Fabrication and characterization of a smart drug delivery system: microsphere in hydrogel

Abstract

In this contribution, a novel smart drug delivery system (DDS) consisting of hydroxyl-functionalized glycerol poly(ε-caprolactone) (PGCL)-based microspheres and poly(N-isopropylacrylamide) (PNIPAAm) hydrogel was developed for prolonged and sustained controlled drug release. Various amounts PGCL-based microspheres were incorporated physically into temperature sensitive poly(N-isopropylacrylamide) (PNIPAAm) hydrogel to form the novel DDSs. Resulting DDSs were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and compression modulus measurements to investigate the morphological, thermal, and mechanical properties. The temperature dependence of swelling ratio and response kinetics upon heating or cooling were also investigated to understand the smart properties, i.e., temperature sensitive properties of these DDSs. Finally, ovalbumin (OVA), used as the model drug, was loaded into PGCL-based microspheres to examine and compare the effects of controlled release at different temperature (22 and 37 °C) of these novel smart DDSs.

Introduction

Drug delivery system (DDS) for control drug release was developed by encapsulating drugs into a specific delivery system in order to provide a predetermined drug amount at a proper time and/or targeted site over the duration from several hours to several years [1], [2], [3], [4]. In some occasions, it would be more beneficial if the drug was delivered through the control of signals from an underlying disease and the necessary amount of drug could be modified upon the stimulation of such a signal. Recent developments of the smart DDS are making this control possible. Brahim et al. [5] developed membranes consisting of crosslinked poly(2-hydroxyethyl methacrylate) intimately combined with polypyrrole for smart controlled release of insulin in response to a glucose signal. Low et al. [6] also reported a smart controlled drug release system where the delivery of drugs is achieved by actuating miniature metal or polymeric valves. The polymeric valves possess qualities of a high swelling hydrogel and a voltage controllable redox polymer.

Over the past years, temperature sensitive hydrogel was designed and developed for the fabrication of smart DDSs. Temperature activation of release has been achieved by utilizing phase transition phenomena of particular hydrogels. The most typical temperature sensitive hydrogel that has been examined is poly(N-isopropylacrylamide) (PNIPAAm) hydrogel, which exhibits a transition temperature (T_tr) or lower critical solution temperature (LCST) at about 33 °C [7], [8], [9], [10]. Due to this unique property, the release rate of loaded drugs in PNIPAAm hydrogels could be activated and self-controlled by an operating principle that is a hydrogel-based device that responses to a temperature trigger provided at a target site. One of the reasons for developing temperature triggering DDSs is to provide prolonged drug release over a specific duration, and quick release of drugs from PNIPAAm hydrogels is not always favorable. Drugs loaded directly into the swollen PNIPAAm hydrogels were found to release quickly due to the swollen and porous PNIPAAm network [11], [12], [13], [14]. On the other hand, over the past decade, microspheres of hydrophobic polymers have been developed and employed as versatile solid DDSs with much prolonged drug release [15], [16]. However, these solid microspheres are unable to respond to external temperature stimulations.

With respect to above considerations, a new DDS for prolonged drug release with temperature sensitivity would be preferable. In this paper, we intended to develop a temperature sensitive DDS by incorporating PGCL-based microspheres into PNIPAAm hydrogel. Drugs were loaded into PGCL-based microspheres, not PNIPAAm hydrogels directly, then drug-loaded microspheres were incorporated physically into PNIPAAm hydrogels. For the purpose of high density of solid microspheres to obtain a more prolonged drug release, PGCL was used to fabricate microspheres since it is a star-shaped polymer [17], [18], [19], [20], [21]. A star-shaped polymer is a branched polymer with more than two linear polymeric arms attached to a center core. Star-shaped polymers have a higher segment density than a homologous linear polymer, therefore exhibiting a smaller hydrodynamic radius and lower solution viscosity.