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Mol Pharm
Mol Pharm
mp
mpohbp
Molecular Pharmaceutics
1543-8384
1543-8392
American Chemical Society

39160132
10.1021/acs.molpharmaceut.4c00665
Review
Patient-Centric Long-Acting Injectable and Implantable Platforms—An Industrial Perspective
Alidori Simone †
Subramanian Raju ‡
https://orcid.org/0000-0003-4894-7765
Holm René *§
† Independent Researcher, Havertown, Pennsylvania 19083, United States
‡ Gilead Sciences, 333 Lakeside Drive, Foster City, California 94403, United States
§ Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark
* Phone: +45 9350 7033; fax: +45 6550 1090; e-mail: reho@sdu.dk.
19 08 2024
02 09 2024
21 9 42384258
16 06 2024
05 08 2024
03 08 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by-nc-nd/4.0/ Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).

The increasing focus on patient centricity in the pharmaceutical industry over the past decade and the changing healthcare landscape, driven by factors such as increased access to information, social media, and evolving patient demands, has necessitated a shift toward greater connectivity and understanding of patients’ unique treatment needs. One pharmaceutical technology that has supported these efforts is long acting injectables (LAIs), which lower the administration frequency for the patient’s provided convenience, better compliance, and hence better therapeutical treatment for the patients. Furthermore, patients with conditions like the human immunodeficiency virus and schizophrenia have positively expressed the desire for less frequent dosing, such as that obtained through LAI formulations. In this work, a comprehensive analysis of marketed LAIs across therapeutic classes and technologies is conducted. The analysis demonstrated an increasing number of new LAIs being brought to the market, recently most as aqueous suspensions and one as a solution, but many other technology platforms were applied as well, in particular, polymeric microspheres and in situ forming gels. The analysis across the technologies provided an insight into to the physicochemical properties the compounds had per technology class as well as knowledge of the excipients typically used within the individual formulation technology. The principle behind the formulation technologies was discussed with respect to the release mechanism, manufacturing approaches, and the possibility of defining predictive in vitro release methods to obtain in vitro in vivo correlations with an industrial angle. The gaps in the field are still numerous, including better systematic formulation and manufacturing investigations to get a better understanding of potential innovations, but also development of new polymers could facilitate the development of additional compounds. The biggest and most important gaps, however, seem to be the development of predictive in vitro dissolution methods utilizing pharmacopoeia described equipment to enable their use for product development and later in the product cycle for quality-based purposes.

Long acting injectables
patient centric
drug delivery
parenteral
Novo Nordisk Fonden 10.13039/501100009708 0068744 document-id-old-9mp4c00665
document-id-new-14mp4c00665
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pmc1 Introduction

Over the past ten years, the idea of patient centricity has attracted more and more attention in the pharmaceutical ecosystem when defining a new product. Social media, more easily accessible information, and business models from other industries are all altering how people receive healthcare, which is influencing patient demands in the pharmaceutical industry. Mankind has developed a good understanding of human biology and a better comprehension of the differences between patient populations and individuals in how they respond to treatments, thanks in large part to advances in genomics. To improve therapeutic outcomes, pharmaceutical companies, regulators, and patients have come to understand the growing significance of greater connectivity to the distinctive characteristics of the intended patient population and their treatment regimen; i.e., the drug development process moves toward a higher interaction with the patients we work to serve.

There is general agreement on the importance of patient centricity in drug development within the industry and in particular age-appropriate drug products for oral delivery was the starting point of the considerations also provided that the majority of medication prescribed and taken are still conventional tablets or capsules.1−9 Patient centricity can be described as the recognition of the needs of an individual patient or distinct patient populations to form the focal point in the overall design of a medicine including the targeted patients’ physiological, physical, psychological, and social characteristics.6,10 From a drug development perspective this can be translated into a patient centric drug development, which will be the process of identifying the comprehensive needs of individuals or the target patient population and utilizing the identified needs to design pharmaceutical drug products that provide the best overall benefit to risk profile for that target patient population over the intended duration of treatment.6,10 Both the U.S. Food and Drug Administration (FDA)11 and the European Medicines Agency (EMA)12 have initiated patient centric design initiatives and both agencies have guidances and reflection papers in development on the topic, stressing its importance.

From a drug delivery perspective an interesting perspective was brought forward as a part of the FDA’s patient focused drug development initiative in 2014, the FDA released a report on the Voice of the Patient affected by human immunodeficiency virus (HIV). This report focused on the perspectives of HIV patients regarding current HIV management approaches and the symptoms they experience due to HIV or its treatment. The patients emphasized the practical advantage of a once-daily drug and single pill regimen in terms of medication adherence. However, many patients also expressed that an ideal treatment goes beyond once a day, thereby reducing the frequency of dosing, i.e., a long acting injectable (LAI),13 which was supported during the development of the combinational LAI treatment with cabotegravir and rilpivirine14 and also in a recent investigation among young adult sexual minority men and transgender women.15 Similar voicings have been reported from schizophrenic patients, supporting LAIs.16 In low- and middle-income countries, numerous reports indicate a preference for injectable contraceptives. These are perceived as highly effective and do not require daily administration like oral contraceptives or usage during sexual activity like barrier methods. Furthermore, injectable contraceptives are favored because they can be used discretely without the knowledge of family.17−20

LAIs are pharmaceutical products designed to be administered at weekly, monthly, or even longer intervals, ensuring a sustained release of the drug and a consistent exposure to the delivered compound.21,22 LAIs offer significant advantages in the treatment of individuals with dysphagia or chronic diseases, where limited patient adherence can negatively impact treatment efficacy. With the increasing prevalence of chronic illnesses and dysphagia in our aging population, many disease areas beyond HIV could therefore benefit from the continuous drug delivery provided by LAI formulations.23,24 LAIs offer the advantage of convenience by eliminating the need for daily tablet intake, which can continuously remind patients of their disease, but the clinical experience with LAIs have also demonstrated that positive clinical outcomes can arise from the use of LAIs, i.e. the delivery approach do not just provide convenience for the patient, but also a better therapeutical treatment.25,26 LAIs is a technical solution that may be offered by the pharmaceutical industries, which could have a patient centricity in mind; hence, it may become an even more important technology in the years and decades to come.

These LAIs are typically administered either intramuscularly (IM) or subcutaneously (SC) as oil solutions, in situ forming gels, microspheres, implants, or micro- or nanosuspensions23,27−29 and a wide range of different formulation technologies have been applied in the already marketed products. Learnings from these historical formulation developments across the formulation strategies have to the best of our knowledge not been presented in a single format; the purpose of the present work was therefore to provide an analysis of the marketed LAIs across therapeutical classes and technologies, an insight into the clinical benefits that have been achieved with LAIs and a condensed technology overview with an industrial focus.

2 Overview of Approved Long Acting Injectables

FDA approved the first IM administered LAI in 1952, which was an antibiotic for injection every second or fourth week, and in the same decade, an additional four products were approved, using either aqueous suspension or oil solution technology. Since then, several additional LAI products have entered the market, an overview of the approved products, including the ones discontinued, their dose, administration frequency, and formulation composition and formulation technology applied can be found in Table 1 below.

