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Jörg Breitkreutz
C H A P T E R
8
Drug Formulations for Children
Prior to prescribing a drug product for a child, the pediatrician has to
consider whether the clinically required drug substance can be administered
completely, conveniently, and safely to the child. A critical review of
available drugs has shown, however, that this is hardly the case for many
authorized medicinal products.1 The route of drug administration, the dosage
form, the composition of the drug formulation, the condition, and childappropriate mode of drug administration have to be carefully evaluated.
Within this process, it has to be realized that the pediatric population is
heterogeneous by nature and undergoes continuing growth and maturation.
There are various reasons why pharmaceutical industry has been reluctant
in developing pediatric drug products. Enormous costs of drug development, a
relatively small market, plenty of specific requirements for children, quite
comprehensive clinical studies on efficacy and safety, related ethical
concerns, and—for many years—unknown regulatory requirements have been
impediments to developing and marketing new pediatric drug products.
Raised awareness of these problems has led to various regulatory incentives
for pediatric drug development in the European Union (EU) and the United
States.2 Whereas for new chemical compounds, it is generally mandatory to
develop and test pediatric drug formulations in clinical practice, it remains a
voluntary task for the off-patent drug substances, which are the majority of
used active pharmaceutical ingredients (APIs) in pediatric clinical practice
today.
As a consequence of the still existing lack of child-appropriate medicines,
the pediatrician might consider alternatives to the authorized medicines for the
pediatric population. This should be carefully performed, reflecting the
different levels of drug quality, scientific knowledge, and experience.
APPROPRIATENESS OF DRUG DOSAGE
FORMS
The pediatric population has been divided by age into five to six categories.
In the International Conference of Harmonization (ICH) E 11 guideline,3 the
age groups of preterm neonates, neonates, infants and toddlers, children, and
adolescents have been defined based on physiologic and pharmacokinetic
differences, for example, metabolic capacity, organ maturation, and drug
clearance.4 These variations affect not only the API but also the entire drug
product. The pharmaceutical excipients, which are required to generate a
child-appropriate drug dosage form out of the pure API, may be absorbed into
the body, distribute into different body tissues, may interfere with the API or
its metabolites, and are eliminated by different pathways.4 Some of these may
be safe for adults, but clearly show some adverse effects or at least safety
signals for the use in children, including organic diluents, preservatives,
antioxidants, and plasticizers.5 Term, and in particular preterm, neonates are
at highest risk for toxic reactions to pharmaceutical excipients, which are
often underestimated.
6
The European Medicines Agency (EMA) has further divided the group of
“children” into two subgroups, “preschool children” between the ages of 2
and 6 years and “school children” from 6 to 12 years old, in order to reflect
the capability of children to swallow or at least to accept solid oral drug
dosage forms, such as tablets or capsules.7 Recent clinical studies on the
acceptability of small-sized tablets, the so-called mini-tablets, in pediatric
patients,8 have raised some doubts, however, on the widely accepted agedependent ratings that have been followed for years by academia and
pharmaceutical industry. By these groundbreaking studies, it was shown that
even neonates may take a mini-tablet orally,9 and older children may take a
couple of mini-tablets as a resulting single dose10 without significant
problems. In all cases, the mini-tablets were at least equally suitable, but
often superior to the liquid control, a sweet syrup. As a consequence, EMA
now encourages pharmaceutical companies within its most recent “Guideline
on pharmaceutical development of medicines for pediatric use” to develop
small-sized solid drug carriers such as mini-tablets or pellets for the use in
children, including the very young children.11 Earlier, the World Health
TABLE 8.1
Organization (WHO) had recommended the development of
“multiparticulates” for the pediatric population.12 Acceptability of these
multiparticulates, including pellets or mini-tablets, has been demonstrated for
both children and adults.13 Besides the superior acceptability, the higher
stability and more precise dosing are advantageous for the multiparticulate
formulations. Some experts have, therefore, claimed a shift of paradigm using
small-sized solid preparations instead of liquid drug formulations.14 Other
alternatives to liquid drug formulations are dispersible drug dosage forms. In
the best case, these solid dosage forms dissolve in the oral cavity immediately
after administration and are, therefore, called “orodispersible formulations.”
15
These new formulation concepts comprise orodispersible tablets,16 oral
lyophilisates,17 and orodispersible films.
18
NEW MEDICINAL PRODUCTS FOR ORAL USE
WITH ADVANCED DOSAGE FORMS
The change of mindset toward solid dosage forms can be observed best in the
most recent drug authorizations in Europe concerning Pediatric Use Marketing
Authorizations (PUMAs) for off-patent drug substances (Table 8.1).
PUMA Products Authorized in the EU
a
The first PUMA product, Buccolam, initially appeared on the market in
2011 as a drug formulation of midazolam hydrochloride preserved by methyl
paraben and propyl paraben. Due to concerns about the safety of propyl