3.1 Extended-Release Formulations

Extended drug release (EDR) formulations play a pivotal role in optimising drug delivery and adherence in the paediatric population by addressing unique challenges inherent to this age group. These formulations are engineered to release active pharmaceutical ingredients (API) gradually over an extended period, maintaining consistent therapeutic levels while reducing dosing frequency [37].

EDR formulations have revolutionised medication regimens by reducing dosing frequency while maintaining therapeutic drug levels. Evidence suggests that simplifying dosing regimens through EDR formulations can significantly improve adherence rates [40, 41]. The pharmacokinetic advantages of EDR formulations not only enhance patient convenience but also help maintain more consistent plasma drug concentrations, potentially reducing side effects that might otherwise lead to discontinuation [42]. The development of various EDR technologies, including matrix systems, osmotic pumps and multi-particulate systems, has expanded the range of medications that can benefit from this approach, encompassing cardiovascular, psychiatric, analgesic and anti-inflammatory drug classes [43,44,45].

Developing flexible drug formulations that can be adapted for paediatric patients is a strategic approach to enhance compliance and therapeutic outcomes. These formulations can be engineered to provide immediate, delayed, or extended drug release patterns on the basis of therapeutic needs. For example, pellets, powders, or granules can be dispersed in water or soft foods, facilitating ease of administration for patients with swallowing difficulties; a common issue in paediatrics [46,47,48,49].

Children exhibit distinct physiological and developmental characteristics that influence the pharmacokinetics and pharmacodynamics of drugs. Traditional drug delivery systems often fail to meet paediatric requirements owing to differences in metabolism, organ maturity and taste preferences. However, the development of paediatric-appropriate EDR formulations faces challenges. Many EDR tablets and capsules are designed for adults and are often too large for paediatric patients to swallow, limiting their applicability in this population [2, 49]. Additionally, manipulating adult EDR formulations, such as crushing tablets to achieve appropriate paediatric dosing, can compromise the integrity of the drug release mechanism, leading to potential safety and efficacy issues [49, 50].

The use of EDR formulations in populations presents several challenges and disadvantages that must be carefully considered. One significant limitation is the lack of dosing flexibility. Since paediatric dosing is often weight-based and requires precise adjustments, the fixed-dose nature of most ER formulations makes it difficult to tailor the medication to an individual child’s needs, potentially leading to suboptimal treatment outcomes [51].

Swallowing difficulties further complicate the use of EDR medications in children. Many of these formulations are available in tablet or capsule form, which may be difficult for paediatric patients to swallow. Unlike immediate-release formulations, EDR tablets and capsules generally cannot be crushed, split, or chewed, as this may alter their drug release properties. The inappropriate modification of these formulations can lead to dose dumping, where the entire drug dose is released at once, increasing the risk of toxicity [49, 52]. This is particularly concerning in paediatric patients, who are more vulnerable to adverse drug reactions owing to their developing physiology.

Gastrointestinal (GI) transit times also play a crucial role in drug absorption, and children exhibit significant variability in GI function. Differences in gastric emptying and intestinal motility can affect the efficacy of EDR formulations, leading to unpredictable drug levels. This inconsistency poses a challenge in maintaining therapeutic drug concentrations, which may result in reduced efficacy or unintended side effects [49]. Another major issue is the limited availability of paediatric-friendly EDR formulations. Most extended-release drugs are developed for adults, leaving few options that meet the specific needs of children. This lack of suitable formulations forces healthcare providers to either modify adult EDR formulations, which may compromise drug efficacy and safety, or prescribe multiple daily doses of immediate-release alternatives, which negates the intended benefits of EDR therapy [2, 52].

Lastly, EDR formulations pose a risk of accidental misuse or overdose. As they contain higher amounts of active ingredients intended for gradual release, improper administration, such as accidental ingestion by paediatric patients, can lead to severe adverse effects. This highlights the importance of caregiver education and secure storage to prevent unintentional ingestion. Given these challenges, the decision to use EDR formulations in paediatric patients should be made cautiously. Clinicians must weigh the benefits of improved adherence against the risks of dose inflexibility, swallowing difficulties, pharmacokinetic variability and potential toxicity. Future advancements in paediatric drug formulation should focus on developing age-appropriate EDR options that balance convenience with safety and efficacy.

