Orally Fast Disintegrating Tablets for Infants and Children

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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15041033

A significant number of current drug formulations are not suitable for children of different age groups because of heterogeneity of the pediatric population, immature Absorption, Distribution, Metabolism and Elimination (ADME) processes, rapid developmental changes, palatability issues, low drug adherence and ethical concerns. Improvements in flexibility of dose administration, tablet size, taste masking, bioavailability, excipient safety and acceptability, stability, manufacturing and affordability represent multiple opportunities at various scales of child-friendly formulations design to overcome clinical and technological challenges in pediatric drug development. Orally Dispersible Tablets (ODTs) are a promising child-friendly drug delivery strategy, offering a potential solution to address unique medical needs in infants and children while maintaining a favorable excipient safety and acceptability profile in these vulnerable patient populations.

child-appropriate formulations orally fast disintegrating tablets pediatrics patient safety formulation excipient worldwide clinical need

1. Introduction

A majority of therapeutics prescribed for the prevention or treatment of diseases in infants and children are medicines designed for and studied in adults. They may not be the most effective, and/or are delivered as non-palatable dosage forms eventually leading to poor patient adherence and inadequate drug exposure. In the 1960s, the acknowledgement of children as “therapeutic orphans” led to a worldwide wake-up call. The need to conduct clinical trials with medicines utilized in infants and children was recognized to be an extremely important way to improve the health of children, especially in areas of high unmet clinical need ^[1]. In 2007, the World Health Organization (WHO) launched the “make medicines child size” (MMCS) campaign by urging countries to prioritize procurement of medicines with appropriate strengths for children’s age and weight. In addition, it was suggested to develop child-friendly formulations such as multi-particulate oral formulations ^[2].

According to Kaushal et al., about 7.5 million preventable medication errors occur with pediatric patients in the US each year ^[3], among which 14–31% result in serious harm or death ^[4]^[5]. Medication errors mainly occur in high-risk settings such as the Emergency Unit, Intensive Care Unit (ICU), Anesthesiology and Neonatology Units, where severe diseases as well as life-threatening conditions are being treated with narrow therapeutic index drugs. In infants and children, systemic anti-infectives are the most prescribed and used drugs particularly in the out-patient setting. Within this age population, the <2-year-old infants have the highest drug prescription prevalence (i.e., 2.2–4.7 prescriptions per person per year) ^[6]. Therapeutic errors frequently occur, following parenteral infusions, oral fluid administration, tablet splitting, tablet crushing, and unlicensed and off-label use of drugs with doses extrapolated from adult literature ^[7]. Human errors associated with system defects and lack of clinical pharmacists in hospitals are other well identified risk factors for medication errors throughout the whole dispensation chain of drugs (i.e., prescription, transcription, dispensing, dosage, administration, compliance monitoring). Child-friendly orally available formulations are necessary, to meet the goal of increased out-patient treatment. As soon as hospitalized children recover from an acute infection and show adequate ability to drink and eat, they should continue their treatment with an oral agent in the out-patient setting. For antibacterial drugs, an early switch from i.v. to oral treatment is possible and also effective ^[8].

Although much progress has been made in recent years, the development and utilization of drugs in newborns, infants and older children is still associated with a wide range of pharmacological and clinical challenges. The lack of funding, small market size, ethical issues, specific ethical concerns and uniqueness of children’s physiological, developmental, psychological, and pharmacological characteristics makes conducting clinical trials in pediatrics more challenging than in adults ^[9]. Less than 50% of drugs entering the market are clinically evaluated in the pediatric age group ^[10]. As pediatric patients are highly diverse, ranging from preterm, term neonates to adolescents, they differ markedly from adults because of developmental changes and continuous growth affecting pharmacokinetics (absorption, distribution, metabolism, and elimination), and pharmacodynamics (desired and undesired effects). In addition, target values of biological parameters or drug concentrations can differ greatly between adult and pediatric patients, as well as between healthy and sick children. Furthermore, formulations are frequently designed for adults and hardly ever for optimal use in children. These factors make it difficult to design pediatric studies, find optimal pediatric dosing, and select an age-appropriate formulation.

Drug prescription in children is often based on extrapolation from clinical trials in adults. Formulations are hardly ever designed for an optimal use in children. Large capsules and tablets (e.g., 6-mercaptopurine, temozolomide), poor taste, high number of dose units, administration volumes and safety of excipients limit the acceptability of many dosage forms in pediatrics and may have an impact on bioavailability ^[11]. As such, there is a need to investigate innovative individualized treatment and care as well as child-friendly oral formulations. Furthermore, novel formulations should take into consideration the situation in low- and middle-income countries, namely compatibility with high and/or humid temperatures, inefficient transport systems and interrupted supply chains, as well as poor storage conditions.