Table 1 Commercialized LAI Drug Products by Formulation Platform Indicated by the Color Codesa

a When multiple options are available, only highest dose and durations are reported. Abbreviations: SC = subcutaneous; IC = intracranial; IM = intramuscular; IGi = intragingivial; NA = not applicable; SD = Subdermal; IC = intracranial; IV = intravenous; IVit = intravitreal; TP = Testosterone propionate; TE = Testosterone enanthate; EV = Estradiol valerate; PE = prasterone enanthate; CAB = Cabotegravir; RPV = Rilpivirine. Other indications for Depo-Durabolin: Acute renal failure; chronic renal insufficiency and anemia of chronic renal failure; Palliative treatment mammary carcinoma; Aplastic anemia.30,32−41,43

After the introduction of the first LAI products, the main products that entered the market were oil-based solutions and a few aqueous suspensions, see Figure 1A. In the 1980s, microspheres entered the market, which were based on the application of a well know biocompatible excipient, which enabled the generation of an LAI, i.e., LAIs for water-soluble compounds. The technology platform for long releasing product was additional expanded in the 1990s with the introduction of implants and in situ forming gels, and from the 2000s and onward a few additional technology classes have been seen in the field, i.e., the self-assembled peptides, the liquid crystals, and the aqueous solution. Currently, the dominating formulation technology is aqueous suspension; however, almost equal numbers of oil solutions and implants have been approved; see Figure 1D. Over the last two decades most new products that have entered the long-acting field have been either suspensions or in situ forming gels, providing a diversity of the technologies applied. The different technologies have their own mechanism of action, manufacturing methods, etc., which will be further discussed below.

Figure 1 Number of marketed LAI products over the decades grouped by formulation platform, excluding (A) and including (B) products that have been retracted from the market. Number of marketed products per indication (C) and per formulation platform (D).

When the approved compounds in Figure 1A are compared with Figure 1B, where the discontinued products are filtered out, it is clear that most of the discontinued products fall into the category of oil solutions, though not exclusively. LAIs and implants benefit the patients most when the medication needs to be taken for an extended period, i.e., for chronic conditions or diseases that require a treatment for an unbound period of time. The predominant indication in the field is the treatment of schizophrenia; see Figure 1C, which matches the chronic need for drug administration. Many products are, however, also marketed in the fields of oncology, hormonal disorders, and contraception, which together account for almost 75% of the marketed products. In total, there are current commercial LAIs available in more than 10 indication classes, which represent an expanding list as new and novel pharmacological targets are being engaged with LAIs in numerous pharmaceutical company pipelines.

As argued above, LAIs can be considered a patient centric formulation approach as it provides both better treatment and relief to the patient from constantly being reminded of the disease/condition by frequent intake of the medication. However, the number of indications currently covered with LAIs is still relatively low compared to the total number of diseases/conditions treated with medication. It could therefore be argued that LAIs currently tend to be used mostly as a disease centric drug delivery technology, i.e., highly utilized for specific disease conditions as presented in Figure 1 rather than being a universal patient centric drug delivery technology offering individualization of dosage at a patient specific level, however, the technology contains the potential in particular for chronical diseases/conditions to address disease centric patient needs.

3 Pharmacokinetic Performance of Long Acting Injectables

LAI pharmacokinetics (PK) is used to sustain efficacious systemic concentrations over the intended duration. LAI PK is a function of three key parameters, and a balance of these determines the dose of the active pharmaceutical ingredient (API) in the LAI. The API dose is delivered via parenteral SC or IM injection at an acceptable dose-volume or via a subdermal implant.44 The LAI API must have an appropriately high potency, a slow continuous input rate from the parental depot, and an appropriately slow/moderate systemic elimination rate that is primarily determined by drug clearance. By design, LAI PK exhibits flip-flop kinetics, wherein the systemic input rate from the parenteral depot is slower than the systemic elimination rate. The advantage for an LAI PK is API delivery at a continuous first order (and in some cases zero order) input rate without a burst release that enables maintaining a narrower range of plasma concentrations within the therapeutic window and minimizes the maximum to minimum concentration swing observed with oral administration.

The in vivo biological response at the site of LAI administration—obviously referred to as injection site reaction (ISR)—affects the LAI PK. ISR is a complex interplay of API dissolution, absorption, and the immune-mediated host response to the foreign API depot. The factors influencing the ISR response include the route of administration, API particle size, dose-level, stabilizing excipients, drug physicochemical properties, local-site host response, and body mass index.45−50 A deeper analysis of this topic is considered out of scope of the present review, however, interested readers are reference to a recent review in the field.46

4 Technologies Applied As Long Acting Injectables

Different technologies are applied to obtain long-acting effects, as discussed above. Five major classes and one novel approach are used as the formulation strategy, which can roughly be divided into sustained release systems and controlled release systems. In the first class of formulations, the compound properties are used in defining the release rate, whereas in the latter the added excipient defines the release. While the formulation strategy has proven their ability to deliver the desired release for some compounds, we will in the following section focus on the potential industrial considerations of these formulations. For all the formulations, sterilization of the final product and the ability to conduct aseptic manufacturing will be critical for both regulatory and commercial success, which is why this should be considered early in the formulation and manufacturing development for all LAIs. An overview of the main classes of LAI formulation technologies and their strengths and weaknesses are presented in Table 2.

Table 2 Strengths and Weaknesses of Main Established LAI Delivery Systems (Modified from Nkanga et al.51)

formulation type	strength	weakness	
sustained release systems	
aqueous suspensions	• simple and cost-effective preparation methods	• micronization is required	
• highest drug loaded carrier system → allowing high drug dosing per volume	• gamma, heat sterilization or aseptic manufacturing is required	
• limited options for tailoring drug release	
oil solutions	• simple and cost-effective preparation methods	• not possible for many drug molecules dissolve in the oil or form an oil soluble prodrug	
• filtration sterilization	• limited options for tailoring drug release	
• easy scale up	
aqueous solution	• simple and cost-effective preparation methods	• the number of compounds that fit the principle is very limited	
• filtration sterilization	
• easy scale up	
controlled release systems	
PLGA-based microspheres	• drug release can be modulated (e.g., from weeks to months)	• gamma sterilization or aseptic production is required	
• in principle it is possible to load both hydrophilic and hydrophobic drugs	• not simple and rather complex manufacturing	
• expensive technology relative to other LAIs	
• high drug loading is challenging, >50% of formulation is polymer	
• difficult to scale up	
preformed implants	• drug release can be modulated to some extent	• gamma sterilization or aseptic production is required	
• it is possible to load both hydrophilic and hydrophobic drugs	• invasive (in some cases surgical procedures are required)	
• for some systems a high drug loading is possible	
in situ forming implants	• drug release can be modulated to some extent	• limitation in dose related to the use of organic solvents	
• limited options for tailoring drug release	• simple and cost-effective preparation methods	
• filtration sterilization	• high drug loading is challenging >50% of formulation is polymer	
• easy scale up	

The commercial products presented as solutions and dispersions in vials or prefilled syringes, lyophilized cakes in vials for redispersion, dual filled syringes with a lyophilized cake and the dispersion media in a closed container, as well as rods for insertion either through small surgery or by the application of a device. While this area is important for the patient in their experience of administration, the topic will not be discussed any further in the present work.

4.1 Sustained Release Systems

Sustained release systems use the formulation’s own dissolution rate/distribution at the site of injection to control the release of the compound. The compounds that in general are used in this class of formulation systems have either a low water solubility or a high lipid solubility, as this defines the possibility of using these technologies. In the sections below, some additional details are provided in the formulation systems including some industrial perspectives on their applicability.

4.1.1 Aqueous Suspensions

Aqueous crystalline suspensions are formulations where the API is present in the crystalline form at a defined particle size (typically within a range of 0.1 to 10 μm) dispersed in an aqueous medium.22,27,52 This approach represents a sustained-release strategy for LAIs, which relies on the low water solubility and high lipophilicity of the API. In recent years, there has been a surge in research activity around the development of suspension based LAIs, as demonstrated by the high volume of publications and patents in the field (Figure 2).

