Importance and Need for Long-Acting Injectables:
Parenteral drug delivery systems are designed for treating various diseases via different routes like intravenous (IV), subcutaneous (SC), intramuscular (IM), epidural, intra-articular injections, or surgically inserted depots. Compared to oral administration, parenteral delivery offers better bioavailability by bypassing the absorption step, gastrointestinal enzyme degradation, and the liver's first-pass effect. However, frequent administration is often required for chronic conditions due to rapid clearance, impacting patient adherence [1, 2]. This challenge has driven the development of controlled-release methods to sustain drug exposure. Long-acting injectable (LAI) formulations have been adapted for local and systemic treatment using polymer particles, implants, in situ depots, suspensions, and liposomes.
Chronic diseases require consistent medication adherence, which can often be challenging for patients due to the frequency of oral dosing. LAIs provide a viable solution by extending the drug's presence in the system over several weeks or months, thus reducing dosing frequency and improving adherence. In psychiatric disorders, such as schizophrenia, where patient compliance is critical, LAIs have been shown to stabilize better and prevent relapses. They also offer significant benefits in managing chronic conditions like diabetes, hormone replacement, and opioid dependence. By simplifying dosing regimens, LAIs ensure consistent therapeutic levels, improving the quality of life and reducing healthcare costs [3, 4].
Historical Perspective:
Long-acting injectables have roots stretching back several decades. In the 1960s, the development of the first-generation LAI antipsychotic Fluphenazine set the stage for this delivery method. Early formulations faced challenges related to safety and tolerability, but advances over the past decades brought second-generation LAIs, such as risperidone, paliperidone, and aripiprazole, to the forefront [5]. In 2003, the LAI suspension of risperidone (Risperdal Consta®, Janssen) significantly increased the use of LAI formulations [6]. Improvements in micro- and nanosuspension technology have since made these formulations vital in LAI development. Today, the sophistication of polymer-based microsphere and nanoparticle technologies further extends the impact of LAIs in various therapeutic areas [7].
Drug molecule property:
In developing LAI formulations, drug candidates must exhibit high potency and slow plasma clearance to minimize dosing frequency. During early drug discovery, potent drug molecules that can be synthesized in sufficient quantities are chosen for in vivo studies to determine the level of target engagement required for efficacy. In addition to potency, candidates should be efficiently incorporated into carrier systems like PLGA microparticles or implants, with sufficient capacity to deliver the desired dose over prolonged periods despite limited injection volumes [8]. Small molecules can be tailored for existing LAI technologies, such as encapsulation in PLGA microparticles or lipid-based formulations. For instance, low aqueous solubility is achievable by manipulating high crystal lattice energy or hydration properties. Molecular features like aromatic rings relate to lipophilicity and solubility, with early solid-state research aiding compound selection [9].
Long-acting injectables can come in various formulations. Polymer-based microspheres use biodegradable polymers like PLGA for sustained drug release, while nanoparticles gradually release the drug systemically. In situ gel-forming systems transition to gels after injection, and oily suspensions release the drug slowly via oil-based vehicles. Each formulation's composition depends on the drug's chemical properties, intended release duration, and targeted disease. Excipients, including surfactants, solvents, and polymers, are vital for ensuring drug stability and modulating release profiles by affecting particle growth, aggregation, and drug-release kinetics [4, 10, 11].
Figure 1 Types of long-acting injectables and their drug release mechanism.
Nano and Microparticle suspension:
Nano- and microcrystal manufacturing utilizes three main approaches: “bottom-up” (drug crystallization from a supersaturated solution), “top-down” (milling or high-pressure homogenization to micronize drug crystals), and a combination of both. The top-down method is widely used to create nano- or micro-suspensions. Wet media milling is a standard technology for nanosuspension production, creating aqueous suspensions of poorly water-soluble drugs in micro- or nanoparticle form with stabilizers [12]. Formulations can be marketed as lyophilized powders or ready-to-use suspensions, although suspensions have stability limitations. Ostwald ripening, where smaller crystals dissolve and redeposit on larger ones, affects drug release kinetics. Temperature fluctuations during storage and autoclaving can accelerate this, leading to caking (crystal sedimentation and agglomeration). Caking hampers dosing accuracy, injectability, and resuspension. Proper formulation composition, viscosity enhancers, consistent particle size, and controlled storage conditions are essential to prevent these issues while ensuring reliable injection [2, 13].
Characterization of LAIs:
Characterizing LAIs suspensions involves assessing key parameters. Physical stability is essential, as resuspendability, and sedimentation impact consistency and homogeneity. Particle-particle interactions and surface charge significantly influence sedimentation and caking, making flocculated systems preferable due to their ease of resuspension. Chemical stability is crucial for efficacy, requiring careful monitoring of degradation, impurity analysis, and solubility. Viscosity also plays a significant role in ensuring optimal syringeability, enhancing patient comfort and facilitating easy injection.
