Paediatric specific dosage forms: Patient and formulation considerations

Key points

• According to the WHO, around 50% of medication issued for long-term conditions is not taken as advised, and around one tenth of medicines prescribed for children in general practice are off-label or unlicensed.
• Differences in the gastrointestinal tract, liver and kidneys change how children absorb, distribute, metabolise and eliminate both drugs and excipients.
• In studies in young children and neonates, small flexible solid oral dosage forms such as mini-tablets were accepted as well as or better than syrups.
• The WHO considers flexible solid oral dosage forms the most suitable dosage form for children.
• Palatability, dose volume and dosing frequency are key formulation factors for adherence; once- or twice-daily regimens improve compliance.

Overview

This review in the International Journal of Pharmaceutics examines patient and formulation factors that affect the safety, efficacy and acceptability of medicines designed for children. It describes how the paediatric digestive tract and pharmacokinetics differ from those of adults, compares current paediatric dosage forms and discusses adherence. The authors see small flexible solid oral dosage forms as a promising alternative to liquid formulations, but note that the availability of high-quality medicines designed for children remains an ongoing challenge.

The paediatric gastrointestinal tract

The oral route is the most preferred in children. In neonates the oesophagus is about 18 cm long, and it reaches the adult length of 25 cm by about 10 years of age. Gastric pH is neutral at birth, drops to pH 1-3 within 24-48 h, returns to neutral by day 8 and reaches adult values only after 2 years of age. This can decrease the bioavailability of drugs such as phenytoin and phenobarbital. Stomach capacity grows from 10-20 mL in neonates to 200 mL at 2 years and 1500 mL by 16 years. The small intestine measures about 300-350 cm at birth and 500 cm at 10 years, and intestinal permeability at birth is three to four times higher than in adults.

Pharmacokinetic differences

Total body water falls from around 80-90% in neonates and infants to 55-60% in adults, which changes the volume of distribution of hydrophilic substances. The blood-brain barrier is immature in neonates, increasing the risk of toxicity from substances such as ethanol and propylene glycol. In children aged 6 to 12 months, the amount of cytochrome P450 (CYP) metabolising enzymes is around 50% of adult levels. Glomerular filtration rate is lowest at birth and reaches adult levels by 1 year of age. Excipients are not inert, and products intended for adults cannot be assumed safe in children.

Paediatric dosage forms

Standard tablets and capsules have a fixed dose and can be hard to swallow, with a higher risk of choking and aspiration in younger children. The minimum recommended age for chewable tablets is 2 years. For orally disintegrating tablets, the FDA suggests a disintegration time of 30 s and a maximum weight of 500 mg; a mini-tablet has a diameter of 4 mm or less. Liquid formulations allow flexible dosing but have drawbacks in palatability, problematic excipients, storage and refrigeration needs, and short shelf life. The EMA draft guidance suggests a maximum dose volume of 5 mL under 4 years of age and 10 mL from 4 to 12 years.

Acceptability and adherence

In a randomised crossover study in 306 children aged 6 months to 5 years, an uncoated 2 mm mini-tablet was more accepted than syrup. In another study, all 151 neonates were able to swallow the mini-tablet. More than 90% of paediatricians linked non-adherence to bitter, unpalatable drugs. Once- or twice-daily regimens have increased compliance to more than 80% compared with three-times-daily schedules. Up to approximately 70% of children with chronic conditions have poor adherence, and a combination of educational and behavioural techniques has been proposed to improve it.

Frequently asked questions

Are liquid medicines always best for young children?

Not necessarily. Several studies found that small solid dosage forms such as mini-tablets were accepted as well as or better than syrups, even in neonates.

Why can adult products not simply be given in smaller doses?

Differences in gastric pH, intestinal permeability, body water, enzyme activity and kidney function change how drugs and excipients behave, so products intended for adults cannot be assumed safe in children.

How many new paediatric medicines have become available in Europe?

Since the paediatric regulation came into force in 2007, only 221 new paediatric medicines and indications have become available in Europe.

Source

Khan D, Kirby D, Bryson S, Shah M, Mohammed AR. Paediatric specific dosage forms: Patient and formulation considerations. International Journal of Pharmaceutics 2022;616:121501. DOI: 10.1016/j.ijpharm.2022.121501. Open access under a Creative Commons CC BY 4.0 licence. This page is a summary prepared by Medpresso from the original publication and is not a substitute for the full text or for medical advice.