Figure 2 Number of publications or patents over the years using search terms “Long-Acting Injectable” and “suspensions” in SciFinder.

This interest is driven by the patient convenience and preference in receiving less frequent dosing,14,53−55 as discussed in the introduction, but also by the ability to maximize drug loadings, hence minimizing injection volumes. Suspensions formulations can be developed at very high API contents, up to 400 mg/mL in the case of Depo-Provera, and by a relatively scalable manufacturing process. In addition, as more and more new lead candidates and market-approved drugs are hydrophobic compounds, categorized under the Biopharmaceutical Classification System (BCS) classes II (low solubility and high permeability) and IV (low solubility and low permeability), the aqueous suspension LAI approach represents an opportunity to develop such therapeutic agents and into viable LAI drug products using the suspension technology provided that the compound dose allows the compound dose to do so. It has been estimated that ∼40% of the attrition rate of candidate-drugs has been associated with poor pharmacokinetic features and toxicity. Poor solubility is, particularly, a very significant impediment in the drug development efforts for oral administration, and the suspension LAI approach can provide a viable way forward to bring transformative medicines to the patient. It is estimated that nearly 60%–90% of the compounds that are being developed exhibit poor water-solubilities56,57 and are categorized under the Biopharmaceutical Classification System (BCS) classes II (low solubility and high permeability) and IV (low solubility and low permeability).57,58 While only 40% of drugs in marketed orally administered products belong to BCS class II and IV, the number of new candidates in these classes ranges between 70 and 90% (Figure 3).59,60 This is driven by discovery efforts through combinatorial chemistry and high throughput screening methods to identify molecules with high specificity and affinity for hydrophobic binding pockets of biological targets. However, poor solubility is a very significant impediment in the drug development efforts and indirectly influence high attrition rates (∼40% of the attrition rate) of new candidate-drugs, as poor pharmacokinetic features and toxicity issues become more relevant,61 however, from an LAI suspension perspective the incoming molecules into the market place will make the technology important if LAIs at a later stage would become interesting for these molecules.

Figure 3 BCS classification system for orally administered drugs (left); estimated percentage of oral drugs based on BCS class in marketed products (center); and in the pipeline (right). Adapted from Bhalani et al.60 available under CC-BY 4.0. Copyright 2022 MDPI.

Suspension technology is the formulation approach that is most exploited in the development of LAIs as discussed above. The first research article on LAI suspensions was published in 1949,62 whereas the first drug products approved by FDA based on injectable suspensions were Depo-Medrol in 1957 (formulation of methylprednisolone acetate, an anti-inflammatory glucocorticoid for IM, intra-articular and intralesional injection, once every 1 or 2 weeks) and Kenalog-40 in 1958 (formulation of triamcinolone acetonide, an anti-inflammatory corticosteroid for IM and intra-articular administration). After the initial approval of a few LAI suspensions, the LAI space became dominated by oily-solution formulations, poly(lactic-co-glycolic acid) (PLGA) microparticles, and SC implants (both discussed below). However, in the early 2000s, the industry shifted its focus to particulate suspension-based formulations, as highlighted by the approval of Depo-subQ Provera 104 in 2004 and Invega Sustenna in 2009. Invega Sustenna represents the first drug product developed leveraging the NanoCrystal milling technology. In the following years, FDA approved Zyprexa Relprevv (Olanzapine pamoate for the treatment of schizophrenia as a monthly IM injection), Abilify Maintena (lyophilized formulation for reconstitution for the treatment of schizophrenia as a monthly IM injection), and Aristada (microsuspension formulation of Aripiprazole lauroxil for the treatment of schizophrenia as a monthly or bimonthly IM injection). More recently, Invega Trinza and Hafyera received FDA approval to further extend the duration of Paliperidone Palmitate to 3 and 6 months, respectively, for the treatment of Schizophrenia. In the HIV space, Edurant (Rilpivirine), and Apretude (Cabotegravir) represent the first long-acting regimens for the prevention of HIV, both dosed as monthly IM injections. More recently, Cabenuva, a copackaging of Cabotegravir and Rilpivirine nanosuspensions as separate drug products, has been approved as the first complete long-acting treatment of HIV, with a monthly or bimonthly frequency.

From Table 1 and Figure 1C, it is clear that the major indications for LAI suspensions for now are Schizophrenia, with seven marketed products, followed by HIV treatment and prevention (three products), contraception (two products), anti-inflammatory disorders (two products), and malignant hyperthermia (one product). The most frequent route of administration is IM (15 out of 17) with one example of SC and one for intravenous injection. Microsuspensions (suspensions with d50 values above 1 μm) are predominant (11 examples out of 17) with 5 drug products in the market as nanosuspensions (d50 value below 1 μm) and drug contents ranging from 20 to 400 mg/mL.

The common approach to manipulate the performance of LAI suspensions release rate relies on changing particle size distribution of the crystalline API. This strategy is fundamentally explained by the Noyes-Whitney equation,63 which describes the dissolution rate of particles in sink conditions (eq 1):64,651

where m is the total dissolved mass, Sw is the total exposed surface area of the particles, D is the diffusion coefficient of the solute in the solvent, h is the thickness of the diffusion layer surrounding the particle, Cs is the solubility, and Cb is the concentration of dissolved drug at any given time.64,66 According to the Noyes-Whitney equation, the dissolution rate is proportional to the total surface area of the drug particles. This concept has been exploited by Janssen in the Invega products, whereby increasing particle size from 0.8 μm (Invega Sustenna) to 4–9 μm (Invega Trinza), extends the duration of effective plasma levels of Paliperidone Palmitate and affords increase in duration from 1 to 3 months.67,68 Similarly, Aripiprazole lauroxil has been developed by Alkermes as injectable nano- (Aristada Initio) and microsuspension (Aristada). Due to the slower dissolution rate of the larger particle size formulation, there is a significant lag-time (between 6 and 7 weeks) with Aristada to reach target plasma concentration for aripiprazole.31 In this case, the nanosuspension drug product provides the option to reach adequate plasma levels in a shorter period of time due to its faster dissolution rate (Figure 4). Aristada Initio can therefore be used as initiation regiment, requiring only 1-day aripiprazole oral dose, as opposed to a 21-day oral regimen followed by administration of microsuspension Aristada.69 Also a few academical studies have reported correlations between the particle size and the in vivo release,70,71 hence it is clearly a point that should be clarified when working with a new compound for a LAI suspension.

Figure 4 Pharmacokinetics of smaller versus larger particle size formulations. Tlast, time last measurable plasma drug concentration; Tmax, time of peak plasma concentration. Reprinted and adapted with permission from Jain et al.31 Available under a CC-BY 4.0. Copyright 2020 Cambridge University Press.

Aside from particle size, other formulation aspects can significantly impact performance, such as formulation composition45,50,72 and the level of flocculation.73 In addition, API crystal form properties, such as morphology, level of amorphous content, and residual solvent in the API,67 may have a significant impact on dissolution, indicating that the selection of version and form is crucial not only for manufacturability and stability purposes, but also for performance.

