HIV is a global public health threat and requires life-long, daily oral dosing to effectively treat. This pill burden often results in poor adherence to the medications. An injectable in situ forming implant (ISFI) with tuneable drug release kinetics would allow patients to replace some of their daily pills with a single injection. We have recently shown promising proof of concept data for a novel ISFI based on a colloidal assembly of two types of nanoparticles. In this system, poly(N-isopropyl acrylamide) (polyNIPAm) nanogels show a synergistic dual-stimuli responsive behaviour which require the simultaneous stimuli of body temperature and physiological ionic strength to cause aggregation of the nanogel particles into a solid implant. The reservoir of drug was provided by solid drug nanoparticles (SDNs) which are nanoparticles composed entirely of solid drug, stabilised by amphiphilic molecules. In our new work, we show how drug release behaviour can be tuned by changing the size of the nanogels. Four polyNIPAm nanogels were synthesised by dispersion polymerisation with mean diameters of 65-450 nm. SDNs of the HIV drug lopinavir were prepared with a mean diameter of 330 nm. The exposure of a mixed dispersion of the nanogels and SDNs resulted in the formation of a solid nanocomposite implant. The drug release behaviour and stability of these nanocomposite implants displayed a single phase of drug release indicated Fickian diffusion. Nanocomposites with the lowest loading of SDNs (33%) showed a linear relationship between nanogel diameter and the dissolution constant (see figure). We hypothesise that the larger nanogels result in more porous nanocomposites which leads to faster drug release. These results show an attractive method for tuning the release of lopinavir from in situ loading implants with high loadings of solid drug nanoparticles (up to 66%) that provide long acting drug release behaviour.

Tuning long-acting HIV drug release from a nanogel-based in situ forming implant

2019 Fall National Meeting

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