STATE-OF-THE-ART REVIEW ARTICLE

Pediatric Drug Formulations: A Review of Challenges

and Progress
AUTHORS: Verica Ivanovska, PharmD, MPH,a,b Carin M.A.
Rademaker, PharmD, PhD,c Liset van Dijk, PhD,d and Aukje abstract
K. Mantel-Teeuwisse, PharmD, PhDa
Children differ from adults in many aspects of pharmacotherapy, in-
aUtrecht Institute for Pharmaceutical Sciences, Utrecht
cluding capabilities for drug administration, medicine-related toxicity,
University, Utrecht, Netherlands; bFaculty of Medical Sciences,
University Goce Delcev, Republic of Macedonia; cDepartment of and taste preferences. It is essential that pediatric medicines are for-
Clinical Pharmacy, University Medical Center Utrecht, Utrecht, mulated to best suit a child’s age, size, physiologic condition, and
Netherlands; and dNIVEL, Netherlands Institute for Health treatment requirements. To ensure adequate treatment of all chil-
Services Research, Utrecht, Netherlands
dren, different routes of administration, dosage forms, and strengths
KEY WORDS
administration, age groups, oral medications, pediatric,
may be required. Many existing formulations are not suitable for
therapeutics children, which often leads to off-label and unlicensed use of adult
ABBREVIATION medicines. New regulations, additional funding opportunities, and in-
WHO—World Health Organization novative collaborative research initiatives have resulted in some re-
Dr Ivanovska conceptualized and designed the study, and cent progress in the development of pediatric formulations. These
drafted the initial manuscript; Drs Rademaker, van Dijk, and advances include a paradigm shift toward oral solid formulations
Mantel-Teeuwisse contributed to the study concept and outline,
and reviewed and revised the manuscript; and all authors
and a focus on novel preparations, including flexible, dispersible, and
approved the final manuscript as submitted. multiparticulate oral solid dosage forms. Such developments have
www.pediatrics.org/cgi/doi/10.1542/peds.2013-3225 enabled greater dose flexibility, easier administration, and better ac-
doi:10.1542/peds.2013-3225 ceptance of drug formulations in children. However, new pediatric for-
Accepted for publication Feb 27, 2014
mulations address only a small part of all therapeutic needs in children;
moreover, they are not always available. Five key issues need to be
Address correspondence to Verica Ivanovska, PharmD, MPH,
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, addressed to stimulate the further development of better medicines
PO Box 80082, 3508 TB, Utrecht, Netherlands. E-mail: for children: (1) the continued prioritization of unmet formulation
[email protected] needs, particularly drug delivery in neonates and treatment gaps in
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). pediatric cancers and childhood diseases in developing countries; (2)
Copyright © 2014 by the American Academy of Pediatrics a better use of existing data to facilitate pediatric formulation de-
FINANCIAL DISCLOSURE: The authors have indicated they have velopment; (3) innovative technologies in adults that can be used to
no financial relationships relevant to this article to disclose. develop new pediatric formulations; (4) clinical feedback and
FUNDING: No external funding. practice-based evidence on the impact of novel formulations; and
POTENTIAL CONFLICT OF INTEREST: Dr van Dijk’s institute (NIVEL) (5) improved access to new pediatric formulations. Pediatrics
has received research funds from Astra Zeneca, Bristol-Myers
2014;134:361–372
Squibb, and Pfizer for studies not related to the present study.
Dr Mantel-Teeuwisse receives no direct funding or donations
from private parties, including the pharmaceutical industry.
Research funding from public/private partnerships (ie, TI
Pharma [www.tipharma.nl]) has been accepted under the
conditions that no company-specific product or company-related
study is conducted. She has received unrestricted research
funding from public sources (ie, the Netherlands Organisation
for Health Research and Development [ZonMW], the EU 7th
Framework Program [FP7], the Dutch Medicines Evaluation
Board [MEB], and the Dutch Ministry of Health). Dr Ivanovska
and Dr Rademaker have indicated they have no potential
conflicts of interest to disclose.

