title: Poly(N-isopropylacrylamide-co-hydroxyethylacrylamide) thermosensitive microspheres: the size of microgels dictates the pulsatile release mechanism.
abstract: Poly(N-isopropylacrylamide-co-N-hydroxyethylacrylamide) (poly(NIPAAm-co-HEAAm)) was prepared as a new thermosensitive copolymer possessing a sharp phase transition around the human body temperature. The effect of the copolymer concentration on the lower critical solution temperature (LCST) was determined under physiological conditions by cloud point (CP) and differential scanning calorimetric (DSC) methods. Then, thermosensitive microspheres were prepared from preformed copolymers by chemical cross-linking of hydroxyl groups with glutaraldehyde at a temperature situated slightly below LCST of the copolymer solution. The volume phase transition temperature (VPTT) of corresponding cross-linked microspheres was determined from swelling degree-temperature curve. The microspheres were loaded with model drug indomethacin by the solvent evaporation method. The DSC analysis proved that the drug is molecularly dispersed in the polymer network. Finally, the influence of the microsphere size on drug release was investigated. It was established that microspheres with the diameter ranging between 5 and 60 μm release the drug with almost the same rate below (in the swollen state) and above the VPTT (in the collapsed state). On the contrary, microspheres with the diameter ranging between 125 and 220 μm release a significantly higher amount of indomethacin below than above the VPTT. This different behavior is enough to assure a pulsatile release mechanism when the temperature changes cyclically below and above the VPTT. However, both small and large microspheres release a large amount of the drug during the collapsing process.
authors.affiliation: Department of Natural Polymers, Bioactive and Biocompatible Materials, "Petru Poni" Institute of Macromolecular Chemistry, Iassy, Romania. Electronic address: ghefun@icmpp.ro.
authors.forename: Gheorghe
authors.initials: G
authors.lastname: Fundueanu
authors.forename: Marieta
authors.initials: M
authors.lastname: Constantin
authors.forename: Ionela
authors.initials: I
authors.lastname: Asmarandei
authors.forename: Sanda
authors.initials: S
authors.lastname: Bucatariu
authors.forename: Valeria
authors.initials: V
authors.lastname: Harabagiu
authors.forename: Paolo
authors.initials: P
authors.lastname: Ascenzi
authors.forename: Bogdan C
authors.initials: BC
authors.lastname: Simionescu
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry*; D001831:Body Temperature; D002152:Calorimetry, Differential Scanning; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding; D016503:Drug Delivery Systems; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage*; D008863:Microspheres; D010316:Particle Size; D044367:Phase Transition; D044366:Transition Temperature
chemical_list: D000180:Acrylic Resins; D004337:Drug Carriers; C052970:poly-N-isopropylacrylamide; C074962:poly-N-(2-hydroxyethyl)acrylamide; D007213:Indomethacin
keywords: AIBN; CP; DSC; Drug delivery systems; ESEM; GA; HEAAm; LCST; Lower critical solution temperature; M(n); M(w); Microspheres; N,N′-azobisisobutyronitrile; N-hydroxyethylacrylamide; N-isopropylacrylamide; NIPAAm; PB; PI; Tg; Thermo-responsive polymer; VPTT; Volume phase transition temperature; cloud point; differential scanning calorimetry; environmental scanning electron microscopy; glass transition temperature; glutaraldehyde; lower critical solution temperature; number-average molecular weight; phosphate buffer; poly(N-isopropylacrylamide); poly(N-isopropylacrylamide-co-N-hydroxyethylacrylamide); poly(NIPAAm); poly(NIPAAm-co-HEAAm); polydispersity index; volume phase transition temperature; weight-average molecular weight