Supplement Article

Drug Formulations: Standards and Novel The Journal of Clinical Pharmacology

2018, 58(S10) S26–S35
Strategies for Drug Administration in 
C 2018, The American College of

Clinical Pharmacology
DOI: 10.1002/jcph.1138
Pediatrics

Yasmin Thabet, PhD1 , Viviane Klingmann, MD, PhD2 , and Jörg Breitkreutz, PhD1

Abstract
Child-appropriate drug formulations are a prerequisite of successful drug therapy in children. Efficacy and safety must be given for the active
pharmaceutical ingredient, but safety also for the used excipients, components of primary packaging materials, and devices. We are presently
experiencing exciting times for pediatric drug development, stimulated by previous governmental incentives in both the European Union and the United
States. The most important advances in pediatric drug formulation development are reviewed and evaluated in this article. Scientific publications and
recent industry strategies indicate a clear shift from liquid dosage forms to novel solid dosage forms. Solid formulations are usually composed from
excipients generally regarded as safe, whereas many liquid formulations contain excipients such as preservatives, antioxidants, or taste-masking agents
that raise concerns. Further, some recent clinical studies on swallowability, acceptability, and preference indicate superiority for small-sized tablets,
so-called mini-tablets, over conventional liquids. In general, multiparticulate solid dosage forms could partly replace the liquids and provide more stable
and cheaper alternatives to existing drug products or new developments. Dispersible solid drug dosage forms like orodispersible tablets, mini-tablets
and films are even better opportunities for efficient and safe use in pediatrics. Novel measuring and administration devices may facilitate the handling
and drug administration of these modern drug dosage forms. Combination products (drug-device combinations) can easily be linked with new e-health
technologies in near future to further improve pediatric drug therapy.

Keywords
acceptability studies, drug delivery devices, multiparticulates, mini-tablets, orodispersible formulations, pediatric drug formulations

