Ultra-long-acting tunable biodegradable and removable controlled release implants for drug delivery

Abstract

Here we report an ultra-long-acting tunable, biodegradable, and removable polymer-based delivery system that offers sustained drug delivery for up to one year for HIV treatment or prophylaxis. This robust formulation offers the ability to integrate multiple drugs in a single injection, which is particularly important to address the potential for drug resistance with monotherapy. Six antiretroviral drugs were selected based on their solubility in N-methyl-2-pyrrolidone and relevance as a combination therapy for HIV treatment or prevention. All drugs released with concentrations above their protein-adjusted inhibitory concentration and retained their physical and chemical properties within the formulation and upon release. The versatility of this formulation to integrate multiple drugs and provide sustained plasma concentrations from several weeks to up to one year, combined with its ability to be removed to terminate the treatment if necessary, makes it attractive as a drug delivery platform technology for a wide range of applications.

Multi-stakeholder consensus on a target product profile for an HIV cure

“…This debate regarding the efficacy of the minimally acceptable cure in relation to highly effective existing options (eg, ART) shaped the discussions on nearly all attributes; indeed, many noted that ART will be even further optimised, potentially with very long-acting options available by the time a curative intervention would be implemented. 23 Although the minimum attributes for a cure were debated, the broad consensus was that there will likely always be a need for a short-term intervention that provides durable health benefits, and that an acceptable cure need not be as safe and effective as optimally delivered ART. An intervention that successfully cured a reasonable fraction of adults would be sufficient to advance to the clinic and would provide important learnings for future iterations.…”

“…Currently, the minimum is based on exceeding the most optimistic case for long-acting ART, which might eventually be up to 1 or 2 years. 21 , 22 , 23 …”

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

“…Recently, we developed an in-situ forming implant (ISFI) injectable formulations for LA delivery of dolutegravir (DTG) ( Kovarova et al, 2018 ; Benhabbour et al, 2019 ). These formulations provided sustained delivery of DTG for up to 9 months and in vivo efficacy against high dose vaginal HIV challenges in a pre-clinical humanized mouse model ( Kovarova et al, 2018 ; Benhabbour et al, 2019 ). In this study, adapting from the recently developed ISFIs, we developed a new and unique process to engineer polymeric solid implants (PSIs) to further improve drug loading capacity to achieve clinically translatable doses within a single administration.…”

The pharmaceutical solvent N-methyl-2-pyrollidone (NMP) attenuates inflammation through Krüppel-like factor 2 activation to reduce atherogenesis

“…Given its safety profile at established doses 30 , 34 and its competence to solubilize multiple types of drugs, NMP has become a common solvent component of in situ forming implants 35 – 37 , for long-term drug delivery 38 , 39 . NMP acts as a co-solvent and as a complexing agent in different embodiments as it has been reported to increase the solubility and permeability of multiple compounds 36 , 40 – 42 . Transcriptional activity of bromodomain-containing proteins is compromised by NMP interaction with the binding pocket of a different bromodomains, what would contribute to its anti-myeloma and immunomodulatory activity 43 .…”

“…NMP is remarkably effective in maintaining dispersions of different types of nanomaterials [31][32][33] . Given its safety profile at established doses 30,34 and its competence to solubilize multiple types of drugs, NMP has become a common solvent component of in situ forming implants [35][36][37] , for long-term drug delivery 38,39 . NMP acts as a co-solvent and as a complexing agent in different embodiments as it has been reported to increase the solubility and permeability of multiple compounds 36,[40][41][42] .…”