The excipients commonly present in a suspension formulation include surfactants, stabilizers, and tonicity agents, as well as buffers when necessary. Surfactants act as wetting agents allowing particles to (i) be processed more efficiently when a top-down manufacturing process is exploited and (ii) prevent agglomeration in the drug product. As reported in Table 1, the most used wetting agents are poloxamer-338, polysorbate-20, and polysorbate-80 as nonionic surfactants. Lecithin is the only ionic surfactant used for the listed suspension drug products, in the case of Bicillin L-A, where the active ingredient is present as a salt. Stabilizers added to the formulations are usually polymers that can decrease the risk of agglomeration of particles in the drug product by reducing interactions between particles. While surfactant molecules absorb on the surface of particles, stabilizers are present in the dispersing vehicle and provide further steric hindrance, which reduces the probability for drug particles to come into close contact. The most exploited stabilizers in marketed products are polyethylene glycols, sodium carboxymethylcellulose, and povidones. The type and concentrations needed for surfactants and stabilizers will depend on the particle size distribution, physicochemical properties of the API, and its propensity to form agglomerates. While empirical assessment can be made to predict the amount of surfactant needed to effectively cover the particle surface, formulation screening is still necessary to identify optimal ranges and verify long-term stability.

The other component that is essential for an LAI suspension formulation is a tonicity agent. Osmolality is a measure of the osmotic pressure that all ionizable and nonionizable soluble species in the drug product can exert across a cell membrane.74 Injection of hypertonic preparations has been associated with increased local pain and discomfort.75,76 Tonicity adjusters and any other soluble component of the formulation should yield osmolarity values lower than 600 mOsms/kg, considered acceptable, with preferred levels ranging from 285 and 295 mOsm/kg (close to the plasma isotonicity value of 300 mOsm/kg).77 Typical tonicity agents identified in LAI products (Table 1) are sodium chloride, mannitol, and sucrose; however, in some cases tonicity may be controlled by other inactive ingredients in the formulation (e.g., polyethylene glycol and povidone). Other excipients that may be present in LAI suspensions are buffering agents, pH adjusters, viscosity modifiers, bulking agents, antioxidants, and antimicrobial preservatives.

Aside from the composition, particle size distribution is a critical product attribute, as also described above. The parameter should therefore be closely controlled to ensure reconstitution and resuspendability (ability to homogeneously distribute the sedimented particles in the vehicle/supernatant), syringeability (ability to be transferred from a vial through a conventional needle into a syringe), injectability (delivering of target dose from the syringe into the body), and not least an appropriate pharmacokinetics performance. Therefore, the selected manufacturing process should enable consistent particle size distributions from batch to batch. Particle size control can be achieved by top-down or bottom-up approaches. The bottom-up methods involve the precipitation of the API into desired particle range from supersaturated solutions.78,79 It is frequently employed for the production of nanosuspensions both in bulk solutions or in single droplets.80 This method is used in a number of pharmaceutical processes and include antisolvent precipitation, high-gravity controlled precipitation, flash nanoprecipitation, supercritical fluid technologies, sonoprecipitation and controlled droplets evaporation methods.80−82 Nanoparticles are obtained after several steps including supersaturation, nucleation, diffusion of the solute molecules, and nanoparticle growth,83 and generally they require charged glyceryl esters, such as lecithin, as an electrostatic stabilizer, to prevent agglomeration. A key to the success of yielding stable nanoparticles with the bottom-up techniques listed above is to control the particle growth kinetics through evaporation rate of the droplets or mixing rate during precipitation.80 While no commercial products are currently produced through this approach, developments in crystallization technology may change this in the future.27

Top-down approaches are based on the size-reduction and breaking down of large materials into particles with nanometer dimensions mainly via wet bead milling and high-pressure homogenization, but also through pulsed laser fragmentation.78 Briefly, during wet bead milling, the drug particles are broken down by impaction by milling beads. The input API is first dispersed in a carrier fluid to create a liquid slurry before being put into a grinding chamber loaded with zirconium oxide or polystyrene beads, where it is recirculated until the desired particle size is achieved. As this process is highly energetic, temperature control is often necessary to prevent compound instability and amorphous formation. To minimize the amorphous content, the drug particles can be milled while suspended in a suitable nonsolvent, usually water for hydrophobic drugs. This encourages recrystallization of any amorphous regions formed during milling. High pressure homogenization can be classified in microfluidization or piston-gap homogenization.80 In microfluidization, particles are fragmented by collision in a high-pressure air jet or by high pressure in a liquid stream. Piston-gap homogenization involves forcing a liquid suspension at a high pressure through a narrow channel or gap inside a pipe. For aqueous media, bubbles form inside the gap due to a reduction in the static pressure of the liquid in this region.84 These bubbles collapse upon exiting the narrow gap, and the cavitation energy generated consequently breaks up the particles. For nonaqueous media or oil, the particles are comminuted by collision and high shear though the gap. Wet bead milling and high-pressure homogenization can create particle distributions in the nanometer or submicrometer ranges, and the liquid slurry can either be used in that form (ready to use) or lyophilized. A comparative assessment of these two technologies for different APIs and formulations reported by Nakach and co-workers85 highlighted a similar behavior and suitability for nanocrystalline suspension development. While wet beat milling resulted in being more powerful in reducing particle size to lower d50 values, high-pressure homogenization led to narrower particle size distributions with lower d90 at the same average as d50, which then produced better thermal stability.85 While these two techniques require the API to be dispersed in liquid media (typically aqueous for highly insoluble compounds), other top-down techniques in dry environments can be exploited, such as micronization through dry-milling. However, due to the lower input energy, particle size distributions achievable through these techniques are in the micrometer range.86

In general, since particle size reduction generates potential form/amorphous change and more surfaces with consequent risk of Ostwald ripening (process where small drug crystals dissolve and redeposit on the surface of larger crystals), agglomeration and formulation instability, the selection of manufacturing process, particle size targets, and excipient composition are interconnected and iterative attempts as well as design of experiments (DoE) composition approaches need to be considered to achieve a manufacturable and stable final product.

The formulated product is then filled into vials or prefilled syringe and delivery device. Ensuring sterility is extremely important for patient safety in the administration of long acting injectables, and two approaches are possible: aseptic manufacturing process and terminal sterilization by steam or gamma irradiation. Sterilization of the vial, prefilled syringe, or device is the most effective way to ensure sterility of the product; however, if the physicochemical integrity of the drug substance or product is affected by the sterilization process, then aseptic manufacturing processes may be exploited. Aside from the potential impact of sterilization on drug substance and excipients, other manufacturing challenges associated with finished LAI suspension products include suspension homogeneity during filling, foaming during high shear homogenization, resuspendability upon storage due to caking (sedimentation and agglomeration, at the bottom of vials), Ostwald ripening, and growth of impurities due to degradation kinetics. Additional quality attributes of a suspension LAI drug product are syringeability/injectability, viscosity, tonicity, bioburden, and endotoxins. An option to mitigate some of the stability challenges highlighted above and prevent physical or chemical instability associated with ready-to-use (RTU) suspension drug products, which leverage a lyophilization process to obtain a powder in a vial for reconstitution by health care professionals prior to administration.87 Details of the lyophilization process are out of the scope of this review; however, a general sequence of the processes and unit operations leading to the development of a RTU or lyophile products is illustrated in Figure 5. As an appropriate crystalline version and form of a new chemical entity is identified and robust crystallization process developed, an aseptic dry-micronization step to reduce particle size is optional to achieve a micron size distribution, amenable for the final product or to ensure consistency in distribution of input for subsequent particle size reduction. The API is then gamma irradiated or handled aseptically for dispersion into appropriate vehicle. The suspension is then aseptically filled into syringes, delivery devices or vials. If sterilization is necessary, then the packaged product can be terminally gamma irradiated into the final RTU. Alternatively, freeze-drying followed by gamma irradiation of the powder in vial can be executed to obtain a sterile lyophilized product. Besides the possibility to stabilize the suspension by lyophilization the use of thixotropy also seems to be an option. The two first generations of aripiprazole LAI suspensions were marketed as freeze-dried suspension for reconstitution before injection, but the latest aripiprazole suspension from Otsuka, Abilify Asimutufii, is marketed as a ready to use suspension in a prefilled syringe. When investigating the details of the formulations it is observed that the added excipients are PEG and PVP, which according to the patent from the company provides a media with thixotropic properties,88 i.e., a very cleaver solution to reduce the activity in the formulation thereby reducing the physical instability using well accepted parenteral grade excipients.