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Drug formulations used in pediatric the absence of suitable medicines for dose variation administered throughout
pharmacotherapy should be adapted to children. We will discuss the progress childhood may be 100-fold.5 More dra-
children’s needs to suit their age, size, achieved so far and determine addi- matically, premature neonates admitted
physiologic condition, and treatment tional steps required to improve the to the hospital can weigh as little as 500
requirements.1,2 Such pediatric medi- development and availability of pedi- g, further highlighting the need for dose
cines are key to achieving safe and atric drug formulations. variability.29,30 Maturation processes in
accurate dose administration, re- children are not linear, and therefore
ducing the risk of medication errors, THE NECESSITY OF PEDIATRIC doses in certain age subsets may be
enhancing medication adherence, and DRUG FORMULATIONS lower, identical to, or higher than in
improving therapeutic outcomes in adults, depending on a drug’s metabolic
Diversity in Children
children.3,4 pathway.32,34,35
It has been well established that chil-
The use of inadequate drug formula- Due to this extensive variability in
dren are not small adults but rather
tions in children may pose problems children, there is an obvious need for
a distinct and heterogeneous patient
not seen in adults, such as difficulty in drug formulations tailored to children
group with regard to pharmacother-
swallowing conventionally sized tab- in all the target age groups. The Inter-
apy.25 They often exhibit a different re-
lets, safety issues with certain excip- national Conference of Harmonisation
sponse to both active substance and
ients that are acceptable in adult divides childhood into 5 age groups
excipients.26 Children present a contin-
formulations, and adherence problems related to the developmental stages,
uum of growth and developmental
with unpalatable medicines.1,5 These derived from the physiologic and phar-
phases as a result of their rapid growth,
issues have led to tragedies in the past, macokinetic differences mentioned ear-
maturation of the body composition,
and they exist partly because only lier.28 These groups (with age ranges)
and physiologic and cognitive changes
a small fraction of all marketed drugs are: preterm newborn infants; term
during childhood.
are available in formulations that are newborn infants (0–27 days); infants
age appropriate.6–12 As a result, many Children differ from adults in many and toddlers (1–23 months); children
adult medicines are used off-label aspects of pharmacokinetics and phar- (2–11 years); and adolescents (12–16
in children, a practice that carries macodynamics, potential routes of ad- years in the United States or 12–18 years
additional health and environmental ministration, medicine-related toxicity, in the European Union).5,36
and taste preferences.3,25 Important
risks.13–15 The European Committee for Medicinal
pharmacokinetic differences between
To strengthen the development of pe- Products for Human Use further sub-
children and adults include the rate
diatric drug formulations, new legis- divides the age group “children” (2–11
of gastric emptying and pH, gastroin-
lation was introduced in the United years) into “preschool children” (2–5
testinal permeability, and the surface
States and Europe, and efforts for years), and “school children” (6–11
area available for drug absorption.
global collaboration were made by the years) to more precisely reflect the
Dissimilarities have also been reported
World Health Organization (WHO).16–20 A children’s ability to accept and use
in drug metabolism, transporter ex-
number of innovative pediatric for- different dosage forms.5 However, the
pression, biliary function, and renal
mulations have followed, but their ac- classification of the pediatric pop-
clearance, resulting in differences in
tual effect on pediatric drug approvals ulation into age categories is to some
drug disposition and elimination.27,28
remains to be seen, as clinical trials extent arbitrary because children of
The largest deviation from adult phar-
and marketing authorization take the same chronologic age may still
macokinetics is observed in the first
a substantial amount of time.21–24 develop at different rates.28
12 to 18 months, when organ functions
To optimize pharmacotherapy in chil- are developing.29,30 In older children
dren, it is important for clinicians to and adolescents, the pharmacokinetic Age-Related Adherence to Pediatric
understand the background of the parameters approach adult values Drug Formulations
aforementioned problems as well as to and are thus easier to predict.26,31–33 Formulation acceptability and prefer-
gain insight into the challenges, devel- The effect of age on pharmacokinetics ences facilitate medication adherence
opments, and potential solutions. The leads to different dosing require- in children, and they are important
aim of the present review was to de- ments for different age groups. From factors in achieving the intended treat-
scribe why there is a specific need for birth to adulthood, the body size and ment outcomes. Formulation acceptabil-
pediatric drug formulations and to il- weight of an average child increases ity differs across age groups as children
lustrate the clinical consequences of up to 20-fold, and the magnitude of gradually develop their cognitive and

