This article presents BEPO®, an in situ forming depot (ISFD) technology mediated by a solvent-exchange mechanism. The matrix of the in situformed drug delivery depot is composed of the combination of a diblock (DB) and a triblock (TB) polyethylene glycol-polyester copolymer. This combination offers a broad capability to tune the release of a wide variety of drugs to the desired pharmacokinetics. The work described in the present article demonstrates that the delivery rate and profile can be adjusted by changing the composition of either TB or DB or the relative ratio between them, among other parameters. It has been shown that the polymeric composition of the formulation has a substantial impact on the solvent exchange rate between the organic solvent and the surrounding aqueous medium which subsequently determines the internal structure of the resulting depot and the delivery of the therapeutic cargo. This has been demonstrated studying the in vitro release of two model molecules: bupivacaine and ivermectin.

Formulations releasing these drugs have been administered to animal models to show the possibility of delivering therapeutics from weeks to months by using BEPO® technology.

This paper presents the in vitro and in vivo degradation of BEPO, a marketed in situ forming depot technology used for the formulation of long-acting injectables. BEPO is composed of a solution of a blend of poly(ethylene glycol)-block-poly(lactic acid) (PEG–PLA) triblock and diblock in an organic solvent, where a therapeutic agent may be dissolved or suspended. Upon contact with an aqueous environment, the solvent diffuses and the polymers precipitate, entrapping the drug and forming a reservoir. Two representative BEPO compositions were subjected to a 3-month degradation study in vitro by immersion in phosphate-buffered saline at 37 °C and in vivo after subcutaneous injection in minipig. The material erosion rate, as a surrogate of the bioresorption, determined via the depot weight loss, changed substantially, depending on the composition and content of polymers within the test item. The swelling properties and internal morphology of depots were shown to be highly dependent on the solvent exchange rate during the precipitation step. Thermal analyses displayed an increase of the depot glass transition temperature over the degradation process, with no crystallinity observed at any stage. The chemical composition of degraded depots was determined by 1H NMR and gel permeation chromatography and demonstrated an enrichment in homopolymers, i.e., free PLA and (m)PEG, to the detriment of (m)PEG–PLA copolymers in both formulations. It was observed that the relative ratio of the degradants within the depot is driven by the initial polymer composition. Interestingly, in vitro and in vivo results showed very good qualitative consistency. Taken together, the outcomes from this study demonstrate that the different hydrolytic degradation behaviors of the BEPO compositions can be tuned by adjusting the polymer composition of the formulation.

Biodegradable and biocompatible polymer materials with tunable physical properties present a great interest for controlled drug delivery applications. A good example is BEPO®, a clinical-stage in situ-forming depot technology based on the utilization of a blend of poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-PLA) diblock and triblock amphiphilic copolymers dissolved in an organic solvent. Once injected, this technology will form a bioresorbable solid polymer depot that will allow the release of a drug from weeks to months. The safety of the final degradation products from this technology, i.e., PEG and lactic acid, is well-documented. However, little information exists about the fate of intermediate degradants, specifically of water-soluble PEG-PLA chains where the molecular weights of the PLA block are short. Herein, we designed a Förster Resonance Energy Transfer (FRET) system for short copolymers, suitable for longitudinal in vivo imaging in the subcutaneous space, allowing to follow the stability of these products. Our results confirm that these species, that might be leaked from BEPO® depots during degradation, are rapidly hydrolyzed in the subcutaneous space of mice, forming approved products by Health Authorities, i.e., PEG and PLA homopolymers and/or lactic acid.