In the present study, novel block copolymers of poly(l-lactide)-block-poly(propylene adipate) (PLLA-b-PPAd) were synthesized in two ratios, 90/10 and 75/25 w/w and were further investigated as long-acting injectable (LAI) polymeric matrices in naltrexone base microparticle formulations. The synthesized polymers were characterized by 1 H-NMR, 13 C-NMR, FTIR, XRD, TGA and DSC. NMR and FTIR spectroscopies confirmed the successful synthesis of copolymers while DSC showed that these are block copolymers with well-defined and separated blocks. Microparticles were prepared by single emulsification method and were further characterized. Nanoparticles in the range of 0.4-4.5 µm were prepared as indicated by SEM, with copolymers giving the lowest particle size. By XRD and DSC it was found that naltrexone was present in the amorphous state in its microparticles. Dissolution study showed a drug release extending over seven days, indicating that these novel PLLA-b-PPAd copolymers could be promising matrices for naltrexone's LAI formulations. It was evidenced that drug release depended on the copolymer composition. Model release studies showed that drug release is controlled by diffusion.Polymers 2020, 12, 852 2 of 24 as drug carriers are ε-polycaprolactone (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), their copolymer poly(lactide-co-glycolide) (PLGA), which are typically prepared by ring-opening polymerizations, and polyesters resulting from the polycondensation of an aliphatic diol and an aliphatic dicarboxylic acid such as poly(ethylene succinate), poly(ethylene adipate), poly(propylene adipate) (PPAd). Among them, PLA is by far the most extensively studied. However, the use of PLA suffers from some limitations due to its high crystallinity and low hydrolysis rate. Copolymerization is an easy method to modulate the properties of a polymer, by varying the rigidity/flexibility of polymer chains, the hydrophilic/hydrophobic balance and the amorphous/crystalline ratio [3]. Copolymerization of PLA with more hydrophilic and amorphous polymers has been carried out to modify the required biomaterial properties for specific applications [4].Naltrexone base (NTX) is a specific opioid antagonist, used in the treatment of both drug addiction and alcohol dependence. It is marketed in tablet form for oral administration but has some pharmacotherapeutic limitations (for example, a low oral bioavailability, as 98% of the drug is metabolized in the liver) and gastrointestinal side effects (nausea, abdominal pain, and vomiting). Treatment by oral administration of NTX requires a daily administration and its efficacy can be compromised due to the patient's non-compliance. Indeed, 37% of patients discontinue the daily oral use of NTX by 12 weeks and more than 80% discontinue its use by six months [5]. Currently there are two major types of sustained-release formulations for NTX delivery: (a) injectable depot formulations for long-acting release (Naltrel ® , Vivitrol ® , and Depotrex ® ), and (b) surgically implantable pellets (Pro...