362 IVANOVSKA et al
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 STATE-OF-THE-ART REVIEW ARTICLE

motor skills, and improve their ability to of sodium or potassium in parenteral guide list of the US Food and Drug Ad-
swallow medications. At certain ages, the formulations.6–9 ministration nor the “generally regarded
dependence on caregivers also plays To prevent such tragedies and ensure as safe” status has been validated for
a role in the administration of pediatric adequate treatment of children of all pediatric use.3,29,30,50 Little is known
dosage forms.1 Pain, discomfort, and an ages, different routes of administration, about the safety of excipients in children,
unnecessary burden on children and/or dosage forms, and strengths are often and accepted daily and cumulative in-
caregivers during drug administration needed for the same active substance.1 takes of excipients have not been estab-
should be minimized to assure ade- Table 1 illustrates the specific purposes, lished. Anecdotal evidence suggests an
quate medication adherence. In older potential strengths, and weaknesses of association between some excipients
children and adolescents, lifestyle and various routes of administration and commonly used in adult medicines and el-
peer pressure may also influence med- dosage forms for pediatric use.1,2,5,43–47 evated toxicity and safety issues in children,
ication adherence and possible prefer- As in adults, the oral route is the pre- especially neonates (Table 2).3,6–9,26,50–60
ences for particular formulations. dominant route of administration in A recent example is the administration
Taste attributes may be critical to ensure children.1,2,43 Alternative nonoral routes of lopinavir/ritonavir (Kaletra [Abbott
acceptable adherence to pediatric oral of administration include rectal, dermal, Laboratories, Abbott Park, IL]) oral so-
formulations. Because children have nasal, pulmonary, and ocular routes.1,2 lution in premature newborns who
a low tolerance for disagreeable taste, were exposed to the risk of ethanol
The selection for clinical use is influ-
the use of tasteless or palatable medi- and/or propylene glycol toxicity. This
enced by the limitations of each dosage
cines can minimize the loss of medica- situation resulted in a Food and Drug
form. Oral solids are associated with
tion from spillage and/or spitting.14,37,38 Administration drug safety communi-
the risk of choking or chewing and with
Taste preferences may differ between cation and a change in the drug label in
limited dose flexibility, whereas palat-
children and adults, as children prefer 2011.61 A number of recent studies in
ability and dose uniformity may be
sweet and salty flavors, and dislike bit- challengingforliquidpreparations.1,2,43,44
NICUs revealed systemic concentra-
ter and peppermint taste. These find- In addition, liquid forms raise issues
tions of excipients that were intol-
ings suggest that taste assessment erable even in older age groups.54,62,63
regarding stability (chemical, physical,
should involve children early in the drug or microbiological) and the require- The urgent need to understand these
formulation development.35,38,39 Chil- ment for clean water; moreover, they safety concerns has led to a collabora-
dren’s communication about taste per- can be bulky, impractical, and expen- tive effort by the United States and the
ceptions can be facilitated by using sive to ship and store, particularly in European Union to create a STEP (Safety
age-appropriate methods, scales, and lower income countries with hot and and Toxicity of Excipients for Pediatrics)
measures.40 Alternative taste-screening humid climates.48,49 database. Its aim is to improve sys-
methods may include adult taste panels tematic data collection on excipient
The use of nonoral routes of drug ad-
with validated design for data trans- toxicity and tolerance in children.64–66
ministration may be hampered by dif-
ferability or predictive electrochemical A similar initiative, ESNEE (European
ficult application, local irritation, fluid
sensor systems (so called “electronic Study of Neonatal Exposure to Excipients),
overload, electrolyte imbalance, or poor
tongues”).41,42 has developed a platform for the sys-
drug acceptability (Table 1).1,2,5,43–47 In
tematic assessment of excipients in neo-
neonates, intravenous administration
CLINICAL CONSEQUENCES OF THE nates.67
may lead to volume overload. Moreover,
ABSENCE OF SUITABLE PEDIATRIC measuring small dose volumes may Concerns Over Off-label and
DRUG FORMULATIONS cause large dosage variations and Unlicensed Use of Medicines in
Potential Limitations of Pediatric errors.47 Similarly, age-appropriate dos- Children
Drug Formulations ing volumes are important to ensure full Pediatric drug development is associ-
Historically, the failure to appreciate the dose ingestion for oral liquids.5 ated with numerous challenges, including
developmental changes in children has Another important concern in pediat- methodologic and ethical requirements
led to many adverse outcomes in clinical ric drug formulations are the excipi- for pediatric trials, high developmental
practice. Examples include infant deaths ents, frequently used as preservatives, costs, and a small and fragmented
from choking on albendazole tablets, the sweeteners, fillers, solvents, and coating market.3,4,50,68–71 As a result of these
lethal use of benzyl alcohol or diethylene and coloring agents. Their selection for challenges, there have only been limited
glycol in sulfanilamide elixirs, and elec- pediatric medicines is challenging be- research efforts to adapt medicines
trolyteimbalancescausedbyhighcontents cause neither the inactive ingredients according to pediatric needs. Thus, only

