Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy

Abstract

Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥1week, ≥1month or ≥6months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.

Keywords: Controlled-release; Drug delivery; Extended-release; Formulation; Nanomedicine; Pharmacokinetics; Sustained-release; Time-release.

Figure 1

Diagrammatic representation of the relationship between pharmacokinetics and potency for theoretical long-acting formulations. It can be seen that a prolonged higher pharmacokinetic exposure, with the associated technological challenges, will be required to achieve a long-acting strategy for an API with lower potency compared with an API with higher potency. Ultimately, potency determines how much drug is required and for how long in order to achieve long-acting delivery.

Figure 2

Results of a Google search with combinations of different nomenclature used to describe long-acting delivery with different routes of delivery, illustrating the interchangeable use of currently applied terminology.

Figure 3

Schematic representation of the main technologies used for long acting injections. Depots may be delivered A) subcutaneously or B) intramuscularly and utilise either C) oil-based solutions, D) drug particle suspensions, E) drug encapsulated in polymer microparticles, or F) in-situ formation of gels or solid/semi-solid structures.

Figure 4

Diagrammatical representation of the anatomical relationship between blood and lymphatic capillaries. Drug may theoretically enter the systemic circulation through either route since the lymphatics ultimately drain into the eventually empties into the left internal jugular and left subclavian veins. It is currently unknown whether intact nanoparticles enter the systemic circulation or whether dissolved molecule predominates. However, as elaborated in the text, there is a theoretical route for direct entry of nanoparticles either through endothelium endocytic mechanisms or through the intercellular clefts between endothelial cells.