Long-acting Drug Delivery Systems
Present and Future
Prof. Eneko Larraneta, Chair in Pharmaceutical Materials Science, School of Pharmacy, Queen’s University Belfast
Dr. Juan Domínguez-Robles, Ramon y Cajal Fellow, Departamento de farmacia y tecnología farmacéutica, Universidad de Sevilla
Conventional drug delivery methods face challenges like fluctuating drug levels and poor bioavailability. Long-acting drug delivery systems (LADDS) provide steady drug release, improving efficacy and safety, especially for chronic conditions. Innovations in materials, nanotechnology, and 3D printing are driving LADDS development, with the market valued at $11.41 billion in 2022.
Current clinical therapies rely predominantly on intermittent drug administration, with oral and intravenous routes being the most employed. These routes deliver high concentrations of drugs into the bloodstream shortly after administration. However, drug levels often fall below therapeutic thresholds within a few hours, leading to the so-called “peak-and-valley” effect. This fluctuation is far from ideal, as excessively high drug concentrations can be toxic, while insufficient levels fail to provide therapeutic benefit.
The oral route poses additional challenges. Drugs administered orally must withstand the harsh conditions of the gastrointestinal tract, including an acidic environment and the presence of numerous enzymes that may degrade the drug before absorption. Furthermore, first-pass metabolism in the liver significantly reduces the bioavailability of many therapeutic compounds. To address these limitations, multiple doses are often required to maintain drug concentrations within the therapeutic window, which is crucial for managing chronic and long-term conditions. This is a pressing issue, as the incidence of chronic conditions is rising globally due to the ageing population.
Some medical conditions demand high drug concentrations at specific sites of action. While increasing the dose can achieve this, it may result in toxic levels in the bloodstream or other organs. Consequently, there is a pressing need for advanced drug delivery systems capable of providing long-term drug delivery. These systems aim to keep drug concentrations within the therapeutic range, thereby maximising efficacy while minimising toxicity and side effects. Long-acting drug delivery systems (LADDSs) represent a promising solution to these challenges.
LADDSs include a wide range of designs, including implants, nanoparticle-based formulations or in situ forming gels among others. The development of these systems requires a multidisciplinary approach, integrating material science, engineering, pharmaceutical sciences, biology, and medicine. The origins of LADDS date back to the 1930s, when hormone-loaded pellets were implanted subcutaneously in livestock to enhance growth efficiency, revolutionising meat production. This technology was later adapted for medical use, such as treating premature menopause in women.
Although LADDS were first introduced nearly 90 years ago, interest in these systems has grown significantly over the past two decades (Figure 1). Their potential extends beyond academic research, as pharmaceutical companies actively invest in developing new LADDS products. These advancements are often part of lifecycle management strategies for existing drugs, as well as for new therapeutic compounds. The global long-acting drug delivery technologies market was valued at $11.41 billion in 2022 and is projected to grow at a compound annual rate of 11.31% through to 2033. This growth reflects the increasing recognition of LADDS as a viable alternative to conventional drug delivery methods.
Recent advances in manufacturing techniques and micro/nanotechnology have expanded the capabilities of LADDS, enabling the creation of more sophisticated systems with enhanced properties tailored to specific clinical needs. For example, nanoparticle-based suspensions and biodegradable implants have emerged as effective strategies to achieve sustained drug release.
LADDS have been utilised across a broad range of medical applications, including contraception, cancer treatment, ocular conditions, pain management, nasal polyps, and disorders affecting the central nervous system. These systems employ diverse materials and methodologies in their design and fabrication. LADDS can take various forms, including solid implants, depot-forming implants, and long-acting injectable formulations. Table 1 shows a summary of commercial LADDS products. A thorough list of approved and discontinued products can be found here:
A wide array of materials is used to create these systems, ranging from metals and biodegradable polymers to non-biodegradable polymers, hydrogels, and self-assembled gels. Each material type contributes unique properties, enabling tailored designs to meet specific therapeutic needs.
As previously mentioned, the development of LADDS requires a multidisciplinary approach. Chemistry plays a key role in many of the latest advancements in this field. Researchers are continually synthesising new polymers and drug complexes to achieve sustained drug release. These polymers can be used to create nanoparticles for drug encapsulation, in situ forming implants, or pre-formed solid implants. One of the most common strategies involves the development of thermoresponsive gels, which remain liquid at room temperature but form gels at physiological temperatures. These gels, often composed of biocompatible polymers such as lactic/glycolic acid polymers and poly (ethylene glycol), can trap drugs within their structure, enabling their gradual release.
Another approach is to covalently bind drug molecules to polymers or other compounds via ester bonds, allowing controlled drug release through hydrolysis. This strategy has been employed in approved prodrugs such as paliperidone palmitate. Additionally, drugs can be combined with polymers to create "drugamers," which depend on enzymatic cleavage to release the active compound from the polymer backbone. Such formulations can be administered via conventional injection. More complex systems have also been developed, such as phosphorylated peptide-based injectable gels. In these systems, drugs are linked to peptide chains, which undergo dephosphorylation post-injection, leading to in situ gel formation and subsequent drug release via hydrolysis. However, the creation of new chemical entities poses regulatory challenges for market approval. An alternative is to chemically combine drugs with already approved polymers or molecules, facilitating a smoother path to clinical translation.
Beyond chemical modifications, alternative approaches exist to control drug delivery. Engineers have extensively developed devices capable of sustaining drug release over prolonged periods. A straightforward method involves embedding drugs within biocompatible polymers to create matrix-type implants, often manufactured via hot-melt extrusion. Process optimisation is crucial in achieving the desired drug release rate, as factors such as drug crystallinity and polymer-drug interactions significantly impact release kinetics. However, this optimisation process can be complex and typically requires substantial amounts of drug and polymer materials. Recently, Vacuum Compression Moulding has emerged as a promising technique for formulation screening using minimal material quantities, potentially accelerating the development of hot-melt extrusion and injection moulding-based formulations.
