A new engineering process of biodegradable polymeric solid implants for ultra-long-acting drug delivery

Abstract

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.

Pathways for Dolutegravir Transformation from a Daily Oral to a Once-a-Year Parenteral Medicine

“…Notably, other groups have also modified the structure and or delivery of DTG to develop the means to extend the drug's half-life [29,[38][39][40][41]. In one LA biodegradable polymeric solid implants were developed by phase inversion producing removable implants [41].…”

Long-acting HIV pre-exposure prophylaxis (PrEP) approaches: recent advances, emerging technologies, and development challenges

“…The formulation provided sustained CAB release above established PrEP benchmarks and durable protection against SHIV infection for up to 6 months and resulted in a short drug tail upon removal [ 107 ]. Combining ISFI technology with micronization and compression, polymeric solid implants (PSI) were fabricated to provide sustained release of DTG [ 108 ] or DTG/RPV in combination [ 109 ] over several months. An injectable LA formulation of doravirine (NNRTI) that forms an implant after SC administration has also been developed and showed that drug plasma concentrations exceeded IC 95 for >5 months in mice and efficiently prevented vaginal HIV transmission after multiple HIV challenges [ 110 ].…”

Polymeric long-acting drug delivery systems (LADDS) for treatment of chronic diseases: Inserts, patches, wafers, and implants

“…Some LADDS require complex manufacturing methods where organic solvents might be used which poses safety concerns. Nevertheless, LADDS have proven to be a success in improving treatment outcomes for patients suffering from chronic eye diseases, diabetes, cancer, and brain diseases; either through improving bioavailability, reducing unwanted side effects, achieving drug targeting or promoting better patient treatment adherence [230,231]. Several issues are yet to be resolved such as the cost and availability of biomaterials used to fabricate LADDS, the nature of complex systems of some LADDS, reliance of drug on external stimuli (light, laser and application of Magnetism) of the carrier for obtaining consistent drug release that make the regulatory approval of some LADDS.…”