Figure 5 Flowchart of typical manufacturing processes for LAI suspensions as ready-to-use (RTU) or lyophile product. Dashed boxes represent steps that are optional.

During the development of a new LAI product, changes in formulation and manufacturing processes, scales, and sites are frequent, which raise the challenge of demonstrating bioequivalence. Two formulations of the same drug or two drug products are claimed to be bioequivalent if they achieve the same therapeutic effect. In order to demonstrate bioequivalence, in vivo BE studies in humans are required, increasing the development costs and time to market. Establishing in vitro in vivo correlations (IVIVC) could support biowaivers, reduce regulatory burden, leading to time and cost savings.89−91 IVIVC is a predictive mathematical model describing the relationship between in vitro drug dissolution and the in vivo response of different formulations. IVIVC can be used to guide formulation and/or process development changes in the various stages of drug product development, and the in vitro dissolution method can be used as a surrogate for bioequivalence studies when preapproval and postapproval changes are required. Currently, there is no regulatory guidance for establishing an IVIVC for LAI products, mainly due to the lack of unified compendial in vitro dissolution methods and to the difficulty in capturing the complexity of in vivo performance, including dissolution from particles, distribution at the depot, inflammatory response and capillary absorption, though in vitro methodologies. The FDA has defined three levels of IVIVC: Level A, Level B, and Level C.92 These levels represent different degrees of correlation between the in vitro and in vivo data and provide varying levels of confidence in the predictions made.Level A: Level A IVIVC is the highest level of correlation and represents a significant relationship between the in vitro dissolution and in vivo drug release. Here, the in vitro dissolution profile can be used to accurately predict the in vivo drug release and subsequently the drug’s pharmacokinetic profile.

Level B: Level B IVIVC represents a moderate correlation between in vitro dissolution and in vivo drug release. Although not as strong as Level A, it still demonstrates a meaningful relationship between the two. This level of correlation allows for a reasonable prediction of pharmacokinetic behavior.

Level C: Level C IVIVC represents a weak correlation between in vitro dissolution and in vivo drug release. The correlation may be qualitative rather than quantitative, meaning it provides some general understanding but not accurate predictions of drug performance. Level C correlations are often exploratory and serve as a starting point for further development or optimization of the drug product.

It is important to note that the FDA does not require a specific IVIVC level for drug approval. However, a higher level of correlation (Level A or Level B) can provide additional confidence in the performance and bioequivalence of the drug product, potentially reducing the need for certain in vivo studies or supporting postapproval changes. Among the commercial LAI aqueous suspension products, only Invega Sustenna reported a clinical Level A IVIVC based on formulations with variations in particle size, whereas for rilpivirine a Level B IVIVC for batches at different particle size was attained (US FDA database).93 As single dose crossover clinical studies to demonstrate IVIVC present challenges related to resources, costs and duration, nonclinical animal models have been used by some groups for in vitro release method development and in silico model approach to achieve IVIVC. Such animal studies may pave the way for the successful development of IVIVCs in humans,93 but also the approach recently presented by Sonntag and co-workers,94 where a population balanced approach is used to predict the performance of a suspended prodrug contains potential interesting approaches that may help removing the need for animal experiments in the design of LAI suspensions.

In interesting development in the field of LAI suspensions is a recent study by Jain and co-workers95 that aimed to develop an in vitro release testing strategy to predict the preclinical performance of both a single-agent and combination LAI suspension product using the USP apparatus 2. The in vitro release profiles reported within 48 h were time-scaled to match the in vivo time scale of approximately 1800 h. Level-A in vitro-in vivo correlations (IVIVCs) were developed and validated for each active pharmaceutical ingredient (API) using rat plasma concentration–time profiles. The work provided a framework for evaluating individual phases of drug release in complex LAIs to predict their in vivo performance95 and also gives an indication that we in the future may look into LAI suspensions containing combinations of compounds in the same formulation.

Currently aqueous suspensions are one of the most important technologies for LAI products, and with current pipelines, the possibility of high drug loads, and established infrastructure to ensure their manufacturing in pharmaceutical companies, this will probably be the case for many years when considering small organic molecules. While multiple products have made it to the market a number of scientific gaps still exists, such as predictive nonclinical models for the performance, better understanding of the stabilizer’s ability to prevent physical instability of the formulation, and not least more research into predictive in vitro dissolution methods.

4.1.2 Oil Solutions

In oil-based formulations, the API is typically dissolved in an organic vehicle, most commonly vegetable oils, such as grape seed oil, sesame oil, and cottonseed oil, fractionated medium chain triglyceride (MCT) oils, or mineral oil, as castor oil. These formulations represent the first successful approach used to generate an LAIs for antipsychotics drugs.96−98 In this class of LAI formulations, Proluton Depot was the first product to be launched in the market in 1955, which was used for women at risk of premature birth (formulation of hydroxy progesterone caproate, a progestin hormone for IM injection once every 2 or 4 weeks). Subsequently, this formulation approach was exploited for antipsychotic drugs such as Haldol in 1967 (formulation of haldoperidol decanoate, as once a month IM injection) and Modecate in 1972 (formulation of fluphenazine decanoate for IM injection, once every 2 or 4 weeks). Aside from antipsychotic treatment, oil based LAIs have also been developed for hormone replacement therapy as in the case of Primodian Depot (coformulation of estradiol valerate (EV) and testosterone enanthate (TE) for IM injection, once every 4 or 6 weeks) and as for contraception Noristerat (formulation of norethisterone enanthate for IM injection, once every 8 weeks).

After the initial wave of lipid based LAIs, only a few products have entered the market after the 1980s, most likely due to a shift of the industry to controlled release systems (e.g., PLGA microparticles and implants) and later on toward leveraging crystalline suspension approach. From a mechanistic standpoint, contrary to the crystalline suspensions, the slow drug release for these formulations is driven by the partitioning of the lipophilic molecules from the organic phase into the interstitial fluid and by the kinetics of local digestion and elimination of the oil vehicle from the injection site.99,100 From Table 1, it is apparent that most of the marketed oil depot products include esterified prodrugs of the active component with long aliphatic chains, apart from Falsodex (fluvestrant) that already bears a long aliphatic chain in its chemical structure. The esterification is typically done on alcohol groups of the drug molecule with fatty acids, aiming to achieve higher solubility into the oil vehicle, while significantly reducing the aqueous solubility to increase the partition into the lipophilic phase. Consequently, the release from the oil phase into the interstitial fluid can be controlled by selecting the appropriate chain length of fatty acids in combination with choosing one of the oil variations, i.e., either a medium- or a long chain triglyceride. Most esters are converted into the active by esterase’s, which are present throughout the body. In addition, the use of endogenous fatty acids, containing aliphatic chains with even numbers of carbons, from 4 to 28, help minimize safety concerns associated with the prodrug.101 The ester prodrugs used in most of the marketed oily based formulations have long saturated aliphatic chains (see Table 1), which produce compounds with a high lipophilicity (LogPs are generally >3.5), as needed to solubilize the drug dose in oil. Decanoate, propionate, enanthate, cypionate, caproate and palmitate are the conformers used in the ester bond with the parent drug.