An optimal pediatric formulation should meet the following requirements: low frequency of dosing, an appropriate dosage form for various pediatric age groups, convenient and reliable administration, minimal impact on lifestyle and daily routines, use of non-toxic and well tolerated excipients, taste masking, and cost-efficient manufacturing ^[12]. In summary, introducing child-friendly, age-appropriate, formulations is part of an innovative approach to enhance drug acceptability and to improve drug adherence and clinical outcomes.

2. Clinical and Technological Challenges

2.1. Palatability and Taste Masking

In pediatric patients, unpleasant, bitter taste of a medicine is one of the most frequent causes of reduced drug-adherence, treatment failure and the importance of building palatability into pediatric medicines is now recognized by the pharmaceutical industry and the regulatory authorities. For this reason, medication palatability is a key element of therapeutic drug-adherence and successful therapeutic outcome in pediatrics where the ability to swallow prescribed drugs can influence the choice of a given medicine or formulation by the treating clinician ^[11].

Taste masking is a well-documented challenge in formulation of oral disintegrating tablets (ODTs) caused by the stimulation of certain receptors in the oral cavity. Several reviews have emphasized the importance of taste masking and palatability in ODTs for ensuring patient acceptance and compliance. Poor adherence to therapy can occur because of a lack of taste masking. The rapid disintegration of ODTs in the oral cavity and immediate release leads to early exposure of the active pharmaceutical ingredient (API) to the taste buds, making it difficult to mask the bitter taste commonly associated with many APIs ^[13]^[14]^[15]^[16]. This challenge is further intensified by differences in taste perception between adult and pediatric patients, which is especially characterized by a rejection of bitter-tasting and a preference for sweet-tasting foods in pediatrics ^[17]. Consequently, a great effort in formulation development must be invested in utilizing excipients for taste-masking of bitter APIs. A common strategy for taste masking is the use of artificial sweeteners in combination with flavors, as they are well known, widely available and typically do not affect the release of the API. However, sweeteners are not efficient in masking bitterness, requiring use of large amounts or combination with different taste masking strategies. Improvement in taste can be also achieved with chemical interactions by complexation (e.g., cyclodextrines). Physical shielding by coating of the API is considered most effective but can affect bioavailability, is expensive and more technologically challenging as it requires dedicated processes and equipment ^[14]^[18].

2.2. Flexibility of Dose Administration

Flexible solid oral dosage forms that would allow to adjust dose depending on body weight and age groups are considered most suitable for children at the global level especially for developing countries ^[19]. Flexible solid oral dosage forms include tablets that are dispersible and can be used for preparation of oral liquids suitable for the younger age groups, powders, granules, and pellets ^[20]. In this context, ODTs have been widely studied and are recognized as a popular and effective dosage form for vulnerable patient populations, including children and the elderly. This dosage form can be easily administered to children and elderly patients without the need for hospitalization or the support of medical professionals, and it has been shown to be well-tolerated and safe ^[21]. Studies have demonstrated that solid dosage forms such as mini tablets or ODTs are more accepted by children than syrup formulations, which are considered the gold standard in pediatric drug delivery ^[22]^[23]^[24]. Furthermore, ODTs offer a high degree of flexibility in terms of administration methods, as the tablet can be pre-dispersed or directly disintegrated within the oral cavity, or even ingested in its whole, depending on the individual’s preference ^[25]. Oromucosal delivery systems are designed to specifically target the highly vascularized oral mucosa for buccal drug delivery using ODT received a lot of attention in recent years. Direct access to the systemic circulation bypasses the gastrointestinal tract, thus preventing hepatic clearance, such as with ororodispersible desmopressin tablets ^[26]. As a result, bioavailability increases, allowing lower doses to be administered and reducing side-effects and systemic toxicities.