3.2 Oral Flexible Tablets

Several recent advancements in oral solid dosage forms fall under the category of oral flexible tablets (OFTs), which can be either immediate- or extended-release and are specifically designed to improve dose adaptability, ease of administration and patient acceptability, particularly in vulnerable populations such as children. Unlike conventional tablets, which often require swallowing whole and lack the flexibility to adjust dosing [53].

A central feature of OFTs is the flexibility of doses. Traditional tablets typically offer fixed doses, and pill splitting is often used to achieve intermediate strengths. However, this method can lead to dose inaccuracy and safety concerns. In response, novel OFT designs have been introduced. OFTs are engineered to provide safer, more individualised therapeutic options without compromising formulation stability [53, 54].

For instance, tablets that can be precisely scored into multiple segments allow for accurate dose modification [55]. Similarly, several formulations incorporate drug-free layers between active segments, which make the tablet easier to divide without affecting the uniformity of the drug’s content [56, 57]. These technologies provide safe, reliable alternatives to unsupervised tablet splitting, enabling precise, flexible dosing.

In addition, single-unit mini tablets can be considered a form of oral flexible tablets when used individually rather than in multiparticulate combinations [58, 59]. Studies have shown that children as young as 6 months old can swallow 2-mm mini tablets, which are often preferred over liquid formulations owing to their better taste masking, dosing accuracy and portability [49, 60]. Their small size significantly enhances swallowability and provides an alternative solid dosage option for populations with swallowing difficulties.

For instance, research has demonstrated the feasibility of creating extended-release OFTs using carbamazepine as a model drug, aiming to enhance compliance among paediatric patients [53, 61, 62]. These formulations can be designed to provide immediate-, delayed-, or extended-drug-release patterns, aligning with therapeutic objectives and improving adherence.

Moreover, the development of age-appropriate formulations is crucial for effective paediatric therapy. Tailoring drug formulations to suit a child’s age, size and physiological condition ensures accurate dosing and minimises adverse effects [49]. The American Academy of Paediatrics emphasises the importance of developing paediatric medicines that align with children’s unique treatment needs, highlighting the need for diverse routes of administration, dosage forms and strengths to ensure adequate treatment across all paediatric age groups [52].

Together, these developments illustrate how OFTs are reshaping the landscape of oral drug delivery. By offering customisable dosing, improved acceptability and greater ease of administration, OFTs address critical limitations of conventional tablets and contribute to more patient-centric pharmaceutical care. They represent a significant advancement in the transition towards more adaptable, safe and user-friendly oral medications across the age spectrum.

3.3 Orodispersible Tablets (ODTs)

Formulations, such as orodispersible tablets (ODTs), have been developed to cater to the needs of paediatric patients. ODTs are formulated to break down rapidly within the oral cavity, typically within seconds, eliminating the need to swallow the tablet whole and thereby preventing choking [63, 64]. In many cases, their rapid disintegration or dissolution allows administration without water. ODTs also offer considerable flexibility, as they can be administered by dispersing them directly in the mouth, pre-dispersing them in a suitable vehicle, or swallowing them whole, depending on patient preference. These advantages contribute to enhanced patient acceptability and improved adherence compared with conventional oral formulations.

While ODTs enhance ease of administration and swallowing, they offer limited dose flexibility compared with conventional tablets. This limitation necessitates the development of a range of fixed-dose strengths to cater to the diverse needs of various patient populations. Additionally, owing to their fragile structure, ODTs are generally unsuitable for splitting, which further restricts individualised dosing [65]. To address these constraints, orally disintegrating minitablets (ODMTs) have emerged as a promising alternative, combining the patient-friendly attributes of ODTs with the flexible dosing advantages of multi-particulate systems [66].