Presence of high levels of drug in the lymph nodes close to injection site after IM administration of decanoic acid esters of fluphenazine102−104 and haloperidol105,106 in sesame oil solutions indicate that the absorption mechanism is more complex than a simple release process from the oil depot. It was suggested that, while the drug can diffuse/partition from the oil depot at the injection site into the tissue, small drops of oil containing the drug were also absorbed by the local lymphatic system, followed by drug release from the depot (Figure 6). In addition, formation of secondary depots within adipose tissue,107,108 entero-hepatic circulation,109 and protein binding110,111 have also been suggested as mechanisms to explain the extended duration of drug concentration in plasma.

Figure 6 Overview of processes influencing the pharmacokinetics fate of drug substances after the injection of lipophilic drug solutions. The drug substance may represent the parent drug or its prodrug derivative.

While oil-based depot formulations present the advantage of simple manufacturing process (compounding, mixing and sterile filtration) and possess long-term stability, they also show a few drawbacks. Particularly, controlling release rate is not easy to achieve through formulation variations, as there is a limited number of variations available. Further, the syringeability of the formulations is often poor due to the high viscosities of the formulation. In this regard, while a reasonably low (<40 mPa·s) vehicle viscosity is preferred for improved syringeability and patient experience, the viscosity of castor oil and MCT at 37 °C is 283 mPa·s and 12 mPa·s, respectively, hence from a patient perspective castor oil should be avoided if possible. In addition, an increased vehicle viscosity might favor a decreased drug release rate at the site of injection and further extension of the terminal apparent half-life. This is particularly relevant when drug diffusion in the oil phase to the oil–water interface is the rate limiting factor to the drug release and absorption from the depot, as opposed to drug partitioning into the aqueous phase.

Development of suitable in vitro release methodologies and models for both quality control and formulation development is a critical activity that should be initiated in the early stage of LAI product development as it can aid in formulation selection and in identifying critical attributes to performance. There is currently no regulatoryly approved in vitro dissolution method and guidance for oil based LAIs. IVIVC has been demonstrated for a bupivacaine oil-solution in a preclinical study through a rotating dialysis cell model after SC administration; however, IVIVC has to the best of our knowledge not been achieved in the clinic, probably due to a lack of robust in vitro release models, capable of mimicking the rate and transport processes of the drug substance and the depot formulation in the interstitial environment.

Altogether, simple oil solutions seem to be a technology less applied in today’s pharmaceutical development, though in particular the low cost of goods and the potential to terminal sterilize the formulation would make it an obvious technology approach in those situations where that is a critical determinant of the product success. There is to the best of our knowledge limited industrial and academical research being conducted in the field though the technology has many potential scientific gaps both with respect to innovations of the formulation systems, better understandings of the biopharmaceuticals for the formulations and investigations of potential in vitro dissolution methods to support both development and commercialization of formulations using the technology.

4.1.3 Aqueous/Cosolvent Solutions as Long Acting Injectables

Aqueous solution LAI is rare because it requires the API to be soluble in an aqueous formulation, to precipitate readily upon parenteral administration, and to have a dissolution limited release to obtain a long-acting PK without an unintended burst release. One recent example exists, where lenacapavir sodium salt is formulated in a polyethylene glycol 300 in water vehicle at 309 mg/mL.112−114 Lenacapavir has a low aqueous solubility (<1 μg/mL in water) and readily precipitates upon parenteral administration as the solvent diffuses away from the injection site forming a suspension and thereby defining the pharmacokinetics of the compound due to dissolution limited release. After a single 927 mg SC dose of lenacapavir, the target plasma concentrations are sustained for at least 6 months.115

Conceptually the formulation principle is simple to understand and has also previously been suggested in the literature as a means to improve the local pain treatment in the joints by intraarticular injection of celecoxib.116 The formulation approach requires a deep understanding of the compound crystallization behavior and the environment at the injection site to really define the size of the precipitated crystals and, thereby, the formulation robustness and the release duration. As the precipitation is primarily driven by the solvent displacement upon injection it should be possible to conduct relevant in vitro dissolution investigations, however, if a level A IVIVC can be obtained is hard to say given the limited research in the field.

From a manufacturing perspective, the formulation technology is relatively straightforward. Solutions can be developed on a small scale and upscaled to a larger scale without major concerns, although the highly concentrated solution applied may challenge the mixing and the mixing time needed. Obtaining sterility of the final product may be possible in the final container though stream sterilization or γ radiation, though with polyethylenglycol (PEG) as the solvent stream sterilization would often lead to oxidation of the vehicle, which is why this would not be suggested. Alternative sterile filtration, as a gentle and effective process, is an option.

4.2 Controlled Release Systems

Controlled release systems are in general used to obtain a defined release of water-soluble compounds, e.g., peptides and proteins, but are also very applicable when very long release times (as in years) is desired. The strategies are heavily dominated by systems using polylactic acid (PLA) or PLGA as the polymer to define the release of the APIs. The use of PLGA in medical products dates back to 1971 when it was first employed as surgical sutures due to its favorable properties of biodegradability and biocompatibility,117−119 hence it is in general considered a safe material and it is commercial available in a number of variations enabling generation of multiple different formulations and release times.

4.2.1 Polymeric Microparticles

Parenteral PLGA microspheres have garnered considerable attention compared, which attributed to several unique advantages of PLGA microspheres, including: (1) lower toxicity and local tolerance at the injection site, (2) enhanced control over drug loading and release profile, and (3) the ability of the formulations to retain water-soluble compounds.120−122 FDA has thus far approved PLGA microspheres as a drug delivery system for small molecules, peptides, and proteins, offering release durations ranging from 1 week to 6 months, as seen in Table 1 above.

The mechanisms of drug release from PLGA-based microparticles involve multiple factors, but the most important are drug diffusion and polymer degradation (by hydrolysis). After administration, PLGA degrades into nontoxic components, lactic and glycolic acids, which are either metabolized or excreted from the body.123 The degradation opens more water-accessible space leading to the interior of the particle.124 Accumulation of lactic and glycolic acid during degradation could lead to a substantial decrease in the interior pH, which can be as low as 3.5,125−128 hence the compounds formulated into PLGA based microspheres should be sufficiently acid stable. The use of PLGA instead of PLA, has been recognized since the 1980s as an effective strategy for developing faster-releasing products, owing to its more rapid degradation129−131 and all modern microspheres use PLGA. Critical polymer attributes like hydrophilicity, swelling degree, and degradation rate are critical elements when defining the specific PLGA polymer for a formulation. For example, a low polymer porosity has been reported to correlate with a reduced initial burst release in vitro, as observed in Bydureon and Sandostatin LAR.42,132,133 Other polymer characteristics, such as molecular weight, blockiness (which refers to the presence of potential glycolic acid clusters in PLGA polyester compared to a random copolymer structure), or architecture (linear versus branched), can also influence the release profile of the encapsulated API.134−136

One feature of PLGA microparticles often mentioned in the literature is their recognition by immune elements and their capacity to stimulate immunization against incorporated proteins,137,138 however, this is only relevant of PLGA particle of less than 10 μm, hence this can be circumvented by formulation design.