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TABLE 1 Potential Clinical Advantages and Disadvantages of Different Formulations and Routes of Administration in Children1,2,5,43–47
Administration and Dosage Forms Potential Advantages Potential Disadvantages
1,2,5,43
Oral Main route for (long-term) treatments in children First-pass effect
Liquid preparations Acceptability from term birth Instability of multidose preparations
• Suspensions Maximum dose flexibility Age-appropriate dosing volume for full-dose ingestion
(,5 mL in younger and ,10 mL in older age groups)
• Solutions, syrup, drops Stability, portability, good dosage uniformity
• Powders and granules Options for different doses and modified release Dose-measuring device critical
for reconstitution
Solid dosage forms Better acceptability (with liquid/semi-solid food) Shaking for dose accuracy (suspensions)
• Tablets Dose flexibility Incorrect dosing for oral drops (criticality of dose)
• Capsules Ease of administration Risks of administration without prior dispersion/dissolution
• Powders, granules, sprinkles, Can be used in neonates and seriously ill infants Ability to swallow intact dosage forms
multiparticulates, mini-tablets
• Orodispersible/chewable preparations Risks of choking and chewing
Administration through nasogastric tubes Limited dose flexibility
Dose-measuring device needed
Compatibility with food/drinks
Limited control over dose intake
Taste-masking requirements
Less stable than standard tablets
Risk of direct swallowing
Intellectual properties costs
Ease of administration and dosing accuracy
(volume, density, viscosity, particle size)
Potential compatibility with feeding tube material
Doses and rinse volume relevant to target age group
Relevant size of feeding tubes
Parenteral1,2,5,43–47 Main route for neonates and emergency cases Infections, phlebitis, embolism
• Intravenous injections Quick/high/constant blood and Fluid overload, electrolyte imbalance
tissue drug concentration
• Subcutaneous injections Sustained-release preparations Inappropriate diluents
• Intramuscular injections Measurement of dose volumes
• Pump systems Lag-volume effects in intravenous line
Small veins, punctuation pain, needle phobia
Incompatibilities with coadministered intravenous medicines
Drug migration into plastic tubes (plasticizer desorption of
phthalates from circuits)
Rectal1,2,5,43 Can be used in severely ill children Size considerations
or those unable to swallow
• Suppositories Limited bioavailability (minor absorption area,
lack of active drug transporters, small fluid volume for
dissolution)
• Rectal liquids
Frequent stooling in breast-fed infants, uncontrolled
defecation in infants
Lower compliance and concordance
Cultural and regional acceptance barriers
Topical, transdermal1,2,5 Provision of constant blood levels Unintended systemic absorption/toxicity risk in neonates
(large skin surface area, thickness, hydration, perfusion)
• Transdermal patches Painless and easy administration of bolus
• Medicated plasters Sustained drug delivery Natural barrier for penetration of many drugs
• Ointments/creams/gels/liquids Safety of excipients
Local skin irritation
Deliberate removal of patches/plasters
Nasal1,2,5 Good nasal transmucosal bioavailability Unwanted systemic effect
• Solutions, drops Needle-free access to systemic circulation Irritation of the mucosa
• Semisolid dosage forms Ineffective in abundant secretion
Pulmonary1,2,5 Avoidance of hepatic first-pass metabolism Increased deposition in upper/central airways
(small airway diameter)
• Metered dose inhaler with Painless application Decreased total lung deposition (reduced motor
spacer/facemask abilities/low inspiration volume)
• Nebulizers (older children) Device use critical to improve inhaled doses
• Dry powder inhalers (older children)

