Prodrug approaches for the development of a long-acting drug delivery systems

Long-acting formulations are designed to reduce dosing frequency and simplify dosing schedules by providing an extended duration of action. One approach to obtain long-acting formulations is to combine long-acting prodrugs (LA-prodrug) with existing or emerging drug delivery technologies (DDS). The design criteria for long-acting prodrugs are distinct from conventional prodrug strategies that alter absorption, distribution, metabolism, and excretion (ADME) parameters. Our review focuses on long-acting prodrug delivery systems (LA-prodrug DDS), which is a subcategory of long-acting formulations where prodrug design enables DDS formulation to achieve an extended duration of action that is greater than the parent drug. Here, we define LA-prodrugs as the conjugation of an active pharmaceutical ingredient (API) to a promoiety group via a cleavable covalent linker, where both the promoiety and linker are selected to enable formulation and administration from a drug delivery system (DDS) to achieve an extended duration of action. These LA-prodrug DDS results in an extended interval where the API is within a therapeutic range without necessarily altering ADME as is typical of conventional prodrugs. The conversion of the LA-prodrug to the API is dependent on linker cleavage, which can occur before or after release from the DDS. The requirement for linker cleavage provides an additional tool to prolong release from these LA-prodrug DDS. In addition, the physicochemical properties of drugs can be tuned by promoiety selection for a particular DDS. Conjugation with promoieties that are carriers or amenable to assembly into carriers can also provide access to formulations designed for extending duration of action. LA-prodrugs have been applied to a wide variety of drug delivery strategies and are categorized in this review by promoiety size and complexity. Small molecule promoieties (typically MW < 1000 Da) have been used to improve encapsulation or partitioning as well as broaden APIs for use with traditional long-acting formulations such as solid drug dispersions. Macromolecular promoieties (typically MW > 1000 Da) have been applied to hydrogels, nanoparticles, micelles, dendrimers, and polymerized prodrug monomers. The resulting LA-prodrug DDS enable extended duration of action for active pharmaceuticals across a wide range of applications, with target release timescales spanning days to years.