Child-appropriate drug formulations are required for
efficient and safe therapy of diseases in childhood. Chil-
dren have different needs and requirements compared
to adults. Due to the continuously varying character-
istics of the juvenile organism during physiologic and
cognitive maturation, the pediatric subpopulations are
an inhomogeneous collective. Various authorized and
often used medicines do not adequately reflect the needs
of children.
In the United States and the European Union, sev-
eral attempts have been made to improve the situation
and to bridge the gaps in pediatric medicines. Ten
years ago, in January 2007, the European Directive No.
1901/2006 on “medicinal products for paediatric use”
came into force.1 Basic pillars of the regulation were
the introduction of a Pediatric Committee at the Eu-
ropean Medicines Agency (EMA) and of a mandatory
Pediatric Investigation Plan (PIP) to be submitted at
the end of clinical phase I and to be negotiated with
the Pediatric Committee in detail. The PIP comprises
all foreseen requirements, actions, and goals during
preclinical and clinical drug development of medicines
in the pediatric population.2
In 2012, the US Food and Drug Administration
filed the Safety and Innovation Act, renewing and
strengthening the Best Pharmaceuticals for Children
Act, the Pediatric Research Equity Act and the Pedi-
atric Medical Device Safety and Improvement Act.3
The Pediatric Research Equity Act was amended by the
Safety and Innovation Act to introduce the mandatory
submission of a Pediatric Study Plan (PSP), typically at
the end of clinical phase II.
In the quality part of both PIPs and pediatric study
plan, the rational choice of the drug dosage form and
its composition plays a major role. However, there is
only one official regulatory document, the “Guideline
on Pharmaceutical Development of Medicines for Pae-
diatric Use” so far, released by the EMA.4 For the
first time ever, compulsory criteria for child-appropriate
drug formulations are defined by this guideline.
1 Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-
University, Düsseldorf, Germany
2 Department of General Paediatrics, Neonatology and Paediatric Cardi-
ology, University Children’s Hospital Düsseldorf, Düsseldorf, Germany
Submitted for publication 27 November 2017; accepted 19 March 2018.
Corresponding Author:
Prof. Jörg Breitkreutz, PhD, Universitätsstrasse 1, Duesseldorf, Germany
E-mail: joerg.breitkreutz@hhu.de
Thabet et al
In general, child-appropriate drug formulations have
the following key attributes5 :
– Sufficient and predictable bioavailability and effi-
cacy of the active pharmaceutical ingredient
– Toxicologic safety of all components (including
the excipients)
– Correct and precise drug dosing (acceptable dose
uniformity)
– Acceptable properties (palatability, handling, etc)
– Sociocultural acceptability (missing stigmatiza-
tion)
– Precise information on safe handling and admin-
istration of the medicine
- “Child-proven” packaging
The impact of the key attributes may vary depending
on the different maturation levels, life conditions, dis-
eases, and individual preferences of children. In most
cases, the child’s age will be considered for categoriza-
tion and dose selection. The International Council for
Harmonisation of Technical Requirements for Phar-
maceuticals for Human Use defines in its guideline
on “Clinical Investigation of Medicinal Products in
the Paediatric Population”6 infants and toddlers (1-
23 months), children (2–11 years), and adolescents (12-
16 or 18 years). In the recent draft revision, the EMA
states, however, “Chronologic age alone may not serve
as an adequate categorical determinant to define devel-
opmental subgroups in pediatric studies. Physiological
development and maturity of organs, pathophysiology
of disease or condition, and the pharmacology of the
investigational product are factors to be considered in
determining the subgroups in pediatric studies.”7 In
the EMA’s “Reflection Paper: Formulations of Choice
for the Paediatric Population”8 the age category “chil-
dren” (2-11 years) was further split into preschool (2-
5 years) and school (6-11 years) children to introduce
an age-related threshold for the swallowability of oral
solid dosage forms. Recent clinical trials on the swal-
lowability, acceptability, and preferences of children
when receiving oral medicines question the evidence of
this threshold (see section 5 of the Reflection Paper)
formerly introduced by an expert group at the EMA.
It is common understanding and also reflected in the
EMA’s guideline4 that the suitability of solid dose
carriers should be justified in relation to a child’s age
and maturation, health conditions, disease develop-
ment and all risks associated with chewing on them,
choking, aspiration, and over- or underdosing. Some
attributes of a new pediatric drug formulation are the
same as for a product for the adult population, but
many are significantly different (see Table 1). New
solid dosage forms with improved key attributes such
as mini-tablets (defined as tablets with both diameter
S27
Table 1. Major Challenges to Be Considered in Pediatric Formulation
Development and Approaches to Overcome the Challenges
Challenges Approaches to Overcome the Challenges
Dose Technology platforms enabling flexible dosing:
heterogeneity/ – Liquid formulations
precise dosing – Multiparticulate formulations
– Use of medical devices for partitioning or
accumulation of doses
Low doses required Industry:
– Carefully chosen and validated blending
process
– Control of drug adhesion to surfaces
– Granulation before tabletting
– Drug printing (in future)
Pharmacy:
– Extemporaneous liquid formulations
– Use of stock solutions/blends
– Magistral preparations preferred
– Compounded capsules, powders,
suppositories
Limited Solid technology platforms facilitating swallowing:
swallowability – Orodispersible dosage forms
– Multiparticulate fomulations
– Mixing with food (has to be validated)
Lacking adherence Taste-masking technologies:
because of a bad – Functional coatings for barrier formation
taste – Complexing API, eg, by ion exchanger
– Increasing viscosity
– Early involvement of taste assessment in
development
– Animal models
– Electronic tongues
– Adult taste panel (if appropriate)
Lack of Designing the dosage form as child-friendly as
understanding of possible
medicine related – Self-explaining administration, eg, X StrawR
topics – Printed motives on drug dosage forms
Toxicity of Careful risk assessment for each component
ingredients in – Toxicologic databases (STEP database)
subpopulations, – Avoid excipients with unclear safety in target
eg, neonates population, eg, preservatives
and height smaller than 3 mm), dispersible or orodis-
persible tablets, and orodispersible films broadened the
opportunities for pediatric drug development by far
and shifted the previous limits significantly.9–11 These
modern drug formulations are often considered as
the dosage forms of choice.11 Some authors claim a
required shift of paradigm from the previously favored
liquid formulations to the novel flexible solid dosage
forms.12 However, solid dosage forms might not serve
for drug administration to neonates, which are a special
subpopulation in this context.13 Specific drug formula-
tions for parenteral drug delivery of child-appropriate
volumes and concentrations in the hospital setting,
for example, with morphine or aminoglycosides, may
be advantageous. In the next sections, we reflect the
physiologic and pharmacokinetic basics, the choice of
excipients, the impact of taste and texture sensation,
S28 The Journal of Clinical Pharmacology / Vol 58 No S10 2018

the acceptability of medicines, the handling procedure

and ease of drug administration on child-appropriate
drug formulations, and finally, some thoughts on
future perspectives of pediatric drug development. As
the preferred and predominant route of administration
is the oral route, the next sections will focus on the oral
route of administration.