Regardless of the manufacturing process employed, the drug release from PLGA/PLA based microspheres can in a simplified description be defined to follows a pattern consisting of three phases,139 see Figure 7. First, there is an initial burst phase where a significant portion of the drug payload may be rapidly released. This initial burst is often argued to be related to the drug molecules located near the surface of the microspheres. However, this rapid release may raise concerns regarding potential toxicity as the drug loading is designed to provide the appropriate dose for the intended release duration, which could be several months. For instance, a burst release of 10% in a one month formulation may exceed the recommended dose for the first days after administration, which may potentially surpass the toxicity threshold. Following the burst phase, a lag phase occurs, typically lasting for days to weeks, during which minimal drug release is observed.140 This lag phase may result in drug exposure falling below the therapeutic threshold, leading to inadequate treatment during this period. The low release during the lag phase is primarily attributed to the intrinsic properties of the polymeric matrix, such as the absence of pores or channels; i.e., it can be controlled by adding pore forming excipients. The third phase corresponds to the continuous release of API as a function of polymer degradation. As the polymeric matrix degrades over time, it allows for a sustained and controlled release of the API, ensuring a prolonged therapeutic effect.141,142 These three distinct phases, initial burst, lag phase, and continuous release, characterize the drug release profile from polyester-based microspheres and need to be considered in the design and evaluation of such drug delivery systems. It should be noted that this description should be perceived from a conceptual perspective, as there are a number of biopharmaceutical processes not included here. The interested reader is referred to some of the recent reviews on PLGA based LAIs for a deeper biopharmaceutical discussion of the details in the release,143 however, from a formulation perspective the description provided here provides a fair framework for how the release occurs from PLGA based microspheres.

Figure 7 Simplified illustration of different stages of PLGA microsphere degradation and erosion describing the three release phases and the release type at the different phases. The last two phases defined the extended release. Reproduced from Hua et al.142 Available under a CC-BY 4.0. Copyright 2021 Taylor & Francis.

The manufacturing process of microsphere-based products poses a limitation for microspheres, which may contribute to the lack of generic products emerging through the 505(j) FDA pathway.144,145 This complexity is evident due to the multistep and multiparameter nature of the procedures, resulting in an extensive list of critical variables to be considered, such as the type of organic solvent, process temperature, extraction volume, poly(vinyl alcohol) (PVA) concentration, etc.146 The classical manufacturing approach of microspheres is the double emulsion solvent extraction method, where an aqueous solution of the compound, potentially including excipients, is emulsified within a polymer vehicle. The polymer vehicle consists of polyesters that have been solubilized in an organic solvent, commonly dichloromethane or ethyl acetate. This initial emulsion is then carefully poured into a second continuous aqueous phase that contains a surfactant, typically PVA. As the solvent is extracted from the emulsion within the second phase, the microspheres undergo solidification, resulting in their formation.141,147,148 Different variations over this process have been applied, e.g., one approach where the first emulsification step is omitted and the API is added as a solid,149 another where the first emulsion is spray dried to obtain particles,141,150−153 and last a process where a coacervation agent, such as silicon oil, is added to the primary emulsion. The organic solvent would diffuse into the silicon oil leading to microsphere precipitation.154−159 The process could beneficially be developed with a Quality by Design (QbD) approach to identify the true critical material and process attributes for the specific product, whereby a robust process can be defined.160 Besides the tedious process, aseptic manufacturing needs to be kept in mind,145,161 which altogether provides a complicated manufacturing process.

Exposure of LAI PLGA/PLA microspheres to elevated temperatures and humidity can have an impact on their release behavior.151,162 Consequently, the majority of LAI PLGA-based microspheres are stored and transported using a cold chain system.160 The stability of the PLGA microspheres is strongly correlated with the glass transition temperature (Tg) of the polymer chains. Microspheres stored at ambient temperatures below their Tg have been shown to remain stable for up to 12 months.163 It is hypothesized that the reduced mobility of the polymer chains at lower storage temperatures results in minimal physical changes over time.163 However, it is important to note that under high humidity conditions, PLGA chains can absorb moisture, leading to a decrease in the Tg of the polymer chains and increased chain mobility.163 This plasticization effect accelerates the degradation of the polymer chains. Additionally, the presence of moisture can induce hydrolytic degradation of the PLGA/PLA chains,163 why lyophilization to isolate the microspheres and resuspension before application would in general be applied increasing the cost of manufacturing further.

Despite the successful commercialization of several LAI microsphere drug products, the development of IVIVCs for these formulations has, to the best of our knowledge, been limited. Existing literature mostly consists of proof-of-concept studies demonstrating the possibility of developing IVIVCs for microspheres,164−170 with the work being complex due to the drug release characteristics of the compound from microspheres,171−173 as also discussed above. Some Level A IVIVC for microsphere drug products containing various small molecules have been described in the literature174,175 as well as one example from a peptide containing microsphere.176 In general, generating level A IVIVCs for microspheres must consequently be seen as a task with a significant risk of failing; however, generating level C IVIVCs may be possible, which at least may support the formulation development process.

The field of microspheres has multiple scientific challenges where additional research could ease the development of the systems as highlighted above. Development of new biodegradable polymers without the pH drop could enable the technology for some compounds, developing easier scalable manufacturing processes, e.g., by microfluidics or similar, and robust IVIVC methods. While the technologies have shortcomings, it is clear that the technology offers the possibility of extending the release of a special class of molecules, i.e., the water-soluble ones, in particular peptides and proteins.

4.2.2 Drug Eluting Implants

Implants constitute a special class of long-acting-release drug delivery systems. The formulations are solids that are inserted either under the skin or locally to release the compound imbedded in the formulation, and currently FDA have approved products that release their cargo from monthly up to 5 years. Implants can hence be used for both short and ultralong release times. As seen in Table 1, there are implants for intravitreal, intercranial, and SC insertion, a process that may be surgical. Implants can be biodegradable or nondegradable, where there currently is an excess of the latter among the marketed products. For the biodegradable implants, the excipients used will be degraded by the body; hence, there will not be a removal procedure as for the nondegradable implants. There may be both technical and market reasons to choose one technology over the other, such as the needed release profile, chemical compatibility reasons, or the potential to be able to remove the implant before it depletes for its therapeutical content, such as for contraceptives where the woman’s family situation may change over a period of five years and pregnancy become desired.

The technologies to ensure long release in the implants are very diverse and innovative. For the biodegradable implants PLGA or PLA has been used as the rate controlling excipient and the range of available PLGA grades from the excipient suppliers allows to generate implants to last up to a year if not more. The excipient is well-known from a safety perspective and the implants are manufactured by hot-melt extrusion.122 For the biodegradable device for intracranial administration (Gliadel wafer), the polymer polifeprosan has been used as the rate releasing polymer. For the nondegradable implants, a larger variation of the use of the ethylene vinylacetate (EVA) or silicon is the most used approach, but a liquid filled titanium rod also exists. The EVA and silicone implants can also be produced by hot-melt extrusion; hence, from a manufacturing perspective the implant production uses a well-known technology.

The insertion of the rods/implants goes from simple prefilled syringe type administrations, where the rod is mounted within a needle and pushed out into the SC tissue after injection, to implants that require smaller surgical procedures for their placement. No matter the level of complication, common for all is that there is a need for healthcare providers to be involved when administering or removing the implant. On the positive side of implants is the high inertness of the polymers used, which in practice allows them to deliver all modalities, provided that they can withstand the short heating involved during the manufacturing. Also, the possibility of generating devices that can release the compound over very extended periods is attractive, which is supported by a better drug to polymer ratio than in, for example, microspheres as only a solid is delivered.

The release mechanism from the implants is dependent on the technology used. For the PLA/PLGA based devices, the release mechanism is similar to the microspheres as discussed above. For the silicon/EVA based implants, the diffusion out of the matrix defines the release, which can be controlled by adjusting the amount of pore forms added. Obtaining IVIVC for the PLA/PLGA based implants is not trivial, as also described above for the microspheres, whereas it is more likely for the nondegradable implants, as the release mechanism is one-dimensional.