364 IVANOVSKA et al
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 STATE-OF-THE-ART REVIEW ARTICLE

TABLE 2 Examples of Excipients With wide, this proportion is up to three- cause practices and guidelines for
Elevated Toxicity and Safety Risks
for (Preterm and Term) Newborns
quarters.77 extemporaneous formulations differ
and Infants ,6 Months of Age7,8,53–60 Risk Management of Compounding greatly among practitioners, there is an
Excipient Adverse Reaction and Manipulation of Medicines for urgent need for a standardization of
Benzyl Neurotoxicity, metabolic Children commonly applied compounding prac-
alcohol7,8,53,54 acidosis tices.78,86 Existing networks, resources,
Ethanol55 Neurotoxicity, cardiovascular Alternative treatment options are often
and guidelines should be stimulated to
problems used to make unavailable drugs ac-
Propylene Neurotoxicity, seizures,
provide appropriate information on the
cessible for children and/or to adjust
glycol54,56–59 hyperosmolarity standards of practice for extempora-
drug doses according to individual
Polysorbate Liver and kidney failure neous formulations.78,84 However, the
20 and 8060 patient needs. These options include the
available information may not always be
modification of administration routes
easily transferable to a local situation or
(eg, oral use of parenteral formulations);
may not be exclusively focused on chil-
one-third of all medicines approved by manipulation of adult dosage forms
dren.87
the European Medicines Agency over (eg, diluting liquid formulations); seg-
the period of 1995 to 2005 were licensed menting tablets and suppositories,
cutting patches, and dispersing open PROGRESS IN DEVELOPING
for use in children.11,23,72 Higher but still PEDIATRIC DRUG FORMULATIONS
unsatisfactory rates were reported in capsules or crushed tablets in water,
New Zealand (35%), Australia (38%), liquid, or food; or extemporaneous New Frameworks for the
and the United States (54%).23,73,74 The dispensing (ie, compounding medi- Development of Pediatric Drug
pediatric market has focused mostly cines from ingredients within phar- Formulations
on only a limited number of thera- macies).5,78 To overcome the aforementioned chal-
peutic areas, such as antiinfectives, Administering medicines in this way lenges, a new pediatric regulatory en-
hormones, and medicines for the re- is difficult and unsafe because limited vironment has been created to stimulate
spiratory and central nervous system.75 data are available to validate stability, the development and availability of age-
Meanwhile, there are hardly any dermal bioavailability, pharmacokinetics, phar- appropriate medicines for children.16–19
preparations and medicines specifically macodynamics, dosing accuracy, tol- The intended long-term aim is to in-
aimed at younger age groups for the erability, and reproducibility.79–84 A tegrate pediatric needs into overall
cardiovascular system, sensory organs, documented example is the crushing drug development, so that each new
and cancers.23 Moreover, especially in of Kaletra tablets for pediatric admin- component is systematically evaluated
younger children and neonates, even istration, which resulted in reduced for its potential use in children. Initial
authorized pediatric medicines may not bioavailability and drug exposure in progress has been made by combining
always be age appropriate with respect children.85 All these manipulations may legal requirements with incentives for
to dosing, suitability of dosage forms, compromise drug efficacy and/or companies to test, authorize, and for-
and excipients. safety, as well as create risks for the mulate medicines for use in children.
This lack of pediatric formulations often environment and individuals handling Over the past decade, the Best Phar-
leaves health care professionals no the dosage forms, particularly in the maceuticals for Children Act and the
alternative but to use adult medicines in case of mutagen and cytotoxic com- Pediatric Research Equity Act in the
an off-label or unlicensed manner. The pounds.79–84 United States, and the Pediatric Regu-
trend is widespread: in the European Producing a medicine by extempora- lation in the European Union, have
Union, 45% to 60% of all medicines are neous dispensing may be the only option fueled an increasing number of pediat-
given to children off-label. This trend is for some children to receive a certain ric clinical trials and innovations in pe-
also true for 90% of medicines adminis- medicine in a suitable dosage form. In diatric drug formulations.22,24
tered to neonates and infants, particu- such situations, the risks can be reduced Nonetheless, therapeutic areas ad-
larly in PICUs.76 Not surprisingly, off-label by applying sound quality assurance dressed by the industry seem to be
use is common for antiarrhythmics, systems. Pharmacists should ensure more aligned with adult drug de-
antihypertensives, proton pump inhibitors, that good manufacturing principles are velopment than with unmet public
H2-receptor antagonists, antiasthmatic implemented, adequate raw materials health needs in children.22,68,88,89 To
agents, and some antidepressants.76 In and formulae are used, and stability guide the efforts toward significant
the United States, two-thirds of medicines studies are validated and conducted therapeutic benefits for children, the
used in pediatrics are off-label; world- by certified laboratories. Moreover, be- US and European Union government