Administration Pathways
In general, the same routes of administration can be
used in children as are common practice in adults.
However, the developmental, physiologic, and phar-
macokinetic differences of children may limit the
opportunities.13 While parenteral drug administration
is common in pediatric wards, in particular in intensive
care units, peroral drug administration is the most
important modality to give medicines to children under
Figure 1. Orodispersible biconvex mini-tablets with a diameter of
domestic conditions. One of the most interesting and 2 mm.
innovative therapeutic areas concerns cardiovascular
drugs for children. Pharmaceutical companies had sub-
mitted 55 PIPs in the area of cardiovascular drugs by
the end of January 2017.14 Of these PIPs, 81.8% are
dosage forms intended for oral use, whereas only 18.2%
use the parenteral route of administration.14 Further
routes of administration for the pediatric population
are rectal, cutaneous, nasal, conjunctival application,
and inhalation. Because of the high variation of the
skin permeation in pediatrics, almost no transdermal
application route is used, in contrast to the adult
population. Only occasionally, a systemic application
of active pharmaceutical ingredients (APIs) is adminis-
tered by inhalation or the transdermal or vaginal route.

Dosage Forms
The impact of administration routes and drug dosage
forms has significantly changed in the pediatric popu-
lation in the past years.
In the reflection paper “Formulations of Choice
for the Paediatric Population,”8 the EMA described
the state of pediatric dosage forms in 2005 and
evaluated various application routes and dosage forms
concerning their applicability for children. The EMA
underlined that more dosage forms are necessary to
cover the needs of all age groups. Based on expert
opinions, without clinical evidence, recommendations
were given regarding which dosage forms are preferable
for different age classes and whether acceptance could
be expected for the dosage forms. This has been
criticized before.15 According to the experts, solid
dosage forms are acceptable only from preschool age
on. New, important achievements in the past years
were the development of solid dosage forms that
enable flexible, precise, and low dosing for the pediatric
population. Mini-tablets (Figure 1) and orodispersible
Figure 2. Orodispersible films (6 cm2 size).
films (Figure 2) containing age-appropriate dose
strength enable easy application.16–18
Mini-tablets typically have a diameter of 2 or 3 mm
and include conventional mini-tablets (coated or un-
coated) and orodispersible mini-tablets. Orodispersible
mini-tablets provide the advantage of a very rapid
integration directly in the mouth, which is a huge
advantage for patients with swallowing difficulties.16,17
Examples of commercially available mini-tablets are
Orfiril long (containing valproic acid; Bayer Vital
GmbH Geschäftsbereich Pharma, Leverkusen, Ger-
many) or Enzym Lefax forte (containing pancreatin;
Bayer Vital GmbH Geschäftsbereich Pharma). An-
other dosage form providing an orodispersible char-
acter is the orodispersible film, which consists of
a thin water-soluble polymer layer that integrates
rapidly inside the mouth. In the past 2 years, several
orodispersible film preparations have gained marketing
Thabet et al
authorization, for example, Setofilm R
(Norgine B.V.,
Amsterdam, Netherlands) containing ondansetron in-
dicated for the treatment of nausea and vomiting
induced by cytotoxic chemotherapy19 or Risperidon R
- for the death of the child. These substances cannot be
Hexal Schmelzfilm (Hexal Pharma GmbH, Vienna,
Austria) indicated for the treatment of schizophrenia
and mania. Orodispersible dosage forms offer an inter-
esting alternative for children to conventional dosage
forms. In 2008, the World Health Organization ap-
proved the benefits of solid dosage forms compared
to liquid formulations and recommended the use of
solid formulations also for infants and toddlers,20
which could be explained by the higher stability of
the dosage forms and the resulting lower distribution
costs and higher global availability. Three years later,
the EMA introduced the first draft of the “Guideline
on Pharmaceutical Development of Medicines for Pae-
diatric Use.”21 In this draft, in contrast to the solid
formulations, liquid dosage forms, especially syrups,
are described as acceptable from the day of birth.
Therefore, no tablets with a diameter of 3 mm should be
administered to children younger than 2 years old and
no tablets with a diameter of 5 mm or higher should
be given to children younger than 6 years old. Because
of several complaints and objections concerning these
age guidelines, the EMA published a new revised draft
in 2013, in which no specific age recommendations
for the acceptability of solid dosage forms were listed.
Instead, it stated that acceptability of the dosage form
should be justified and supported in any case by clinical
evidence.22 In 2014, the final version became effective,4
