Long acting (LA) formulations of therapeutic compounds is of great interest in the current development of drug formulations. This is particularly true for chronic, life-long conditions such as HIV, where there is an associated pill burden for patients and the need for strict compliance with antiretroviral (ARV) regimens. Nanoformulation of hydrophobic ARV compounds has been utilised to facilitate long acting formulations of the integrase inhibitor cabotegravir and non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivrine-LA, but other classes of LA agents are needed. The LA approach aims to generate once monthly to quarterly or longer administration formats. Water soluble ARVs like nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are not suitable for common nanoformulation approaches, such as milling or Oil-in-Water emulsion templating. Here we describe a novel nanoformulation strategy in which Water-in-Oil (W/O) Solid Drug Nanoparticles (SDNs) of a highly water soluble dye (1,3,6,8-pyrenetetrasulfonic acid tetrasodium salt) (PTSA) were synthesised and subsequently dispersed within an oil depot. A total of 7 W/O SDN candidates were selected from the initial screening of stabiliser compounds. These SDNs had average hydrodynamic diameters that ranged from 86 nm to 257 nm. These candidates were synthesised with both 10 wt% and 50 wt% PTSA relative to stabiliser. Maximum release after 6 hours was 24% and 12.5% total mass of PTSA, for 10 wt% and 50 wt% loadings respectively. In both cases, the lead candidate showed 55% release of total mass of PTSA after 72 hours. Subsequently, the NRTI tenofovir disoproxil fumarate (TDF) was loaded in place of PTSA, and a single-phase nanoprecipitation approach used to increase drug loading to 80 wt%, relative to stabiliser. This method of synthesis allowed SDNs to be homogenously dispersed in an oil depot, with in vitro release assays using simulated interstitial fluid showing that the lead candidates had a release rate in the range of 0.0060 h-1 to 0.0124 h-1. This rate agreed with previously published PBPK data suggesting 1 month of therapeutic TDF levels could be achieved. The data show that water soluble agents can be dispersed within an oil depot, with subsequent release into an aqueous environment. This indicates a promising approach to developing sustained release SDN formulations of water soluble compounds, by encapsulating them within a hydrophobic environment.

Solid drug nanoparticles synthesised using water-in-oil emulsion templating and nanoprecipitation: From proof of concept to in vitro validation of long acting depot

254th National Meeting (2017)

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