The application of implants has centered around a limited number of diseases this far, probably due to the complications of the insertion; however, with the potential to obtain very long release times, there may be a space for even more devices in the future. Scientifically development of new biodegradable polymers without the local pH disadvantage PLGA could be beneficial. Also, there is limited academic pharmaceutical research in the field, which makes industrial formulators depend on internal knowledge within the organization and the excipient suppliers. Expanded independent research may make it easier for new companies to engage in the field with its huge potential.

4.2.3 In Situ Forming Gels

In situ forming gels, also sometimes called in situ forming implants, are typically formulated by combining a drug, solvent, and biocompatible polymer to regulate the release of the drug. Currently, there are six in situ forming gels market, where five out of six are based on PLA/PLGA, such as Sublocade (buprenorphine), Eligard (leuprolide acetate), and Perseri (risperidone). These five products utilize the Atrigel technology, which involves a combination of the cosolvent N-methyl-2-pyrrolidone (NMP) and the PLGA polymer.143,177,178 The first in situ forming gel was brought to the market in 1998 for local treatment by subgingival administration and the first in situ forming gel for systemic administration came in 2004 with the approval of Eligard and the latest approval is in 2023 with Uzedy.179 This recent approval uses dimethyl sulfoxide (DMSO) as the cosolvent and a novel copolymer composition based upon PLA and PEG.179

The compounds formulated in the in situ forming gels are, as for the biodegradable polymeric microspheres, water-soluble; i.e., the three controlled release strategies describe here, i.e., the microspheres, the implant, and the in situ forming gels, are among the first formulation strategies to consider when a LAI with a water-soluble compound should be defined. The number of biocompatible cosolvents are limited, e.g., DMSO, NMP, and low molecular weight PEG, and the compounds should preferably be soluble in these to fit the formulation platform. It is, however, possible to market a formulation where the API is a suspension in the cosolvent, as seen for the highest dose of Eilgard.122 Also, for a compound to fit into an in situ forming gel based on PLGA, it would need to be stable at the lower pH that will be formed in the gel, as discussed above with PLGA microspheres.

Eligard consists of two parts: a polymer NMP solution and a lyophilized powder containing the API, which is the acetate salt of leuprolide. Before administration, these two components need to be thoroughly mixed together.177 The later marketed Camcevi, also containing leuprolide, used the mesylate salt of the compound had been used, which improved the stability sufficiently to allow marketing of a ready to use drug product.180 The other in situ forming gels also comes as ready to use drug products, which range in the administration interval from two weeks to two months.

Following injection of the in situ forming gel, the polymer forms a gel or solid polymer matrice at the injection site through phase separation. This phase separation is triggered by the exchange of tissue fluid (nonsolvent) and used cosolvent. Several important parameters influence the kinetics of phase separation. These parameters include the inflow of water or tissue fluid, the outflow of cosolvent, the miscibility between water and cosolvent, and the physicochemical properties of the polymer, such as molecular weight, weight distribution, and monomer ratio. Due to the miscibility of the cosolvents with water, the exchange between water inflow and cosolvent outflow occurs rapidly. This rapid exchange can lead to the quick precipitation of the polymer at the interface between water and cosolvent. As a result, a shell is formed on the surface, acting as a barrier to further water inflow and cosolvent outflow. An initial burst release may be seen in the phase, which is commonly attributed to the highly hydrophilic nature of molecules included in the formulation, which allows them to rapidly diffuse into the surrounding environment. The complete phase separation process, including solidification, can take hours to days, depending on factors such as the properties of the polymer, its concentration, and the solidification process itself. The kinetics of phase inversion can be modified by adjusting the composition of the formulation and the concentration of the cosolvent.181

In comparison to the manufacturing processes of polymeric microspheres and implants, in situ forming gels offer a more straightforward manufacturing process. If a drug substance is insoluble and unstable in the cosolvent, then it is typically supplied as a lyophilized powder to be mixed before injection, as with Eligard. However, if the API is soluble and stable in the same cosolvent used for the polymer, then the formulation can be supplied as a solution. The viscosity of the formulation depends on the concentration and molecular weight of the polymer used and can be highly challenging during compounding and filtration processes. Therefore, optimizing the molecular weight and concentration of the polymer is crucial not only for achieving the desired release profile but also for facilitating the ease of manufacturing. Despite the initial burst effect, in situ forming gels offer several advantages over polymeric microspheres and implants that make them appealing for future product development. These advantages include the potential for higher drug loadings compared, a simple sterilization process typically achieved through sterile filtration, and like the solid implant the flexibility of being removable if needed.141 In vitro dissolution and obtaining a level A IVIVC have same complexity as the two other technologies described above, a topic where there clearly is a scientific gap, together with potential new polymers that do not affect the local pH within the gel.

5 Concluding Remarks

LAIs provide sustained release of drugs over an extended period, typically weeks to months. They are designed to overcome the limitations of daily oral medications or frequent injections, offering convenience, improved adherence, and stable drug levels in the body, i.e., potentially providing an optimal therapeutic effect. LAIs and implants constitute an important formulation class for patient centric products, which includes a high number of different formulation technologies and strategies with a high diversity. The LAIs and implants have been in use for more than 70 years and have thereby proven to be a very valuable technology, which continuously is in development both with respect to applied technology as well as the indications it is used for. LAIs are administered via IM or SC injections and are formulated using various technologies to control drug release, as discussed in this review. Currently, the most important technology platform for LAI products is aqueous suspensions, however, LAIs reach the market using other technologies with multiple implants, polymeric microspheres and in situ forming gels being approved recently. The detailed discussion of the different LAI technologies demonstrated a high variety in the mode of action the approaches take as well as different manufacturing options and challenges. In general, the ability to define in vivo relevant in vitro dissolution methods have huge scientific gaps. The field is highly innovative, but a high number of systematic insights are missing, and additional investigations and research would have a high chance of generating additional innovations in the field for the benefit of the patients.

The market was not dominated by one specific technology. The formulation strategy used for most commercial products was aqueous suspension, which was also one of the two first used strategies historically in the LAI area, but in the last 20 years addition of LAIs for water-soluble compounds in implants, polymeric microspheres, and in situ forming implants have been quite remarkable demonstrating the need to continuously develop the available formulation platforms to ensure that also the next generation of modalities have a LAI technology that can help transfer these into LAIs.

LAIs have been developed for a wide range of therapeutic areas, including mental health, such as antipsychotics for schizophrenia, mood stabilizers for bipolar disorder, and long-acting opioids for pain management. LAIs are also used in other fields, such as contraception and the treatment of certain chronic diseases. Overall, LAIs offer a valuable treatment option for various conditions, improving medication adherence and providing sustained therapeutic benefits while reducing the burden of frequent dosing. However, individual patient preferences, treatment goals, and potential side effects should always be carefully considered in determining the most appropriate treatment approach.

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

R.H. has received funding from the Novo Nordisk Foundation grant agreement No. 0068744.

The authors declare no competing financial interest.

Abbreviations Used

API active pharmaceutical ingredient

BCS biopharmaceutical classification system

DMSO dimethyl sulfoxide

EMA European Medicines Agency

EVA ethylene vinylacetate

FDA U.S. Food and Drug administration

HIV human immunodeficiency virus

IM intramuscular

ISR injection site reaction

IVIVC in vitro in vivo correlations

LAI long acting injectable

NMP N-methyl-2-pyrrolidone

MCT medium chain triglyceride

PEG polyethylene glycol

PK pharmacokinetics

PLA polylactic acid

PLGA poly(lactic-co-glycolic acid)

PVA poly(vinyl alcohol)

RTU ready-to-use

SC subcutaneous

Tg glass transition temperature
==== Refs
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