Self-aggregating long-acting injectable microcrystals

Abstract

Injectable drug depots have transformed our capacity to enhance medication adherence through dose simplification. Central to patient adoption of injectables is the acceptability of needle injections, with needle gauge as a key factor informing patient discomfort. Maximizing drug loading in injectables supports longer drug release while reducing injection volume and discomfort. Here, to address these requirements, we developed self-aggregating long-acting injectable microcrystals (SLIM), an injectable formulation containing drug microcrystals that self-aggregate in the subcutaneous space to form a monolithic implant with a low ratio of polymer excipient to drug (0.0625:1 w/w). By minimizing polymer content, SLIM supports injection through low-profile needles (<25 G) with high drug loading (293 mg ml⁻¹). We demonstrate in vitro and in vivo that self-aggregation is driven by solvent exchange at the injection site and that slower-exchanging solvents result in increased microcrystal compaction and reduced implant porosity. We further show that self-aggregation enhances long-term drug release in rodents. We anticipate that SLIM could enable low-cost interventions for contraceptives.

Main

Long-acting drug delivery systems that can be self-administered via subcutaneous injections are highly desired. Such technologies combine the long-term drug release of surgically administered implant systems, which improve patient compliance by eliminating the need to remember to take a pill every day, with the ease of administration of injectables, which is particularly important for patients in low-resource settings without easy access to medical infrastructure (Fig. 1a)1. Needle size is a crucial consideration for the commercial translation of subcutaneous injectables: patient acceptance of therapeutics increases as needle size decreases, which is probably related to how smaller needles tend to cause less bruising or bleeding at the injection site (Fig. 1b)2,3. Furthermore, self-administration is possible only for relatively low formulation viscosities because patients can only comfortably apply a maximum of 64 N of force to a syringe by hand4. So far, however, it has been challenging for most marketed long-acting injectables to combine long durations of action (>3 months) with the capacity for self-administration through small-gauge needles as they rely on polymer excipients to sustain long-term drug release and secure mechanical integrity, which often substantially increase solution viscosity at required concentrations.

Existing long-acting injectables can be divided into two categories: microparticle suspensions and in situ forming implants (ISFIs)2. Microparticle suspensions leverage sustained release from micrometer-sized (1–1,000 μm) particles encapsulating solid or liquid drug substances within a polymeric matrix, whereas ISFIs are liquid or semisolid formulations that transform into solid-like structures at the target site. These systems release drugs through various mechanisms, including polymer degradation, cross-linking, phase separation via solvent exchange, and self-assembly into hydrogels5,6. In both types of formulations, it is challenging to combine effective long-term release with injectability through small-gauge needles compatible with self-administration, a problem that is particularly relevant for low-potency drugs (Supplementary Tables 1 and 2)7,8,9,10. While microparticle suspensions can achieve long release durations using slowly degrading polymers such as polylactic acid or polycaprolactone (PCL), their relatively low drug loading (% w/w) remains a potential concern for long-acting applications. Increasing particle size hampers injectability through smaller needles owing to clogging. Furthermore, the inability to easily retrieve these microspheres once administered poses challenges in scenarios where reversibility is required, such as removing contraceptive drugs to enable a return to fertility. Meanwhile, most previously reported ISFIs utilize formulations with high ratios of polymer to drug (typically >1:1 w/w), and increasing formulation concentration to increase drug loading reduces injectability because viscosity increases dramatically with higher concentrations of polymer excipients11. Indeed, the only currently US Food and Drug Administration-approved ISFIs (Atrigel and its derivatives, including Eligard, Sublocade and Perseris) all require administration through large 18–20 G needles (Supplementary Table 2)6.

Injectables in the form of micro/nanocrystal drug suspensions could circumvent the aforementioned challenges because they do not depend on polymeric excipients to modulate release. Instead, drugs are released through the surface-based erosion of each crystal12. Surface erosion can translate into markedly extended release times for poorly soluble drugs as compared with solubilized compounds. However, most drug crystal suspensions are aqueous formulations with limited duration of release and poor consistency because of their high surface area and the fact that their release kinetics depend on the crystal size distribution, which is difficult to control13,14. As with microparticle suspensions, drug crystal suspensions also cannot be easily retrieved after administration.

Although these challenges are applicable to most long-acting injectables, we focus on their unmet needs for contraception. A long-acting contraceptive implant that can be self-administered via injection would be a much-needed addition to the current suite of family planning options available to women, especially for people in low-resource settings where options for contraception and health care facilities are limited15. Currently, the only self-administrable commercialized contraceptive injectables are Depo-Provera and Sayana Press, which are both aqueous microcrystal suspensions that can be injected through moderately small needles (23 G and 26 G) because of the absence of polymer excipient16,17. However, compared with the surgically inserted 1.5-year-long contraceptive implant Nexplanon18, their duration of action is limited to only 3 months potentially because of the high surface area of the injected drug crystals.

To address the key challenges in self-administrable long-acting injectables, we designed self-aggregating long-acting injectable microcrystals (SLIM) for the contraceptive drug levonorgestrel (LNG), a progestin drug with a partition coefficient (logP) of 3.8 that is poorly soluble in aqueous environments19,20. The SLIM system has the following characteristics: (1) high drug loading (293 mg ml−1) with a low polymer-to-drug ratio over an order of magnitude lower than previous ISFIs (0.0625:1 w/w), (2) sufficiently low formulation viscosity to support injection forces <64 N through a 25 G needle and (3) the ability to self-aggregate into a solid implant in situ in the subcutaneous space with sufficient mechanical robustness and low surface area to enable sustained release over 3 months. This combination of properties is achieved by driving the self-aggregation of solid LNG microcrystals, with an average diameter of 2–3 μm (Supplementary Fig. 1), from suspension into a monolithic and compacted implant. Consistent with other granular systems comprising micrometer-scale particle building blocks, we propose that contact forces between compacted microcrystals are sufficient to enable the aggregated implant to behave like a monolithic solid (Fig. 1c)21. Furthermore, because LNG microcrystals are water-impermeable solids, LNG molecules are released into surrounding media via surface erosion (Supplementary Fig. 2). Without accounting for water infiltration into the aggregated implant, increasing the packing density of the LNG microcrystals is expected to reduce the average flux of active drug species from the implant and, thus, extend the total release time by reducing the outer surface area (Supplementary Note 1 and Supplementary Fig. 3). This effect is expected to be further magnified by the fact that increasing compaction should also reduce water infiltration into the bulk of the implant, which should increasingly confine drug release to the outer implant surface7.

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Feig, V.R., Park, S., Rivano, P.G. et al. Self-aggregating long-acting injectable microcrystals. Nat Chem Eng 2, 209–219 (2025). https://doi.org/10.1038/s44286-025-00194-x

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