Biodegradable polymeric solid implants for ultra-long-acting delivery of single or multiple antiretroviral drugs
Panita Maturavongsadit, Roopali Shrivastava, Craig Sykes, Mackenzie L. Cottrell, Stephanie A. Montgomery, Angela D.M. Kashuba, S. Rahima Benhabbour,
International Journal of Pharmaceutics,
Volume 605, 2021,120844, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2021.120844.
(https://www.sciencedirect.com/science/article/pii/S0378517321006499)
Lack of adherence is a key barrier to a successful human immunodeficiency virus (HIV) treatment and prevention. We report on an ultra-long-acting (ULA) biodegradable polymeric solid implant (PSI) that can accommodate one or more antiretrovirals (e.g., dolutegravir (DTG) and rilpivirine (RPV)) at translatable human doses (65% wt.) in a single implant. PSIs are fabricated using a three-step process: (a) phase inversion of a drug/polymer solution to form an initial in-situ forming solid implant, (b) micronization of dried drug-loaded solid implants, and (c) compression of the micronized drug-loaded solid powder to generate the PSI. DTG and RPV can be pre-combined in a single PLGA-based solution to make dual-drug PSI; or formulated individually in PLGA-based solutions to generate separate micronized powders and form a bilayer dual-drug PSI. Results showed that in a single or bilayer dual-drug PSI, DTG and RPV exhibited physicochemical properties similar to their pure drug analogues. PSIs were well tolerated in vivo and effectively delivered drug(s) over 180 days with concentrations above 4× PA-IC90 after a single subcutaneous administration. While biodegradable and do not require removal, these PSIs can safely be removed to terminate the treatment if required. The versatility of this technology makes it attractive as an ULA drug delivery platform for HIV and various therapeutic applications.
Keywords: Polymeric solid implants; Long-acting drug delivery; Poly(lactic-co-glycolic acid) (PLGA); Dolutegravir; Rilpivirine; HIV prevention
A new engineering process of biodegradable polymeric solid implants for ultra-long-acting drug delivery.
Maturavongsadit, P., Paravyan, G., Kovarova, M., Garcia, J. V., & Benhabbour, S. R. (2020).
International journal of pharmaceutics: X, 3, 100068.
https://doi.org/10.1016/j.ijpx.2020.100068
We present a long-acting (LA) biodegradable polymeric solid implant (PSI) fabricated using a new process combining in-situ phase inversion and compression. This robust process allows fabrication of solid implants that can have different shapes and sizes, accommodate high drug payloads, and provide sustained drug release over several months. Herein the integrase inhibitor dolutegravir (DTG) was used to develop PSIs for HIV prevention. PSIs were fabricated using a three-step process by (a) phase inversion of DTG-loaded polymer solution to form an initial in-situ forming implant in an aqueous solution, (b) micronization of dried DTG-loaded solid implants, and (c) compression of the micronized DTG-loaded solid implants to form the PSI. High drug loading (up to 85 wt%) was achieved in the PSIs. DTG exhibited minimum burst release in the first 24 h (<6%) and sustained release kinetics over 6 months. The release kinetics of DTG can be fine-tuned by varying drug-loading concentration, the ratio of polymer (poly(lactic-co-glycolic acid), PLGA) to solvent (N-methyl-2-pyrrolidone, NMP) and polymer (PLGA) molecular weight in the precursor solution. The physical/chemical properties of DTG were retained post-storage under accelerated storage conditions (40 °C/75% relative humidity) for 6 months. The versatility of this technology makes it an attractive drug delivery platform for HIV prevention applications.
Keywords: Solid implants, In-situ, Phase inversion, Compression, Long-acting drug delivery, Poly(lactic-co-glycolic acid), HIV prevention