2.3. Excipient Safety and Acceptability

Excipients are used to optimize the formulation, improve palatability (influenced by drug-s crystalline structure and solubility), shelf-life and manufacturing processes. When selecting excipients, it is crucial to conduct a thorough assessment of toxicity and risks, considering regulatory compliance, acceptable daily intake levels, purity, tolerability, and the age of the intended patient population. Even excipients generally recognized as safe (GRAS) can be unsafe in young children due to their immature ADME processes ^[27]. Developmental pharmacology concerns related to excipients have been raised, with elevated toxicity and safety risks for preterm and term newborns and infants younger than 6 months of age ^[28]^[29]. Use of several excipients hold significant safety warnings in pediatrics as is the case for benzyl alcohol used as preservative, which can lead to neurotoxicity and metabolic acidosis. Ethanol may also lead to neurotoxicity and cardiovascular issues; propylene glycol to neurotoxicity (Box 3, Regulatory case study 3), seizures and hyperosmolarity; polysorbate 20 and 80 to liver and kidney failure; sucrose to dental caries and azo dyes to hyperactivity; acetem (acetylated mono- and diglycerides) present in syrup can solve plastics (e.g., when administered by nasogastric tube or PEG connection, PVC connections).

2.4. Tablet Size

Swallowing of traditional tablets, designed for adults, is often a problem for young children and patients with underlying comorbidities ^[30]^[31]. In infants aged 6 to 12 months, 2 mm diameter tablets are considered acceptable ^[32]. For children aged 2 to 6 years, tablets less than or equal to 3 mm diameter are considered suitable ^[33]. As such, the size of an ODT must be minimized to ensure safe administration and increase acceptability in pediatric patients. This constraint significantly reduces the potential drug dose. For example, oral administration of drugs requiring high doses, such as many antibiotics, is not feasible in the form of solid dosage forms any longer. In addition, the amount of used excipients becomes a limiting factor. In particular, the formulation of ODTs relies on excipients for taste masking, super-disintegrants, fillers, binders for mechanical strength, and lubricants ^[34]. These excipients not only affect the tablet size, but also the amount of API that can be incorporated into the formulation. They are necessary to ensure proper performance such as rapid disintegration and taste masking ^[15]^[35]. Therefore, ODT formulations are mainly used to formulate highly potent active pharmaceutical ingredients. The major challenges in this regard are content uniformity and precise dosing. Manufacturing of low-dose ODTs necessitates additional processing steps, such as granulation, which can increase time and cost associated with production.

2.5. Onset of Action and Emergency Situations

Auvi-Q (epinephrine injection) is a low dose epinephrine auto-injector for the emergency treatment of allergic reactions in infants and toddlers. However, this approach is expensive due to the use of an auto-injector and the product has a limited shelf-life. Traditional oral formulations have a time to reach clinical efficacy, which is often too long in emergency situations, such as resuscitation and intensive care.

ODTs are a type of solid oral dosage form that rapidly disintegrate within the oral cavity, typically within a few seconds. The Food and Drug Administration (FDA) recommends a disintegration time <30 s for a tablet to be classified as ODT ^[36]. Orally disintegrating tablets are frequently formulated to elicit a more rapid onset of therapeutic action since drugs are taken up by the buccal mucosa. This is crucial in certain acute or emergency conditions, such as pain, tonic-clonic seizures, status epilepticus, and anaphylaxis ^[30]^[31]^[37]. It should be noted that differences in rate of absorption of a given drug affects time (t_max) to maximal drug concentration (C_max); e.g., liquids have a more rapid onset of action than tablets (no disintegration step), while differences in the extent of absorption affect the C_max or area-under-the-curve (AUC).

2.6. Impact of Developmental Pharmacology on Drug Absorption, Distribution, Metabolism and Elimination (ADME)

Pediatric patients are not small adults. Pediatric patients are a heterogeneous population ranging from preterm and term neonates, infants, older children to post-pubertal adolescents ^[38]. As such pediatric patients differ markedly from adults in the sense that developmental changes and continuous growth have an impact on body composition, organ maturation and physiological and biochemical processes that govern the pharmacokinetics (absorption, distribution, metabolism, and elimination) and pharmacodynamics (desired and undesired effects) of medicines, as well as pharmacogenomics (e.g., gene switching during development or different isoforms from post-translational spicing during development). In neonates, gastric pH approximates neutral pH values directly after delivery and then decreases to acidic pH values shortly after birth ^[39]^[40]. Slower gastro-intestinal but faster intramuscular absorption in infancy surely influence the choice of route of administration of a given drug. Body weight and composition also dramatically changes in the first months of life. Drugs distribution depends on the body composition and on the physio-chemical properties of a given drug. For instance, hydrophilic drugs have a larger volume of distribution in newborns due to their higher percentage of extracellular water (around 70 to 80%). Due to limited protein binding in infants, newborns might thus require a higher dose per kilogram of bodyweight to ensure effective distribution through tissue and plasma ^[41]. A larger brain/body weight ratio and higher blood–brain barrier (BBB) permeability in younger children leads to high drug intake of drug able to cross the BBB. Different metabolic pathways and drug-metabolizing enzymes (DMEs), e.g., cytochrome P450-dependent enzymes, show various and non-uniform maturation profiles during first months of life ^[42]^[43].