PEDIATRICS Volume 134, Number 2, August 2014 365

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agencies have produced priority med- analysis on a case-by-case basis.1,2 35 kg) with a cure rate comparable to
icines lists, highlighting areas with Taking into consideration the het- that of the Coartem tablet.103,104
substantial off-label use in children erogeneity of children and specific For oral medicines requiring precise
and gaps in pediatric data.90,91 characteristics of each dosage form dose measurement, a new flexible
Simultaneously, a WHO initiative (“Make (Table 1), the industry has recently platform technology was proposed to
Medicines Child Size”) has drawn at- proposed a composite assessment tool produce solid multiparticulate dosage
tention to the fact that the lack of med- to guide optimal formulation choices forms (eg, mini-tablets, pellets) and
icines most acutely affects children for individual patients.44 This struc- dosage forms dispersible in liquids or
living in developing countries.20,92 A fo- tured framework is based on 3 pre- sprinkled on food.92 This platform
cus on the development of suitable determined criteria for each drug technology has the potential flexibility
dosage forms to treat diseases of high formulation: product efficacy and ease to construct fixed-dose combination
burden in childhood in low-resource of use (eg, dose flexibility, drug ac- products, especially for chronic dis-
settings could greatly reduce child- ceptability, convenient handling, correct eases such as HIV or tuberculosis.105–107
hood morbidity and mortality.92 There use), patient safety (eg, bioavailability of Table 3 illustrates some of the quality-
have been comprehensive WHO activi- active substances, safety of excipients, certified, innovative oral pediatric dos-
ties to improve access to and use of safe medication stability, risk of medication age forms brought to market, including
and appropriate pediatric medicines. errors) and patient access (eg, prod- much needed heat-stable formulations
These activities include establishing uct manufacturability, affordability, de- and fixed-dose combination products
a model list of essential medicines for velopment, production speed).41 The for low-resource settings.97,104,108–116
children and a list of priority life-saving choice between alternatives is based on
Current surveys reveal that novel oral
medicines for women and children, de- a quantitative scoring system for each
solids may be used in children at an
veloping model formularies for chil- pharmaceutical formulation option.44
earlier age than previously antici-
dren, updating childhood treatment This individualized approach to optimal
pated.5,117,118 Initially, in 2009, Thomson
recommendations, and including pedi- formulations can also be replicated in
clinical settings if the selection criteria et al119 demonstrated that 46% of 2-
atric medicines in the prequalification year-old children and 86% of 5-year-old
process.93–97 include relevant aspects of patient care.
children could swallow innovative 3-
Furthermore, the present reward sys- Novel Oral Pediatric Formulations mm mini-tablets without choking or
tem has not proved to be an adequate Recent progress in pediatric drug de- aspiration. The age limit was further
incentive for investment in off-patent velopment mostly concerns oral for- decreased in an exploratory study
drug research.69,89 This tendency may mulations.22,101 Until recently, liquid which demonstrated that children
be linked to prescription reimburse- formulations were preferred for youn- aged 6 to 12 months were capable of
ment rules that attach little value to ger children because of their easy and swallowing uncoated, drug-free, 2-mm
old medicines, even if they include simple dosing across age subgroups.5, mini-tablets and accepted them better
new child-friendly formulations.69 To 10,102 In 2008, a WHO expert forum pro- than sweet liquid formulations.120,121
generate more interest in off-patent posed a paradigm shift toward pedi- For infants aged ,2 years, a new
medicines, new public funding oppor- atric oral solids in view of stability promising development is the orally
tunities in academia and small- and problems and the high transportation disintegrating mini-tablet, which com-
medium-sized enterprises have been and storage costs involved in liquid bines mini-tablets and fast-dissolving
provided by both the US Eunice Kennedy formulations.92 From then on, flexible dosage forms.111
Shriver National Institute of Child Health oral solid dosage forms, such as oro- A complementary research area is the
and Human Development Pediatrics For- dispersible tablets and/or tablets used development of pediatric dosing de-
mulation Initiative and the EU’s Seventh to prepare oral liquid preparations vices, which facilitate the accurate and
Framework Program for Research.98–100 suitable for younger children, have consistent administration of oral pe-
However, new technologies developed become the recommended pediatric diatric formulations.1,122 New devices
from these initiatives must be adopted by dosage forms worldwide. In 2009, generally assist the oral delivery of
the industry and marketed so they can Coartem Dispersible (Novartis Inter- liquids to small children by using mod-
realize their full potential. national AG, Basel, Switzerland, and ified feeding bottles and pacifiers with
There is also increased recognition that Medicines for Malaria) was launched medicines placed in a reservoir, help
the selection of appropriate pediatric to offer flexible artemisinin-based improve the palatability of oral solutions
formulations requires a risk/benefit combination therapy for children (5– by using a dose-sipping technology, or

