Fabrication of Polymeric Materials as Thermo-responsive Gels for Drug Delivery System

Abstract

Novel thermo-responsive hydrogels comprising 4% w/w Methylcellulose (MC) and various Pluronic F127 (PF) concentrations (12, 14, 16, 18, and 20% w/w) were successfully developed and characterized. The interesting thing in this work was neat 12PF and 14PF solutions did not form gel but blending with MC could form gel. Visual appearance of the PF/MC blends (12PF/MC, 14PF/MC, 16PF/MC, 18PF/MC, and 20PF/MC) were clear solutions at ambient temperature and exhibited turbid hard gel at physiological temperature. The turbidity during heating of these blends may be caused by the effect of MC on the PF system. The critical micelle concentration (CMT) and the enthalpy of micellization were reduced by including MC into PF. The sol-to-gel transition temperature can be modulated and decreased by increasing PF concentrations. Besides, 4x10-3 M Etidronate sodium (EDS); used to treat hypercalcemia and osteoporosis was added into hydrogels and investigated their gels behavior. EDS at a centration of 4x10-3 M, did not alter the thermosensitive gelation and the phase behavior of the blends. Thus, this study indicates that blending of PF with MC is a potential method to improve the thermal characteristics of in situ gel-forming drug delivery systems. Among of the blends, 12PF/MC and 14PF/MC blends were selected for further study. Since their characteristics were in solution state near ambient temperature (24 °C) and formed in situ gels at body temperature (37 °C). These mixtures were found to be suitable as injectable implant matrices. 12PF/MC and 14PF/MC showed substantially better mucoadhesive properties than neat 12PF and 14PF, respectively. Furthermore, the biocompatibility of these mixtures was well shown on fibroblasts. The next study was addition the Doxycycline hyclate (DX) at concentrations of 0.25 and 0.5% w/w into 12PF/MC and 14PF/MC blends and evaluated its effectiveness for using as a periodontal drug delivery system. Although, the gelation temperature and viscosity of the DX-loaded blends were changed at high temperatures range. However, all blends still exhibited gel-like characteristics covering the ambient and body temperature. Moreover, DX-incorporated 12PF/MC and 14PF/MC blends presented the same antibacterial activity as the pure drug solution. This indicated that both PF/MC matrices did not prohibit the antibacterial activity of the drug. The 12PF/MC and 14PF/MC also exhibited slow-release profile of DX. Therefore, in the present study demonstrated that the appropriate mixtures of thermo-responsive of PF/MC are promising matrices for the development of an efficient periodontal drug delivery system. The small-angle X-ray scattering (SAXS) was applied for study the behavior of PF/MC blends which related to the temperature-dependent phase transition and rheological characteristic. The blending of PF/MC in this study were 11PF, 17PF, 11PF/MC, and 17PF/MC. As results of test tube tilting method and rheological analysis, 11PF cannot form gel. But blending 11PF with 4% w/w methylcellulose (MC) (11PF/MC) enabled the system to form gel upon heating. In addition, adding MC into 17 PF (17PF/MC) could reduce the gelation temperature of 17PF. The ordered structure of these gels exhibited a face-centered cubic (FCC) phase at intermediate temperature above the gelation temperature; the steep upturn of the SAXS curves was observed in the small scattering vector range at high temperatures (55–70 °C). This occurrence was a result of MC-assisted interconnected network of micelles at high temperatures. This gelation may be related to that MC assisted intermicellar organization the PF micelle structure, similar to the gelation network of MC. In addition, EDS was incorporated into the matrices. The results found that the drug did not significantly affect the thermosensitive gelation and the ordered structure of the polymeric systems. Moreover, the blend of 11PF/MC was solution at 25 °C and became gel at body temperature of 37 °C. Therefore, this study revealed that blending PF with MC is a potential strategy for modulating the thermosensitive characteristics of the in situ gel forming drug delivery.