2.7. Novel Formulations and Pediatric Clinical Development

There are many barriers to pediatric drug development, including ethical concerns and economic barriers. Development of child-appropriate formulations can be time-consuming and cost intensive, due to aforementioned challenges and potential need to develop more than one formulation to allow easy administration to pediatric patients across all age groups. In addition, manufacturing cost of specialized formulations, especially when weighed against return on investment and particularly for small markets or niche products, can be high compared to well-established, non-complex formulations manufactured on a large scale. Furthermore, once a new drug received marketing authorization for adults, several years are often needed to obtain a pediatric indication. Indeed, generating enough data for finalization of Paediatric Investigation Plans (PIP) is often delayed.

To encourage development of pediatric-friendly dosage forms, such as ODTs, various regulatory incentives such as the Best Pharmaceuticals for Children Act (BPCA) have been established and the PIP was implemented by health authorities. Ideally, a pediatric-appropriate formulation should be bioequivalent to an adult product to minimize prescription errors and enable switching of formulations at a given age. A review from Batchelor et al. showed that current pediatric formulations were not equivalent to the reference adult product in 40% of cases ^[44].

Selection of a dosage form and its composition are pivotal aspects of regulatory documentation. However, it should be noted that a decade after initiation of the PIP, increase in availability of child-friendly dosage forms on the market has yet to materialize and significant deficiencies persist ^[27]^[45]^[46]. To date, one official regulatory document, the “Guideline on Pharmaceutical Development of Medicines for Pediatric use” has been published by the European Medicines Agency (EMA) ^[22].

Lack of suitable delivery system is one of the main reasons for trial failure in pediatric drug development ^[47]. Drug adherence, palatability and acceptability are even more important factors in pediatric than in adult drug development. A recent survey on drug-handling issues and expectations in parents and children shows that this topic is of high concern and an often-encountered situation. Medication related factors, particularly administration and drug formulation play a key role. The oral route is the preferred method of drug delivery ^[48]. As such, appropriate taste-masking is essential to overcome these challenges in pediatric studies.

2.8. Socioeconomic Aspects

Stability is a formulation property that ensures uniformity in drug administration and optimal drug preparation management in hospitals. For instance, five different hydrochlorothiazide oral formulations prepared with traditional compounding techniques in hospital pharmacies to treat heart failure and edemas in babies were compared and subjected to quality control tests (pH, particle size, viscosity, dose content and stability). Only one studied formulation met the defined quality criteria and allowed for a correct dose to be administered. Shelf-life was 3 weeks when stored at 5 °C and protected from light ^[45].

In the majority of low- and middle-income countries (LMICs), water is either lacking or a limited resource. Drug reconstitution is therefore often problematic. Rapid disintegration of ODTs upon contact with saliva eliminates the need for drinking water, making them an attractive dosage form for pediatric patients, particularly in developing countries ^[49]. Poor hygiene and environmental limitations (heat, humidity) are additional constraints in drug administration. Liquid dosage forms are not desirable for the hot and humid tropical conditions found in most LMICs. Furthermore, they require bulkier packaging than solid formulations. Fragmented transportation systems found in many LMIC countries prevent distribution of refrigerated products. In contrast to liquid dosage forms, ODTs are solid dosage forms associated with improved chemical stability. This facilitates storage and logistics in harsh climate conditions ^[21].

3. Novel Multifunctional Excipients for the Design of Orally Dispersible Tablets

3.1. Excipient Design for Orally Dispersible Tablets (ODT)

Utilization of conventional excipients in the development of ODTs has been found to be inadequate to meet current clinical needs and requirements by health authorities. New excipients are necessary for successful formulation of ODTs. Efforts in developing new excipients can be classified into three categories: modified, co-processed, and novel excipients. The development path for each class of excipient varies. For instance, development of novel excipients is a costly and time-consuming process, typically lasting 6 to 7 years requiring compliance with regulatory and safety standards. Due to these factors, development of co-processed excipients with pre-approved functions is often preferred by pharmaceutical industries, as it simplifies the regulatory approval process, reduces development costs, and increases likelihood of success ^[50].