ODTs typically disintegrate in the mouth and are then swallowed, allowing drug absorption to occur primarily along the gastrointestinal tract [64]. However, in several formulations, the tablet may be retained in the oral cavity to enable buccal or sublingual absorption, potentially offering a faster onset of action and enhanced bioavailability for drugs that are well absorbed through the oral mucosa. Formulations designed for mucosal absorption often include bioadhesive layers to enhance retention at the target site within the mouth [64, 67]. It is essential that the intended route of absorption, gastrointestinal versus buccal, is clearly specified to avoid medication errors, as the time a formulation remains in the mouth can significantly influence its pharmacokinetic profile.

As ODTs disintegrate directly in the oral cavity, taste masking is critical, particularly for formulations containing bitter or unpalatable active pharmaceutical ingredients. While sweeteners and flavouring agents are frequently added to enhance palatability, their effectiveness is often limited, and their use may raise safety concerns, especially in paediatric populations. More robust taste-masking strategies include coating drug particles, a technologically challenging but effective approach. Several patented ODT technologies have successfully addressed this issue by using microencapsulated drugs or polymer-coated particles, thereby improving both organoleptic properties and drug release profiles [68,69,70].

3.4 Orodispersible Films (ODFs)

Orodispersible films (ODFs) are thin, drug-loaded polymeric matrices designed to rapidly disintegrate in the oral cavity, releasing the API without the need for water. Similar to ODTs, ODFs facilitate swallowing owing to their rapid dissolution in saliva. Their discreet and elegant appearance, along with ease of use, makes them an appealing option for many patients. A key advantage of ODFs over tablets is their dose flexibility, as different strengths can be achieved by simply cutting the film to the desired size [71].

One major challenge in ODF development is achieving effective taste masking and controlled drug release. Traditional coating techniques commonly used for these purposes in solid dosage forms are difficult to apply to ODFs because their manufacturing process typically requires the API to be dissolved [71]. In several cases, multi-layered films have been developed using polymers with different release properties to achieve sustained release. However, these formulations often adhere to the buccal mucosa and are designed for timed drug release, thereby compromising the advantage of rapid disintegration. Moreover, owing to the limited absorption capacity of the oral mucosa, controlled-release ODFs are often better suited for topical or local delivery rather than systemic absorption [72].

The need for specialised equipment for both manufacturing and packaging can pose a barrier to the widespread adoption of ODF technology. Indeed, several ODF products have been withdrawn from the market in the past, largely owing to manufacturing complexities and limited commercial returns [65]. Presently, ODFs dominate the over-the-counter segment, with applications in vitamins, dietary supplements, antihistamines, breath fresheners and cough suppressants [73]. The first prescription-only ODF approved in the USA was ondansetron oral soluble film, indicated for both adults and children aged 4 years and older [64].

3.5 Chewable Formulations

Chewable dosage forms, including chewable tablets, soft chews and medicated chewing gums, are designed to be mechanically processed in the mouth to facilitate the disintegration and/or dissolution of the active pharmaceutical ingredient. These formulations eliminate the need for water and assist with swallowing or, in the case of chewing gum, may even bypass swallowing altogether [64]. Their favourable aesthetic properties and ease of use often make them more acceptable to patients compared with conventional tablets. However, similar ODTs, chewable formulations offer limited dose flexibility, as they are not readily adjustable to meet individual dosing requirements, especially in paediatric patients, where dose precision is extremely important [64].

The disintegration and subsequent swallowing of chewable forms depend on the patient’s active chewing and/or sucking. Consequently, taste and mouthfeel become critical quality attributes. Careful selection of excipients, particularly sweeteners and fillers such as mannitol, sucrose and sorbitol, is necessary to enhance palatability [64, 74]. A major limitation of chewable products is their reduced suitability for taste masking and controlled release via coating techniques, as the mechanical forces exerted during chewing can disrupt such protective layers. Additionally, drug release and, consequently, therapeutic response may vary depending on the patient's chewing ability, contributing to both intra- and inter-individual variability.

The requirement for chewing may limit the use of these formulations in very young paediatric patients. Nonetheless, available evidence supports the safety and tolerability of chewable tablets in children aged 2 years and older. By contrast, chewing gum formulations are not intended to be swallowed. For these, the duration required for complete drug release must be clearly stated on the product label. Owing to limited safety data, chewing gum is only recommended for children aged 6 years and older, according to current guidelines. Furthermore, there are concerns regarding potential misuse, as children may mistake medicated gums or soft chews for confectionery, raising issues related to accidental ingestion and dosing errors [23, 64].

