A novel oral iron-complex formulation: Encapsulation of hemin in polymeric micelles and its in vitro absorption

作者：Span Kimberley; Verhoef Johan J F; Hunt Hedi; van Nostrum Cornelus F; Brinks Vera; Schellekens Huub; Hennink Wim E^*

来源：European Journal of Pharmaceutics and Biopharmaceutics, 2016, 108: 226-234.

DOI：10.1016/j.ejpb.2016.09.002

• Polymeric micelle
• Nanomedicine
• Caco(2)
• Solubilization
• Heme
• Anemia

Anemia resulting from iron deficiency is one of the most prevalent diseases in the world. As iron has important roles in several biological processes such as oxygen transport, DNA synthesis and cell growth, there is a high need for iron therapies that result in high iron bioavailability with minimal toxic effects to treat patients suffering from anemia. This study aims to develop a novel oral iron-complex formulation based on hemin-loaded polymeric micelles composed of the biodegradable and thermosensitive polymer methoxy-polyethylene glycol)-b-poly[N-(2-hydroxypropyl)methacrylamide-dilactate], abbreviated as mPEG-b-p(HPMAm-Lac(2)). Hemin-loaded micelles were prepared by addition of hemin dissolved in DMSO:DMF (1:9, one volume) to an aqueous polymer solution (nine volumes) of mPEG-b-p(HPMAm-Lac(2)) followed by rapidly heating the mixture at 50 degrees C to form hemin-loaded micelles that remain intact at room and physiological temperature. The highest loading capacity for hemin in mPEG-b-p(HPMAm-Lac(2)) micelles was 3.9%. The average particle diameter of the hemin-micelles ranged from 75 to 140 nm, depending on the concentration of hemin solution that was used to prepare the micelles. The hemin-loaded micelles were stable at pH 2 for at least 3 h which covers the residence time of the formulation in the stomach after oral administration and up to 17 h at pH 7.4 which is sufficient time for uptake of the micelles by the enterocytes. Importantly, incubation of Caco-2 cells with hemin-micelles for 24 h at 37 degrees C resulted in ferritin levels of 2500 ng/mg protein which is about 10-fold higher than levels observed in cells incubated with iron sulfate under the same conditions. The hemin formulation also demonstrated superior cell viability compared to iron sulfate with and without ascorbic acid. The study presented here demonstrates the development of a promising novel iron complex for oral delivery.

• 出版日期2016-11