Rilpivirine Prodrug Nanoformulation (NM3RPV)

Associated long-acting platforms

Aqueous drug particle suspension

Administration route

Intramuscular

Therapeutic area(s)

Use case(s)

Use of drug

Dosage

Drug information

Delivery device(s)

No delivery device

Scale-up prospects

The NM3RPV formulation is in preclinical development and has only been produced at small-scale for research use.

Tentative equipment list for manufacturing

Avestin EmulsiFlex-C3 high-pressure homogenizer, rotary evaporator, silica column chromatography. RPV and M3RPV samples were separated on a Phenomenex Kinetex 5 μm C18 column (150 × 4.6 mm) (Torrance, CA).

Manufacturing

Nanoformulations of RPV and M3RPV (NRPV and NM3RPV, respectively) were manufactured using an Avestin EmulsiFlex-C3 high-pressure homogenizer (Ottawa, ON, Canada). NRPV was prepared to best replicate RPV LA developed by Janssen. Specifically, 1% (w/v) P338 was dispersed in H2O, followed by the addition of 10% (w/v) RPV-free base and mixing overnight. Similarly, NM3RPV contained 2.1% P407 and 21% M3RPV in H2O. Formulations were homogenized at 20,000 psi to generate homogeneous nanocrystals of uniform size and polydispersity.

Specific analytical instrument required for characterization of formulation

Nanoparticle physicochemical characterization for size (nm), PDI and zeta potential (mV) were evaluated by dynamic light scattering (DLS, Malvern Zetasizer Nano-ZS, Worcestershire, UK). NM3RPV and NRPV drug quantitation was conducted by UPLC-UV/Vis. Drug quantitation was performed on a Waters ACQUITY ultra-performance liquid chromatography (UPLC) H-Class system with TUV detector and Empower 3 software (Milford, MA).

Proprietary excipients used

Not provided

Novel excipients or existing excipients at a concentration above Inactive Ingredients Database (IID) for the specified route of administration

The novel excipient poloxamer 338 (P338) is used in the final RPV (NM3RPV) formulation. Following both an in-vitro mammalian chromosome aberration and an Ames test, it was considered to be non-genotoxic with no evidence for mutagenicity. Further P338 fertility, genotoxicity and development studies have been conducted with no negative effects, in addition to a 6-week and 9-month minipig repeat-dose toxicity study. No adverse local or systemic toxicity was reported in the minipigs at 100mg/month (Margin of Exposure:19).

Residual solvents used

Not provided

There are either no relevant patents or these were not yet submitted to LAPaL

Publications

James R. Hilaire, Aditya N. Bade, Brady Sillman, Nagsen Gautam, Jonathan Herskovitz, Bhagya Laxmi Dyavar Shetty, Melinda S. Wojtkiewicz, Adam Szlachetka, Benjamin G. Lamberty, Sruthi Sravanam, Howard S. Fox, Yazen Alnouti, Prasanta K. Dash, JoEllyn M. McMillan, Benson J. Edagwa, Howard E. Gendelman, Creation of a long-acting rilpivirine prodrug nanoformulation, Journal of Controlled Release, Volumes 311–312, 2019, Pages 201-211, ISSN 0168-3659, DOI: https://doi.org/10.1016/j.jconrel.2019.09.001.(https://www.sciencedirect.com/science/article/pii/S0168365919305346)

Antiretroviral therapy requires lifelong daily dosing to attain viral suppression, restore immune function, and improve quality of life. As a treatment alternative, long-acting (LA) antiretrovirals can sustain therapeutic drug concentrations in blood for prolonged time periods. The success of recent clinical trials for LA parenteral cabotegravir and rilpivirine highlight the emergence of these new therapeutic options. Further optimization can improve dosing frequency, lower injection volumes, and facilitate drug-tissue distributions. To this end, we report the synthesis of a library of RPV prodrugs designed to sustain drug plasma concentrations and improved tissue biodistribution. The lead prodrug M3RPV was nanoformulated into the stable LA injectable NM3RPV. NM3RPV treatment led to RPV plasma concentrations above the protein-adjusted 90% inhibitory concentration for 25 weeks with substantial tissue depots after a single intramuscular injection in BALB/cJ mice. NM3RPV elicited 13- and 26-fold increases in the RPV apparent half-life and mean residence time compared to native drug formulation. Taken together, proof-of-concept is provided that nanoformulated RPV prodrugs can extend the apparent drug half-life and improve tissue biodistribution. These results warrant further development for human use.

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