Co-processed mannitol is a commonly utilized excipient for the direct compaction of ODTs due to its slight sweetness, taste-masking properties, non-hygroscopic nature, and improved disintegration characteristics in comparison to polyoles. Despite the availability of pre-formulated mixes such as Pearlitol^® Flash, Ludiflash^®, Parteck^® ODT, Pharmburst^® 500, and Prosolv^® ODT, some of the mentioned ready mixes reveal a poor disintegration behavior even at very low compressive forces. Their use as excipients for ODTs is therefore limited ^[51]. Alternative pre-formulated mixes for direct compaction, such as Orasolv^®, which uses effervescent-based disintegration, exhibit low mechanical strength, are susceptible to moisture, and necessitate specialized packaging. Subsequent development has led to Durasol^®, which demonstrates improved compactibility due to its composition of primarily nondirect compression fillers, including mannitol, lactose, sorbitol, and sucrose. However, the primary drawback of this technology is its limited capacity for drug incorporation. Its use is therefore limited to the formulation of small doses only ^[52].

3.2. Multifunctional Porous Calcium Carbonate/Phosphate Carriers

One particularly promising multifunctional excipient that gained significant attention is functionalized calcium carbonate (FCC) ^[53]. Inorganic porous carriers are a promising technology due to their stability, well-defined surface properties, high pore volume, narrow pore diameter distribution and large surface area ^[54]. These an inorganic porous microparticles have an average size of 10–20 µm and a specific surface area of 30–70 m²/g ^[55]. Unlike mesoporous silica particles, which have been frequently cited for oral drug delivery, FCC is biodegradable and considered safe, as it is a mixture of calcium carbonate and hydroxyapatite, both of which are monographed ^[56]. The lamellar surface of FCC provides large contact surface, resulting in excellent compressibility and leading to extremely strong tablets and the ability to be dry granulated using a roller compaction. In contrast to traditional excipients, tablets made with porous inorganic carriers exhibit exceptional mechanical strength while maintaining a high degree of porosity. High particle porosity was found to cause rapid disintegration of tablets, surpassing the performance of many commercially available excipients ^[53]^[57]. Utilization of an excipient with multiple functionalities can lead to a reduction in the need for additional excipients, thereby improving drug adherence and compatibility in pediatric populations ^[58]^[59]. These characteristics demonstrate the potential of porous carriers for pediatric formulations and provide the basis for further clinical evaluation of the excipient’s mouthfeel properties and acceptability. However, as outlined below, the loading capacity of these carriers is limited.

Given favorable acceptability of the excipient in children, it is important to evaluate stability of the excipient to ensure consistent performance of the formulation and safety. Stability studies of caffeine and oxantel pamoate tablets containing FCC as an excipient demonstrated that they could withstand stress conditions and maintain the stability of the drug substance stable for prolonged periods. However, it was shown that humidity and temperature affected disintegration time, dissolution rate and hardness, emphasizing the need to store tablets at room temperature and in dry conditions ^[60].

A key feature of porous inorganic calcium phosphate is its ability to encapsulate small molecules, oils, and proteins. Loading can protect sensitive APIs and improve their stability, as demonstrated by loading proteins into FCC which were reported to be stable and preserved their functionalities ^[61]. Additionally, for poorly soluble molecules, it has been observed that drug loading of porous calcium phosphate results in an improvement of the dissolution rate, attributed to the enlarged surface area and micronization of the drug substance by loading ^[62]^[63]. Furthermore, loading of bitter drugs into the pores can also lead to taste masking, which is critical for the formulation of ODTs ^[64]. The previous discussion has highlighted that one of the obstacles encountered in the development of low-dose ODT containing highly potent API, is the issue of content uniformity. Utilization of porous carriers as a formulation strategy is a suitable approach for addressing this issue as they are typically loaded with API solutions, resulting in high content uniformity ^[65].

From a drug product formulation perspective, use of inorganic porous carriers as a means of drug loading offers the potential to prevent alterations in excipients performance as the API is encapsulated in the carrier. Characteristics of the tablet are still determined by the excipient and not by the API, as it is encapsulated within the particle ^[66].This results in the elimination of variability in performance of ODT due to the use of different mono-functional excipients and quantities and allows for more predictable ODT performance and simplified formulation design ^[67].

A technical limitation associated with FCC is the limited drug loading capacity. During the loading process, it is frequently observed that drug substance depositions occur on the surface of the carrier, leading to modifications in the surface properties. Consequently, FCC loses its multifunctionality, in particular its ability to form hard, rapidly disintegrating tablets ^[64].

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