Meeting Challenges of Pediatric Drug Delivery: The Potential of Orally Fast Disintegrating Tablets for Infants and Children
A majority of therapeutics are not available as suitable dosage forms for administration to pediatric patients. The first part of this review provides an overview of clinical and technological challenges and opportunities in the development of child-friendly dosage forms such as taste masking, tablet size, flexibility of dose administration, excipient safety and acceptability. In this context, developmental pharmacology, rapid onset of action in pediatric emergency situations, regulatory and socioeconomic aspects are also reviewed and illustrated with clinical case studies. The second part of this work discusses the example of Orally Dispersible Tablets (ODTs) as a child-friendly drug delivery strategy. Inorganic particulate drug carriers can thereby be used as multifunctional excipients 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.
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.
The first part of the present review focuses on clinical and technological challenges and opportunities associated with the design of child-friendly formulations. This includes factors contributing to patient acceptance, dosage form design, the choice of excipients, the impact of dosage forms on pharmacokinetics and pharmacodynamics, regulatory aspects, economics and sustainability. Practical implications of these factors are highlighted by examples from the clinical practice in the form of box-inserts. Illustrations taken from our clinical experience or from the literature will thus provide a comprehensive overview of the challenges and hurdles that paediatricians face in their daily clinical practice. Table 1 summarizes these factors.
The second part of the review discusses the example of orally dispersible tablets as an innovative and novel strategy to overcome the above mentioned challenges. In particular, we will introduce porous inorganic drug carriers as a novel multi-functional excipient for pediatric use. Alternative formulation strategies are presented in Table 2, but are not discussed in detail as several excellent review articles have already summarized these established and traditional technologies [13,14].
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ODT excipients named in the study: Pearlitol® Flash, Ludiflash®, Parteck® ODT, Pharmaburst® 500, and Prosolv® ODT, Orasolv®, Durasol®
Golhen, K.; Buettcher, M.; Kost, J.; Huwyler, J.; Pfister, M. Meeting Challenges of Pediatric Drug Delivery: The Potential of Orally Fast Disintegrating Tablets for Infants and Children. Pharmaceutics 2023, 15, 1033. https://doi.org/10.3390/pharmaceutics15041033
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