Poly(N-isopropylacrylamide-co-acrylamide) cross-linked thermoresponsive microspheres obtained from preformed polymers: Influence of the physico-chemical characteristics of drugs on their release profiles

Abstract

Poly(N-isopropylacrylamide-co-acrylamide) copolymer was synthesized as an interesting thermoresponsive material possessing a phase transition temperature of around 36 °C in phosphate buffer, pH 7.4 (PB); the concentration was 10%, w/v. The copolymer maintains a sharp phase transition at a relatively high percentage of acrylamide. The lower critical solution temperature (LCST) of the copolymer is influenced by the concentration of copolymer solution in PB. The copolymer was transformed in thermoresponsive microspheres by chemical cross-linking of amide groups with glutaraldehyde. The key factors for the successful preparation of microspheres are the use of a concentrated polymer solution, a temperature (38 °C) that is high enough but lower than LCST, and a long reaction time (48 h). The microspheres were characterized by optical and scanning electron microscopy, swelling/deswelling kinetics, swelling degree, and PB retention at different temperatures. Finally, the influence of hydrophilicity/hydrophobicity and the molecular weight of the drugs (propranolol, lidocaine, vitamin B₁₂) on their release profile from thermoresponsive microspheres were examined. Above LCST the hydrogel matrix is in the dehydrated state and hydrophobic interactions between the hydrophobic drugs and the polymer occur, modulating the release rate of the drugs. For hydrophilic drugs, the release rate is modulated mainly by the steric interaction between the drug molecule and the matrix.

Introduction

Thermally responsive drug delivery systems have attracted ever-increasing attention because they can control the release of drug in response to changes in body temperature and therefore act as self-regulating systems [1], [2], [3], [4]. Poly(N-isopropylacrylamide) (PNIPAAm) is the most popular polymer among the thermoresponsive polymers since it exhibits a sharp phase transition close to 32 °C [5], [6]. The temperature at which this transition occurs is called the lower critical solution temperature (LCST). Below the LCST the polymer chain is hydrated and adopts an extended coil conformation, while above it the polymer is dehydrated and adopts a globular conformation. Correspondingly, the cross-linked hydrogels obtained from these polymers swell under the LCST and shrink above it. The biomedical and biological applications of such gels usually involve the chemical modification of poly(NIPAAm). These modifications are usually performed to introduce functional groups that can increase the LCST towards body temperature [7], [8], to improve the mechanical properties [9] or to interact with certain drugs [10]. However, copolymerization of NIPAAm with acrylate-type comonomers usually leads to gels possessing relatively weak thermosensitivity [11]. Therefore, the comonomer needs to be chosen carefully to preserve the thermosensitivity of the gel structure. Most of the studies concerning the applications of thermoresponsive hydrogels have focused on the use of devices in the form of discs or slabs [12], [13], [14]; few papers have dealt with the preparation and characterization of thermoresponsive microspheres. The majority of microspheres are prepared from monomers by suspension polymerization [15], [16]. Thermoresponsive microspheres from preformed polymers are prepared by dropping a polymer solution into a liquid at a temperature above the LCST [17], [18], [19]. These microspheres are not stable or easy to handle, and have a reduced number of biomedical applications. The most studied drug used as a model for pulsatile on–off drug release from thermoresponsive hydrogels is the hydrophobic indomethacin [20], [21].

The main objectives of this paper were the preparation of stable thermoresponsive microspheres from performed polymers and the study of the influence of physico-chemical characteristics of drugs on their release profile.

Here, the poly(NIPAAm-co-AAm) copolymer was prepared as a thermoresponsive polymer with it’s LCST tailored towards body temperature. This copolymer was transformed into thermoresponsive stable microspheres by an original approach that assumes the cross-linking of the amide group of acrylamide with glutaraldehyde under particular conditions (long reaction time, temperature slightly below the LCST, concentrated polymer solution). The microspheres were characterized by optical and scanning electron microscopy in the dried, swollen and shrunken state, and the degree of swelling and rate of swelling/deswelling were determined. Finally, the influences of drug hydrophilicity/hydrophobicity and molecular weight on the release profiles were examined.