which describes essential aspects for the formulation
development of child-appropriate dosage forms, for
example, the evaluation of the toxicity of excipients, the
taste-sensing and taste evaluation, and the acceptability
of dosage forms. The shift from liquid to solid formula-
tions could also be confirmed by analyzing the PIPs in
the cardiovascular field: In addition to the conventional
solid dosage forms as capsules and tablets, there are
also enteric coated mini-tablets, orodispersible mini-
tablets, and an orodispersible film.13 The solid formula-
tions (70%) clearly predominate the liquid formulations
(19%).
Pharmaceutical Excipients
The toxicology and compatibility of an API is mostly
evaluated during comprehensive preclinical model in-
vestigations in line with the development of the medici-
nal product and proved with clinical studies in children
of different age groups. For children, not only the
toxicity of the API is of high importance, but also the
clinical safety of the excipients, which has not been
investigated systematically, neither in the past nor prob-
ably in the future.23 Substances that were considered
S29
safe in higher amounts for the adult population, such as
benzyl alcohol and propylene glycol, led to severe side
effects in children, which in some cases were responsible
metabolized by small children because the essential en-
zyme systems are not formed sufficiently at that point.
These substances and resulting degradation products
permeate the blood-brain barrier, which causes acute
neurologic disorders, for example, in the worst case,
seizures resulting in the death of the child. The current
EMA guideline4 offers a decision tree (Figure 3) that
can be used during formulation development. Accord-
ing to the guideline, suitable documents of regulatory
authorities of different sectors (eg, the food industry)
or expert opinions with varying evidence levels can be
consulted for the evaluation of excipients.
Approved documents of the Committee for Medic-
inal Products for Human Use of the EMA with high
relevance are not available except for a new guideline
on the use of phthalates and a consultation paper on
the use of parabens despite the fact that parabens are
known to be potentially harmful.24 Furthermore, the
European Study of Neonatal Exposure to Excipients
has collected data for neonates regarding the safety,
efficacy, and quality of excipients.25
The European Paediatric Formulation Initiative is
continuously working on the STEP (Safety and Toxicity
of Excipients for Paediatrics) database, which provides
toxicologic information on selected pharmaceutical
excipients for pediatric use.26 These methods should
increase the safety for children but also enable the use
of novel excipients and dosage forms for the pediatric
population.
Taste Sensation and Taste Masking
If a medicinal product is refused by the patient because
of its unpleasant taste, a therapeutic effect cannot be
achieved. Human taste is generated by the binding of
chemical compounds to taste receptors on the tongue.
Five basic tastes can be distinguished: sweet, sour,
bitter, umami, and salty. The human taste sensation is
experienced quite subjectively, and children are more
sensitive to bitter substances than adults. Therefore,
the taste of the medicine is of crucial importance,
and clinical trials with products that are sensed as
unpleasant tasting within the pediatric population are
pointless because the compliance of the patient at the
time of dose administration mainly determines
the bioavailability of the API. Medicinal products that
are administered via the oral route should not generate
an unpleasant taste. However, an enjoyable taste may
increase the risk of intoxication in children. In general,
a “neutral” taste is considered the most desirable taste
sensation. Old and new methods for masking the bad
S30
Figure 3. Decision tree considering the evaluation of the safety profile of excipients in paediatric formulations (EMA/CHMP/QWP/805880/2012
Rev. 2).
taste enable the production of medicinal products that
are adapted to children’s taste, which can significantly
differ from adult preferences.27 Solid dosage forms
can be coated with a saliva-resistant film that prevents
disintegration inside the mouth and therefore leads
to suppression of the bad taste. Matrices built out
of fats or waxes can reduce the diffusion of the API,
which leads to lower concentrations inside the saliva,
and the taste-sensing receptors in the taste buds
The Journal of Clinical Pharmacology / Vol 58 No S10 2018
on the tongue cannot detect the API. Complexing
agents like cyclodextrins or ion exchangers can be
utilized in solid or liquid dosage forms. Here, the
toxicology of these excipients plays an important role
for the target patient population (see section 4 of the
EMA’s Reflection Paper). Reliable safety threshold
values for neonates, for example, do not exist and are
almost impossible to determine. Another major issue
is the measuring or quantitation of a taste signal in
Thabet et al S31