366 IVANOVSKA et al
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 STATE-OF-THE-ART REVIEW ARTICLE

TABLE 3 Examples of Recently Marketed/Prequalified Novel Oral Drug Formulations for Children97,104,108–116
Dosage Form International Nonproprietary Name Regulatory Agency Authorization/WHO PQ Year
97,108–110
Multi-particulates
Sprinkles, granules and pellets Para-aminosalicylate granules WHO PQ 2009
TFV granules FDA 2012, EMA 2012
Rabeprazole sprinkles FDA 2013
Flexible dispersible formulations97,104,111–114
Dispersible and orodispersible tablets Artemether/lumefantrine dispersible tablets Swissmedic 2008 /
WHO PQ 2009
3TC/NVP/d4T WHO PQ 2008
Isoniazid/pyrazinamide/rifampicin WHO PQ 2009
Isoniazid/rifampicin WHO PQ 2009
3TC/NVP/AZT (Mylan Laboratories) WHO PQ 2009
ABC WHO PQ 2010
3TC/d4T WHO PQ 2011
3TC/AZT WHO PQ 2011
EFV WHO PQ 2012
3TC WHO PQ 2012
Artemether/lumefantrine WHO PQ 2012
Isoniazid/pyrazinamide/rifampicin WHO PQ 2012
Isoniazid/rifampicin WHO PQ 2012
Benznidazole WHO PQ 2012
Lamotrigine orodispersible tablets FDA 2012
AZT WHO PQ 2013
Orodispersible films (wafer) Ondasetron FDA 2010
Chewable dispersible tablets Lamotrigine FDA 2012
Orally disintegrating mini-tablets Hydrochlorothiazide Model drug under investigation
Other novel oral formulations115,116
Chewable tablets Atorvastatin EMA 2011
Raltegravir FDA 2012
3TC, lamivudine; ABC, abacavir; AZT, zidovudine; d4T, stavudine; EFV, efavirenz; FDA, US Food and Drug Administration; ODT, orodispersible tablet; PQ, prequalification; NVP, nevirapine; TFV,
tenofovir.

help increase product stability by using Nevertheless, a significant number of better acceptance in children. Despite
a pulp-spoon with a single dry dose of drug formulations are unsuitable for these advances, the new pediatric for-
medicine (see Table 4 for more detailed children, which leads to unsafe off-label mulations are still only a small part of
examples).3,116,122 and unlicensed use of adult medicines. the full therapeutic arsenal needed to
Recent initiatives promoting pediatric serve all pediatric patients.
FUTURE STEPS drug development have made some The following 5 priorities have been
The ideal pediatric formulation should initial progress in the neglected area of identified as critical for the further
have flexible dosage increments and pediatric formulations. Most efforts development of appropriate pediatric
minimal excipients, be palatable, safe have focused on age-appropriate oral formulations. The first key issue is the
and easy to administer, and be stable solid preparations, which enable dose continuous prioritization process that
with regard to light, humidity, and heat. flexibility, easier administration, and focuses on unmet public health issues