In addition to matrix-type implants, engineers have developed more sophisticated systems in which drugs are encapsulated within semipermeable membranes to regulate release (31). By controlling membrane porosity—ranging from nanometres to microns—the permeability of drugs can be finely tuned. Compared to matrix-type implants, reservoir implants offer a key advantage: they can achieve zero-order release kinetics, preventing initial burst release. Furthermore, biodegradable polymers can be used for membrane fabrication, eliminating the need for implant removal. Additionally, these systems can be prepared to be refilled externally after depleting their cargo.
Pharmaceutical formulation is another crucial aspect of LADDS development. The combination of drugs with appropriate excipients or polymers offers a relatively simple and cost-effective means of enhancing drug delivery. Unlike chemical synthesis, which involves the creation of new chemical entities, using approved excipients can expedite clinical translation. This approach is applicable across various LADDS technologies, including micro- and nanoparticle-based formulations that encapsulate drugs within pharmaceutical-grade polymers. Another well-established strategy involves combining drugs with thermoresponsive polymers such as Poloxamers, along with excipients that modify gel formation and release profiles.
Formulation strategies are also essential for solid implantable devices. Selecting the right excipients for incorporation into polymers during hot-melt extrusion can significantly alter drug release from matrix-type implants, making excipient choice critical in the design of these delivery systems. Additionally, complex reservoir-type implants rely on drug solubility to achieve optimal release. Again, the choice of excipients in the implant core can influence device performance. For example, cyclodextrins have been used in core-shell implants to enhance the release of hydrophobic drugs. Alternatively, biodegradable polymers capable of generating a micro-acidic environment upon degradation can be employed to improve the solubility of certain hydrophobic drugs.
Through these multidisciplinary approaches—spanning chemistry, engineering, and pharmaceutical formulation—LADDS continues to evolve, offering innovative solutions for sustained drug delivery. While LADDS offer numerous advantages over conventional drug administration methods, they are continually evolving to overcome existing limitations. Traditional LADDS, such as solid implants, nanoparticulate suspensions, and injectable formulations, provide sustained drug release but often require invasive procedures for administration. Implantable LADDS necessitate the use of a trocar or minor surgery, while injectable formulations, though less invasive, can still pose challenges, such as the generation of medical waste and the risk of needlestick injuries. Additionally, both methods require healthcare professionals for administration, increasing treatment costs.
To address these challenges, researchers have been developing minimally invasive alternatives. One promising approach involves the use of microarray patches (MAP) to administer nano/microparticulate-based LADDS. These devices feature arrays of tiny projections that penetrate the skin’s outer layer painlessly, creating microchannels for drug delivery. When combined with water-soluble polymers, MAP dissolve upon insertion, releasing the long-acting formulation into the skin, where the drug is gradually absorbed. Importantly, MAP can be self-administered, reducing reliance on healthcare professionals and improving patient accessibility. Although they may not deliver the same volume of medication as conventional injections, their ease of use and painless application make them a viable alternative for certain therapies, such as long-acting anti-HIV formulations. Furthermore, hybrid MAP with implantable PLGA tips, which remain within the skin as microimplants after patch removal has been recently developed. This system enables sustained intradermal drug release while ensuring easy and complete removal of the hydrogel base.
Another innovative development is the use of biodegradable microimplants, which employ longer, individual needles made from degradable polymers. These devices function similarly to MAP but are designed for the delivery of biopharmaceuticals, providing controlled drug release over time. Additionally, novel LADDS approaches seek to improve drug release precision. Traditional systems rely on passive diffusion or slow solubilisation, but advanced implants now incorporate stimuli-responsive materials and microelectronic components. Smart implants can be engineered to respond to external stimuli, such as temperature or pH, or be remotely controlled, allowing patients or healthcare providers to adjust drug release as needed. These electronic-based systems, however, present challenges, including higher production costs and a lack of biodegradability.
In addition to novel LADDS technologies, advances in manufacturing techniques, particularly 3D-printing, are expanding the potential of personalised drug delivery. This technology enables the production of intricate solid implants tailored to individual patient needs, allowing for more effective and customised treatments. Moreover, it enables the production of medical devices with complex geometries and intricate designs that are challenging to manufacture using conventional fabrication techniques. 3D-printing opens a range of possibilities for researchers and industry professionals in the development of LADDS. This technology can be used not only to create drug delivery systems tailored to patients' needs at the point of care but also to accelerate medical device development by streamlining the prototyping stage. Additionally, the cost of 3D printing equipment has decreased significantly in recent years, making this technology more accessible, including in developing countries.
As research continues, these emerging innovations are set to enhance the efficiency, accessibility, and precision of LADDS, offering improved therapeutic outcomes across a range of medical applications.
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Author Bio
Prof. Eneko Larrañeta, Chair in Pharmaceutical Materials Science at Queen’s University Belfast, specializes in drug delivery and biomaterials. He has extensive experience in developing and characterizing a wide range of drug delivery systems, with a particular focus on long-acting implantable drug delivery systems. He has published over 100 papers and has been included in the prestigious Clarivate Highly Cited Researcher list and in Stanford’s list of the world’s top 2% scientists, based on Scopus data.
Dr. Juan Domínguez-Robles, a Ramón y Cajal Fellow at the University of Seville, specializes in polymer-based drug delivery and medical devices. He has extensive experience in the formulation and characterization of implantable drug delivery systems. He has authored more than 100 publications and is included in Stanford’s list of the world’s top 2% scientists, based on Scopus data.
