From Depots to Smart Delivery: Evolution of Long-Acting Drug Delivery Systems

Abstract

Long-acting drug delivery systems (LADDS) provide prolonged and controlled drug release, reducing dosing frequency and improving therapeutic consistency. This review discusses the development of long-acting injectable and implantable systems, focusing on crystalline and nanocrystalline depots, oil- and prodrug-based formulations, polymeric microspheres, lipid-based systems, injectable hydrogels, in-situ forming depots, and implantable platforms. The mechanisms governing drug release, including dissolution, diffusion, polymer degradation, swelling, and erosion, are also discussed. Recent advances in smart and programmable systems are highlighted alongside formulation, manufacturing, sterility, stability, and regulatory challenges. Overall, emerging LADDS aim to achieve predictable release, improved patient acceptability, and enhanced clinical translation.

Introduction

Long-acting drug delivery systems are designed to maintain therapeutic drug concentrations for days, weeks, months, or longer while reducing dosing frequency and fluctuations in drug exposure. Long-acting injectables (LAIs) achieve this by creating a drug depot at the administration site. Major challenges include burst release, injection-site reactions, injectability, formulation stability, and manufacturing complexity.

The fundamental principle is depot formation, in which the formulation remains at the injection site and gradually releases the drug. Modern injectable systems may transform from low-viscosity liquids into semisolid or solid depots through processes such as polymer cross-linking, organogel formation, or solvent exchange. The resulting release profile depends on drug properties, depot architecture, polymer characteristics, particle size, drug loading, and the surrounding physiological environment.

Major drug-release mechanisms

The review identifies several mechanisms governing drug release:

1. Diffusion-controlled release – Drug molecules migrate through polymer matrices, hydrogels, lipid phases, or pores into surrounding tissue.
2. Dissolution-controlled release – Particularly important for poorly soluble crystalline drugs, where dissolution rate determines how rapidly the drug becomes available for absorption.
3. Polymer degradation/erosion – In systems such as PLGA depots, water penetration and polymer hydrolysis progressively create pores and eventually cause matrix erosion.
4. Swelling and polymer relaxation – Hydrophilic polymers and hydrogels absorb fluid and expand, increasing drug mobility and diffusion pathways.
5. Stimuli-responsive release – Temperature, pH, enzymes, or ionic conditions can trigger or modify drug release.
6. Combined mechanisms – Most practical LAIs involve multiple simultaneous mechanisms, such as diffusion followed by polymer degradation or sequential release through multiple barriers.

Release kinetics

Mathematical models are used to interpret experimental release profiles and identify the mechanisms that may dominate. The major models discussed are:

The review appropriately notes that a good kinetic-model fit does not necessarily prove a single release mechanism, because several processes can occur simultaneously.

Injectable LAI systems

The text then classifies injectable long-acting systems according to their depot architecture.

1. Crystal and nanocrystal depots

Here, the drug itself forms the depot. Poorly water-soluble drugs are formulated as microcrystals or nanocrystals, with release primarily controlled by particle size, solubility, crystallinity, and exposed surface area. Larger crystals generally provide slower dissolution and longer release.

The montelukast example demonstrates this size-dependent behavior: approximately 200-nm and 500-nm particles released substantially faster than 3-μm crystals. The study also illustrates that the biological response at the injection site can contribute to the overall release behavior.

2. Oil- and prodrug-based depots

These systems use an oily vehicle to reduce drug contact with aqueous tissue fluids and thereby slow dissolution and absorption. Converting a drug into a more lipophilic prodrug can further increase tissue retention and prolong release. The text introduces entecavir 3-palmitate (EV-P) as an example of this approach.

Overall concept

The complete release process can be summarized as:

Injection → Depot formation → Hydration/solvent exchange → Dissolution or swelling → Diffusion and/or polymer degradation → Tissue release → Systemic absorption

The dominant rate-controlling step determines the duration, magnitude of burst release, and overall shape of the pharmacokinetic profile.

Central research theme

The key design challenge in LAI development is achieving a balance among:

Long duration + controlled release + high drug loading + easy injectability + acceptable local tolerability + formulation stability

Conclusion

Long-acting drug delivery systems have evolved into diverse injectable and implantable platforms capable of providing prolonged and controlled drug release. Injectable depots, polymeric microspheres, lipid-based systems, hydrogels, and implants employ mechanisms including dissolution, diffusion, polymer degradation, swelling, and erosion to extend therapeutic exposure. However, successful LAI development requires more than prolonged release, with burst release, injection-site tolerability, material variability, manufacturing complexity, and prediction of in-vivo performance remaining important challenges. Future development should therefore integrate rational formulation design, appropriate release-kinetic evaluation, predictive in-vitro methods, reproducible manufacturing, and patient-centred considerations. Such integration can support safer, more predictable, scalable, and clinically translatable long-acting therapies.

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Copyright

Copyright © 2026 Ritu Londhekar, Svaraj Nalavade, Mr. Rajratan Thorat. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.