-fold after subcutaneous injection, and to completely release their payload within 3-4 d. In conclusion, PE spherulites represent a promising lipid platform for the extravascular parenteral administration of highly dosed small hydrophilic drugs.

Self-Assembled Homopolymeric Spherulites from Small Molecules in Solution

“…Self-assembly is ubiquitous in nature. − Natural molecules such as amino acids, peptides, proteins, and DNA can form cooperative self-assemblies that execute vital biological functions. − Such self-assembly can be considered a versatile bottom-up synthesis method and has led to a myriad of functional hierarchical structures in life science and materials engineering. − Spherulites are one type of self-assembled systems and polycrystalline structures in which acicular crystals radiate from a common center and grow nearly synchronously, leading to a spherical structure. Indeed, spherulites can be obtained from a wide range of materials (e.g., metals, minerals, organic molecules, proteins, and synthetic polymers) and have garnered extensive attention in drug delivery, tissue engineering, and sensing. − Moreover, manipulating the formation of spherulites is an important topic in biological systems. For example, the formation of spherulites by amyloid fibers has been linked to neurodegenerative pathologies (e.g., Alzheimer’s diseases). , Controlling spherulite morphology and exploring the mechanism of spherulite growth are vital steps in enhancing material performance and achieving effective disease treatment. − …”