3.6 Implantable and Injectable Long-Acting Formulations

Implantable and injectable long-acting formulations (LAFs) have emerged as innovative strategies to enhance drug delivery and adherence, particularly in paediatric patients [75]. These formulations are designed to release medications over extended periods, reducing the frequency of administration and addressing common challenges associated with daily dosing regimens.

The pharmacokinetic profiles and safety of long-acting formulations in children may differ from those in adults. Therefore, comprehensive studies are essential to determine appropriate dosing, efficacy and safety parameters for paediatric use [76]. In paediatric patients, maintaining consistent medication adherence can be challenging owing to factors such as taste aversion, swallowing difficulties and reliance on caregivers for administration [77, 78]. LAFs, such as long-acting injectables and implants, offer the advantage of sustained drug release, minimising the need for frequent dosing and thereby improving adherence [79]. This approach not only simplifies treatment regimens but also reduces caregivers’ burden, thereby improving therapeutic outcomes. A report by Unitaid highlights the promise of long-acting formulations in paediatric medicine, emphasising their potential to improve compliance and therapeutic efficacy [80]. Studies suggest that infants, children and adolescents living with HIV may benefit from these formulations, as they are thought to enhance treatment adherence, resulting in improved health outcomes [76].

The successful, accelerated development of a paediatric oral formulation of dolutegravir provides a valuable model for rapidly developing, testing and scaling child-friendly treatments [81]. This road map is particularly relevant as LAFs for HIV prevention and treatment show growing promise in paediatric populations. While intramuscular injections of cabotegravir and rilpivirine have been well tolerated by adults and preliminarily accepted by adolescents, challenges such as injection fatigue, needle aversion in paediatric patients and unsuitability for infants owing to injection volume and pain must be considered [82]. In several contexts, injections are favoured over oral medications, but barriers such as travel costs, injection site pain, negative healthcare experiences and cultural beliefs can limit adherence and retention, as seen in penicillin prophylaxis for rheumatic heart disease [83, 84].

Subcutaneous injections may offer a more acceptable and feasible alternative for children, including neonates and infants, as they tend to be less painful and easier to administer. Broadly neutralising antibodies (bNAbs) delivered subcutaneously are under investigation for preventing postnatal HIV transmission and may potentially be integrated into routine childhood immunisation programs [83]. This integrated approach, while promising, will require careful evaluation of feasibility, cost-effectiveness and scalability.

Moreover, innovative delivery platforms such as microarray patches and long-acting oral formulations are being explored to minimise the burden of daily dosing and the discomfort of injections [83, 85]. These technologies have the potential to significantly enhance the quality of life for children with chronic conditions. Drawing from the example of paediatric dolutegravir, the early prioritisation of paediatric-specific development is essential to ensure that these advancements are both accessible and effective for younger populations.

While LAF systems offer the advantage of reducing the need for daily medication decisions, thereby minimising cognitive and motivational barriers to adherence, they also raise important considerations regarding patient autonomy. The irreversible nature of an injection means that once administered, the medication remains active for an extended period, which may not align with a patient’s changing preferences or circumstances. This trade-off is particularly pertinent in vulnerable populations or individuals with fluctuating capacity for medical decision-making [86, 87].

However, the development and implementation of LAFs in these populations requires careful consideration. Age-related physiological changes can affect drug metabolism and distribution, necessitating tailored pharmacokinetic evaluations to ensure safety and efficacy. Moreover, patient-centric design is crucial; formulations must be developed with the specific needs and preferences of paediatric patients in mind to enhance acceptability and adherence [88]. In conclusion, implantable and injectable long-acting formulations hold significant potential to optimise drug delivery and adherence in both paediatric and geriatric populations. By addressing the unique challenges faced by these groups, LAFs can improve health outcomes and quality of life. Ongoing research and development, guided by patient-centric principles, are essential to fully realise the benefits of these advanced drug delivery systems.