early drug development, when API toxicity is still

unknown. Taste trials with juvenile, healthy patients
are prohibited in contrast to adults. However, an
indicative knowledge should be present at the time of
submitting a pediatric study plan or PIP. To overcome
these problems, several attempts have been described
in literature. The use of electronic tongues as a tool
for investigations concerning taste-masking effects
of excipients may give a hints whether the developed
formulation will be accepted by the patients.28 It could
be shown that the electronic tongue measurements
show a good correlation with in vivo taste-sensing
studies.29 Another nonhuman taste assessment model Figure 4. Acceptability (arithmetic mean ± 95% confidence interval) of
is the rat brief access taste aversion model, where coated and uncoated mini-tablet as well as 15% glucose syrup from the
the taste of substances is evaluated according the three performed clinical trials.
number of licks at the investigated substances by the
rats.30 Investigations showed that the brief access taste
aversion model also revealed good correlation with
human taste panels31 and also with the results of
electronic tongue measurements.32 These nonhuman
taste-sensing models are a promising tool for taste
assessment during early drug development.

Acceptability of Drug Dosage Forms

In the relevant guideline,4 the EMA provides a general
definition of acceptability: “The overall ability and
willingness of the patient to use and its care giver
to administer the medicine as intended.” Successful
acceptability is demonstrated by the child’s swallowing
the medication reliably. Furthermore, the EMA lists
factors that influence acceptability and demands clin-
ical trials testing the acceptability of different dosage
forms in children. How to adduce evidence for such
acceptability is shown below using the example of mini-
tablets with a diameter of 2 mm, which were adminis-
tered to children in our children’s university hospital.
We focused our standardized assessment methodology
on measuring acceptability including swallowability as
defined and standardized in our studies33–35 because
they have proven to be reliable parameters to objectively
assess the suitability of oral formulations for children,
resulting in recommendations for the most appropriate
oral pediatric formulations. Based on the results of a
pilot study33 with 60 children in 6 age groups aged
from 6 months to 6 years, a confirmatory crossover
study34 was conducted in 306 children in the same
age groups with placebo coated and uncoated mini-
tablets in comparison to diluted 15% glucose syrup.
The primary end point of this study was to investigate
the acceptability of the uncoated mini-tablet. Sufficient
acceptability was defined as immediate and complete
swallowing of the administered dose (criterion 1) or
swallowing of the main bolus after previous chewing
(criterion 2). A significant superiority of the uncoated
Figure 5. Newborn child with uncoated mini-tablet in the cheek pouch
before swallowing.
mini-tablet over the syrup over all age groups could
be demonstrated. Even the acceptability of the coated
mini-tablet was significantly superior to the syrup over
all age groups (Figure 4). The swallowability of the
uncoated or coated mini-tablets was significantly su-
perior to the syrup over all age groups. No significant
difference between swallowability and acceptability of
the coated and uncoated mini-tablet could be demon-
strated. All 3 dosage forms were well tolerated. No child
choked on the syrup or the uncoated mini-tablet. Only
2 of the 306 children (both in the age group of children
aged 6 to 12 months) coughed after the administration
of the coated mini-tablet, but in both cases without
clinical relevance.
Because of the surprising acceptability of the mini-
tablets in the age group of 6- to 12-month-old children,
the question occurred whether solid dosage forms could
be appropriate even for neonates. Therefore, a third
clinical trial was performed in 151 neonates between 2
and 28 days old,35 also taking into account late preterm
neonates. Each child received in a randomized order
one uncoated mini-tablet (Figure 5) or 15% glucose
syrup. In this study, the primary end point acceptability
S32
was a combination of the criteria “completely swal-
lowed” and “partially swallowed.” This acceptability
was 100% for both the uncoated mini-tablet and the
syrup (Figure 4). Full swallowability as a secondary end
point was higher for the mini-tablet (82.2%) than for the
syrup (72.2%). No neonate choked on the mini-tablets
or the syrup.
Because 1 mini-tablet often does not contain enough
APIs, a forth clinical trial was performed to investigate
the acceptability and swallowability of several hundred
mini-tablets per application compared to syrup. A
total of 374 children aged 6 months to 6 years were
recruited and divided into 2 age groups (age group 1:
6-23 months; age group 2: 2-6 years). Age group 1
