Surmounting substance use disorder using an ultra-long acting injectable platform. - Substance use disorder (SUD) is a relapsing condition and demands pharmacotherapy for several years. Long-
acting injectables and implants have improved patient adherence to medications used for SUD. For both
naltrexone and buprenorphine, although implants exhibit significantly longer release, compared to injectables,
they require surgical intervention for insertion/removal, are prone to local infection and inflammation, and have
sub-optimal pharmacokinetics (PK). Long-acting injectables of naltrexone and buprenorphine only provide 30
days of drug release, which is sub-optimal, as SUD is a relapsing condition and typically demands therapy for
several years. Additionally, previously developed long-acting injectables for SUD result in significant initial burst
release of the drug, and a steady plasma level is attained only after 30-60 days, which increases the risk for side
effects. Despite the clear unmet need for an ultra-long-acting injectable for SUD treatment, hydrophilicity of
clinically relevant drugs, including naltrexone, buprenorphine, acamprosate, and nalmefene makes it extremely
difficult to formulate their ultra-long-acting injectables. We have recently engineered a solvent-free and injectable
in situ crosslinking depot (ISCD) from an ultra-low molecular weight, liquid polymer which forms a dense mesh-
neatwork and enables ultra-long-lasting delivery of hydrophilic drugs. The solid monolithic depot integrates the
unique advantages of injectability and retrievability. Our overall objectives in this application, are to (i) explore
the feasibility of this platform for ultra-long-acting delivery of naltrexone in vitro and in vivo, and (ii) evaluate
loading and in vitro release of other SUD related therapeutics with varying hydrophilicity. Our central hypothesis
is that the dense mesh network of ISCD will minimize water influx/efflux and this combined with minimal initial
burst due to solvent-free nature of ISCD will achieve long-term sustained drug release. Our long-term goal is to
utilize this ISCD platform for developing ultra-long-acting injectables of promising therapeutic agents for the
treatment of SUD. To achieve our overall objectives, we will pursue the following specific aims: 1) maximize
naltrexone loading in ISCD, and tune release kinetics, 2) evaluate biocompatibility of naltrexone-loaded ISCD,
and determine degradation, and 3) evaluate loading and in vitro release of other therapeutics relevant to SUD.
The research proposed in this application is innovative, in our opinion, because it focuses on a new injectable
formulation, wherein an ultra-low molecular weight polymer undergoes chemical transformation to form a dense
mesh, which limits water influx/efflux and hence the drug release. Additionally, liquid state of the polymer obviates
the need for solvent, preventing high burst release due to solvent exchange process, as observed in ISFI.
Utilizing this innovative platform, we will be the first to demonstrate long-acting release of naltrexone and other
SUD related therapeutics for at least 4-6 months from an injectable platform, thereby opening new horizons for
development of ultra-long-acting therapies for SUD patients.