Preparation and characterization of pH- and temperature-sensitive pullulan microspheres for controlled release of drugs

作者：Fundueanu Gheorghe^*; Constantin Marieta; Ascenzi Paolo

来源：Biomaterials, 2008, 29(18): 2767-2775.

DOI：10.1016/j.biomaterials.2008.03.025

• intelligent microspheres
• pH/thermo-responsive copolymers
• pullulan
• lower critical solution temperature
• drug delivery

Most part of pH- and temperature-sensitive microspheres used for the controlled delivery of drugs are not biodegradable. Therefore, the aim of this work is to prepare pH- and temperature-sensitive microspheres from biodegradable and biocompatible natural polymers. Pullulan microspheres were prepared by suspension cross-linking with epichlorohydrin of an aqueous solution of the polymer. In order to confer them temperature sensitivity, poly(N-isopropylacrylamide-co-acrylamide) was grafted onto pullulan microspheres. Then, the pH-sensitive units (-COOH) were introduced by reaction between the remaining -OH groups of the pullulan with succinic anhydride. The grafted pullulan microspheres are more hydrophilic than pullulan microspheres, their swelling degree as well as water regain increase significantly. The thermo-sensitivity of the carboxylated microspheres depends to the number and the ionization form (-COOH/-COO(-)) of carboxylic groups. At a low exchange capacity (0.35 meq/g), microspheres are thermo-sensitive both in the protonated and deprotonated form of -COOH groups. At a higher exchange capacity (2.25 meq/g), microspheres are almost unswellable in the protonated form and swell extensively in the ionized form (up to 28 times than their dried form) loosing in a great extent the thermo-sensitive properties. In isotonic phosphate buffer pH = 7.4, both thermo-sensitive and pH/ thermo-sensitive microspheres possess a phase transition temperature close to that of the human body temperature. Loading and release profiles of lysozyme, taken as a molecular model system, were investigated.

• 出版日期2008-6