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

Gheorghe Fundueanu, Marieta Constantin, Paolo Ascenzi

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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.

Original languageEnglish
Pages (from-to)2767-2775
Number of pages9
Issue number18
Publication statusPublished - Jun 2008


  • Drug delivery
  • Intelligent microspheres
  • Lower critical solution temperature
  • pH/thermo-responsive copolymers
  • Pullulan

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering


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