received 25 mini-tablets, 100 mini-tablets, and 5 mL
of syrup. Age group 2 received 100 mini-tablets, 400
mini-tablets, and 10 mL of syrup. Superiority was
demonstrated in age group 1 for acceptability and
swallowability (both 25 and 100 mini-tablets) com-
pared to syrup. In age group 2, noninferiority of
acceptability was found only for 400 mini-tablets but
not for 100 mini-tablets. Subgroup analysis revealed a
strong sequential effect: if only comparing mini-tablets
when given as a first dose, superiority was found for
both doses compared to syrup. Noninferiority could
be demonstrated for swallowability of 100 mini-tablets
but not of 400 mini-tablets as compared to syrup. In
the subgroup analysis, noninferiority was demonstrated
when the children received 100 mini-tablets as a first
dose but not when receiving them as a subsequent dose.
The results of this clinical trial are currently awaiting
publication.
Other working groups have also investigated the
suitability of mini-tablets in the past few years.36–39
Thomson et al40 were the first group to publish the
findings of administration of 1 placebo uncoated mini-
tablet (3-mm diameter) to children aged 2 to 6 years.
The authors concluded that it was safe to use 3-mm
mini-tablets in children aged 4 to 6 years because of
their finding that only 46% of the 2-year-old children
were able to swallow the mini-tablets, whereas up to
86% of the oldest children were capable of swallowing.
However, the authors did not use a liquid control and
did not include children younger than 2 years of age.
Van de Vijver et al41 conducted a randomized phase
II study in 16 children, aged 6 to 30 months, suffering
from cystic fibrosis, in which 4 different doses of pan-
crelipase via 1 to 4 enteric coated, 2-mm-diameter mini-
tablets were administered over 5 days. The primary
end point of this study was the clinical efficacy of
pancrelipase. Palatability of the mini-tablets was a
secondary parameter, which was “scored fair to good
by the parents in each of the treatment groups.”41
Van Riet-Nales et al.37 investigated the acceptability
of and the preference among different oral placebo
The Journal of Clinical Pharmacology / Vol 58 No S10 2018
formulations (4-mm tablets, syrup, suspension, and
powder) in 148 infants and preschool children aged 1 to
4 years. The parents were asked to indicate the child’s
acceptability and the preference of the child and of
themselves. Results showed that the tablets were the
best-accepted formulation and that the tablets and the
syrup were most preferred.
Kluk et al38 performed a clinical trial in sixty 2- to
3-year-old children testing the acceptability of several
mini-tablets administered at one time, which showed
that most of the children were able to swallow 5 to ten
2- and 3-mm mini-tablets with soft food.
In the pharmaceutical industry, those systematically
designed and conducted acceptability studies led to
a tremendous change. Various companies switched
from the early development of liquid formulations
such as syrups, drops, or juices to the development of
multiparticulates such as mini-tablets or pellets. This
could be reflected in the current PIPs, for example,
in the area of cardiovascular diseases. Mini-tablets
can be produced on conventional tableting machines,
at least if the APIs and the appropriate excipients
can be easily compressed to a tablet, do not need
risky excipients, and often show a higher stability in
comparison with the liquid formulations. If the mini-
tablet is also orodispersible and disintegrates within the
oral cavity, an ideal child-appropriate dosage form may
be accomplished.16 Orodispersible mini-tablets stay sta-
ble within the primary package, are easy to handle,
and after administration behave nearly like a liquid
formulation but without their risky excipients such as
preservatives, antioxidants, or organic solvents. They
enable a precise dose adjustment and a specific dose
titration of the API. Since 2015, the first orodispersible
mini-tablets containing 0.25 mg and 1.0 mg of enalapril
maleate have been utilized within a multicenter clinical
trial for the treatment of congenital heart failure in
children of all age groups, from birth to adolescence.39
Handling and Administration
Child-appropriate dosage forms often also must be
parent-friendly for administration at home because par-
ents prepare the medicinal product for administration
and give it to their children. Commercial dry syrups
often are difficult to prepare and afterward to apply
the correct dose—for parents as well as for experts.42
Clear instructions in the information texts such as the
package insert or professional information are of high
importance.
Application devices ensure the better, easier, or safer
administration of dosage forms. Also, discrete admin-
istration can be beneficial to protect children from
blame and mockery. Medical devices, especially within
the pediatric area, are of high importance because
Thabet et al

