Thermogelling Materials for Topical Drug Delivery

Abstract

This thesis describes the synthesis and characterisation of thermogelling materials and their evaluation as topical drug delivery excipients. Thermogelling materials are polymers which transition from solution to gel when heated above a critical temperature. For topical administration, these materials offer the benefit of easy application via an applicator and allow for enhanced retention and prolonged drug delivery in the gel state when warmed by the body. A review of the literature highlighted that poloxamer 407 is the most studied thermogelling polymer for drug delivery. However, these gels are typically weak as a result of their shear thinning behaviour and exhibit poor mucoadhesion as well as rapid dissolution. Alternate thermogelling materials within the literature are block copolymers containing a component which become insoluble in aqueous solution with an increase in temperature, also known as a lower critical solution temperature (LCST). For example, ABA copolymers of poly(N-isopropyl acrylamide) (PNIPAM) (A) (LCST = 32 °C) and PEG (B) exhibit thermogelling behaviour. Unfortunately, there are only a small number of polymers which exhibit LCSTs between 25 and 37 °C, required for topical drug delivery applications. Therefore, the first results chapter discusses the development of quantitative structure property relationships (QSPRs) with the aim of guiding the development of novel LCST exhibiting polymers. The best model derived in this work had a training set r2 of 0.56, training q2 of 0.35 and test r2 of 0.17, indicating this model not able to adequately predict LCST to within the narrow temperature range required for topical drug delivery applications. Guided by the literature, PNIPAM, poly(N,N-diethyl acrylamide) poly(2-Ndimethylamino) ethyl methacrylate) and poly(diethylene glycol methyl ether methacrylate) were used to synthesise novel ABA triblock copolymers with LCST exhibiting arms (A) and a central poly(ethylene glycol) (B) block. These were synthesised to target molecular weights of 10-4-10, 20-4- 20, 10-10-10 and 20-10-20 kDa. Following successful synthesis, the phase behaviour of these polymers was investigated in aqueous solution. All triblock copolymers were found to increase in viscosity with temperature at 20 % (w/v). The mechanism by which this gelation occurs was investigated by DLS and SANS, which highlighted these materials form polymer micelles which in concentrated solution interact, resulting in a gel. Some correlation was observed where smaller micelles formed more viscous gels, which is evaluated against existing theories governing the rheology of disperse systems. SANS indicated that the smaller aggregates are spherical micelles whereas larger structures are cylindrical in nature, negatively impacting the ability to form a gel. Two triblock copolymers were taken forward for further study, PNIPAM10-PEG10-PNIPAM10 and PDEA20-PEG10-PDEA20, based on the strengths of the gels formed and their biocompatibility. The rheology, mucoadhesion and stability of these polymers were found to offer advantages over poloxamer 407, indicating that both may have application in topical drug delivery. The solubility and release of progesterone and tenofovir disoproxil fumarate was investigated for all three polymers, as exemplar hydrophobic and hydrophilic drugs relevant to vaginal drug delivery. Sustained release over 140 h and 24 h was achieved for progesterone and tenofovir disoproxil fumarate from both synthetic thermogelling materials, respectively, prolonging delivery relative to poloxamer. Thus, these materials are attractive as novel thermogelling materials for topical drug delivery.