Excipients:
Injectable medications often contain excipients that preserve, stabilize, or enhance the formulation quality. These include buffering agents, viscosity modifiers, stabilizers, surfactants, lyoprotectants, and tonicity agents, all of which can influence a patient's perception of injection pain.
• Surfactants: Surfactants are essential in long-acting injectable (LAI) formulations due to their stabilizing effects, ensuring consistent dosing and drug distribution by preventing particle aggregation. They reduce interfacial tension, enhancing drug particle dispersion for improved homogeneity. By forming a protective layer around particles, surfactants prevent drug adsorption onto containers and inhibit Ostwald ripening and aggregation. They also adsorb to the particles to some extent and prevent them from sticking to each other. Moreover, surfactants facilitate controlled drug release by influencing carrier-drug interactions and maintaining an optimal viscosity for smoother syringeability, ultimately reducing injection pain and improving patient compliance [11, 14].
• Stabilizers: Stabilizers are essential in long-acting injectables (LAIs) as they maintain drug formulation consistency and effectiveness over extended periods. They protect against degradation, safeguarding the integrity of active ingredients. In flocculated systems, stabilizers aid in controlled nanoparticle aggregation, forming loosely packed sediment that can be easily redispersed. This prevents compact caking and maintains nanoparticle stability, ensuring accurate dosing and better patient outcomes [11, 14].
• Buffers: Buffers are crucial in maintaining a stable pH, usually at a level that minimizes chemical and physical degradation. Ideally, the pH should align closely with the physiological pH of subcutaneous /intramuscular tissue (7.35-7.45). Most products are formulated with a pH between 5 and 7, as values below pH 3 can cause pain and vein inflammation, while those above pH 9 may lead to tissue necrosis. Common buffers include histidine, phosphate, citrate, and acetate, with strengths typically ranging from 5 to 50 mM. Lowering buffer concentration can help reduce the perception of injection pain [15, 16].
Table I Different phases of drug product development and key considerations of respective activities.
Device Perspective:
Effective injection of parenteral formulations through standard needles is essential for the clinical success of long-acting injectables (LAIs). Syringeability is the ability of a formulation to flow from a vial through a needle into a syringe, while injectability indicates how well it transfers into the body. Critical factors like particle size, shape, density, viscosity, and suspension concentration greatly influence syringeability and injectability. Robert Langer's research revealed that needle and syringe geometry greatly impact injectability. Using computational fluid dynamics (CFD), his team designed a custom syringe and needle that enhanced PLGA microsphere injectability sixfold over standard syringes. This system improves efficiency for microparticle and microcrystal drug delivery. The devices used for LAIs are as crucial as the formulations themselves [17]. Key considerations include avoiding needle clogging and ensuring syringeability, as viscous formulations or particle aggregation/agglomeration can block needles. Drug-syringe interactions should also be managed to maintain product integrity, and devices must facilitate easy resuspension of particles. Administering smaller doses in low volumes enhances patient compliance and treatment effectiveness [16].
Pharmacokinetics and Modeling:
Pharmacokinetic modeling of long-acting injectables (LAIs) is intricate due to several challenges. Flip-flop kinetics is a key factor, where the drug's absorption rate is slower than its elimination, making absorption the rate-limiting step. The unpredictable release patterns of some LAIs complicate the establishment of a reliable in vitro-in vivo correlation (IVIVC), challenging the accurate prediction of in vivo behavior. Additionally, uncertainties surrounding the long-term systemic effects necessitate thorough clinical studies to better understand effectiveness limitations and optimize dosing. Addressing these challenges is crucial for improving LAI design and ensuring consistent therapeutic outcomes [3, 18].
Patient Perspective:
The patient's perspective is vital for the successful adoption of long-acting injectables (LAIs). Injection site reactions (ISRs), though typically mild, should be minimized with appropriate formulations to enhance comfort. Patients often prefer treatments that are easy to administer, especially when self-administering. User-friendly devices are essential, featuring clear instructions and ergonomic designs. For LAIs given by healthcare professionals, detailed guidelines on proper administration can improve patient outcomes. Additionally, reduced dosing frequency is appreciated, as it enhances adherence and simplifies treatment routines. Comprehensive support and education empower patients, helping them understand and manage their treatment with confidence [19, 20].
Figure 2 Critical Aspects related to drug product and clinical study design.
Conclusion:
The potential for long-acting injectables in revolutionizing pharmacotherapy is undeniable. As the field advances, addressing challenges in formulation stability, delivery devices, and patient-centered design will shape the next generation of LAIs. Through continued research and collaboration, this promising delivery method will continue to improve treatment outcomes and enhance patient adherence across various therapeutic areas.
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