R
Figure 6. A, XStraw technology to administer mulitparticulate
dosage forms through a straw.B,Balda liquid dispensing device for precise
dosing.
administration of the drug is often quite challenging.43
Modern medical devices for liquid medicinal prepa-
rations show a distinct trend to oral syringes. Beside
exact dosing and easy application, complete draining
and easy cleaning are some of the advantages over
commercial measuring caps or spoons.32 New, inno-
vative application systems were introduced recently to
ensure precise dosing by administering multiple pel-
lets or mini-tablets.44 Now, various systems that work
mechanically or with electronics are available. Some
systems even enable connection to a smartphone to
increase patient compliance.45 Other innovative ad-
ministration devices for solids were introduced to the
market recently. To combine a precise application of
multiparticulate dosage forms and easy handling with
potential taste masking, a straw has been developed
that enables the application of pellets in various bev-
erages (Figure 6A).46 In addition, a device for high-
precision dosing of liquid formulations was developed
(Figure 6B). These efforts show that much research
focuses on the development of precise application tools
for the pediatric population to improve the compliance
and safety of the treatment.
Future Perspectives for Pediatric Drug
Formulations
Many medicines for children are presently under de-
velopment, which will lead to important innovations
for the future and bridge existing gaps in the supply
of appropriate medicinal products for the pediatric
population. Because of the complex clinical studies
and the elaborate approval process, it will take time,
but the European legislature has already changed a
great deal concerning pediatric medicine. The most
recent 10-year report of the EMA to the European
Commission47 illustrates an increase in clinical studies
conducted in the pediatric population, a tremendous
number of submitted and reviewed PIPs, but only a few
S33
Paediatric Use Marketing Authorisations for off-patent
drug substances. Obviously, the benefits of a 10-year
exclusivity period for the generated clinical data have
been overestimated by the authors of the European
pediatric guideline. Another reason for this disappoint-
ing outcome of the Paediatric Use Marketing Autho-
risation incentive could be reimbursement issues in the
various member states, which reduce the profit margins
of the pharmaceutical sponsors. Extraordinary high
prices are often not accepted by the insurance com-
panies or the hospital pharmacies, which may prefer
to extemporaneously compound the medicines as they
did before the marketing authorization.48 Therefore,
high-quality magistral preparations for hospital and
community pharmacies (where it is still feasible) will
be required today and in the future. The Council of
Europe, in which there are many more member states
than in the European Union, has filed a resolution for
the preparation of medicinal products in pharmacies49
in order to standardize and to improve quality and to
ensure the safety of extemporaneous preparations.50 At
the European Directorate for the Quality of Medicines,
a working group has been established to generate
a pediatric formulary based on predefined specifica-
tions with recipes of high-standard and well-established
preparations. It should not replace existing or upcom-
ing market authorizations of medicinal products, but
bridge the existing gaps in pediatric drug treatment.
Potentially, new dosage forms will show up for ex-
temporaneous compounding like orodispersible films18
and novel manufacturing technologies such as drug
printing could offer more opportunities.51
Conclusions
This article focuses on recent developments in the field
of pediatric oral dosage forms, the most frequent and
convenient mode of administration of medicine to
children. New solid dosage forms have recently reached
clinical practice. Mini-tablets have proven to be a safe,
reliable, and easy dose approach to administer oral
medication to young children. The basis for a broad
use of this new pharmaceutical dosage form for many
different drug classes and treatment options in the near
future was provided. Various successful trials on the
acceptability and swallowability of mini-tablets have
demonstrated that this dosage form might be a
suitable platform for the pharmaceutical industry.
But there are still many more investigations required.
Orodispersible formulations that could be based on
films, tablets, and mini-tablets show evidence for being
acceptable replacements for the classical liquid formu-
lations in the future.
Due to the comprehensive authorization process and
lacking financial incentives, there will still be a need for
S34
off-patent drug substances in the future. Activities to
standardize compendial extemporaneous preparations
are appreciated in order to ensure the efficacy and
safety of compounded medicines. Overall, the various
political incentives in both the European Union and the
United States seem to bring a change in pediatic drug
formulations and will improve the present situation by
far.
Declaration of Conflicting Interest
The authors declare no conflict of interest.
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