TABLE 4 Examples of Novel Drug Devices That Facilitate Oral Administration of Medicines in Children3,116,122
Novel Drug Devices Examples of Medicines Administered With Drug Purpose of Use
Devices (Brand Name, Manufacturer)
Modified teat/pacifier with drug-loaded reservoir Nystatin (Mykundex, Bioglan Giessen, Germany) Constant delivery of medicine (in oral cavity) in
neonates/infants
Dosing spoon filled with liquid medicine Diphenhydramine (Benadryl, Pfizer Consumer Exact measurement of single doses, low risk of spillage
Healthcare, Madison, New Jersey)
Coated particles on dosage spoon (pulp-spoon) Azythromycin powder for oral pulp (predosed Exact measurement of single doses, low risk of spillage
azithromycin spoon; Sandoz Kundl, Austria) improves stability of medicines
Dropper tube Codeine drops (Paracodin, Abbott Laboratories, Ensures dose uniformity
Abbott Park, IL)
Dose-sipping technology (straw with Clarithromycin micropellets (Clarosip, Grünenthal Improves palatability and adherence
medicine and beverage) GmbH, Aachen, Germany)
Solid dosing pen Carvedilol/metoprolol tartrate (model drugs) Exact measurement of doses

PEDIATRICS Volume 134, Number 2, August 2014 367

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and ensures that drug development livery systems, new chemical entities bility might be improved by an in-
aligns with the true clinical needs in (eg, dendrimers), and remote trigger- creased market size (eg, global scale,
children. Special attention should be ing devices. These treatments may inclusion of geriatric patients and
paid to innovations that improve drug have significant applications in chil- adults with swallowing difficulties);
delivery in neonates, fill treatment gaps dren, and the identification of appro- new incentive schemes (particularly
in pediatric cancers, and treat diseases priate animal models for pediatric for off-patent drugs), such as limited
of high burden in developing coun- preclinical studies should be a re- exclusivity and premiums, funding, and
tries.49,90,91,94,123 search priority.128–130 tax breaks; and public–private part-
Second, better use of existing data are Fourth, ongoing technologic advances nerships that support the development
required to facilitate pediatric drug need to be accompanied by relevant of orphan drugs and other less profit-
development. Some innovative scenar- patient outcome studies and clinical able niches.69,98–100
ios under investigation include pre- feedback on efficacy, safety, patient In sum, to reach these goals, it is es-
liminary “enabling” formulations that acceptability, preferences, and adher- sential that there is a committed
bridge existing adult formulations and ence regarding new formulations; collaboration between stakeholders
potential pediatric market formulations, currently, such studies and feedback that extends across disciplines and
adjustments of adult in vitro gastrointes- are lacking.131 Practice-based evidence geographic regions. Moreover, this
tinal models to study drug bioavailability on the impact of novel formulations, collaboration should have the in-
in children, and refined criteria for the generated by health care professionals novative potential to further shape the
extrapolation of adult efficacy data to the and caregivers, could provide further pediatric drug development agenda
pediatric population.124–126 support for the development of pedi- and thus to close the adult–child
Third, future research on pediatric atric medicines with clear clinical medicine gap.
formulations could potentially benefit advantages.
from existing or innovative technolo- The fifth priority concerns finance. Be- ACKNOWLEDGMENT
gies under development in adults.127 cause innovative technologies are We acknowledge Dr Richard Laing
Novel experimental treatments of adult costly, the ultimate challenge is to (WHO) for his advice on the progress
cancers, infections, and asthma have make these new pediatric formulations analysis and recommendations for
used nanoparticle-targeted therapy, available on the market and in daily improving pediatric drug formula-
novel smart polymer-based drug de- practice.22,89,132 Their commercial via- tions.

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POUTINE: Church Street is a pedestrian street that runs through the heart of
downtown Burlington, Vermont. During the summer and fall, the street is
crowded with food vendors selling all kinds of different foods. However, as re-
quired by city ordinance, street vendors may only sell foods that do not directly
compete with restaurants on or immediately adjacent to Church Street. That is
the reason no food vendors sell pizza or hamburgers. Just recently, though, I
noticed a new vendor on the street selling poutine, a Canadian dish made of
French fries and nuggets of curd cheese smothered in gravy. As reported in The
Wall Street Journal (In Search Of: May 2, 2014), poutine is not classically asso-
ciated with fine dining. In fact, there is a debate as to whether something such as
“great poutine” even exists. Still, the dish seems to exploding in popularity,
moving from humble trucks stops and cafes in rural Quebec to fine dining
establishments in New York and Chicago. The roots of poutine are a bit myste-
rious. Some say the dish was created in the mid-20th century after a cook in
Warwick, Quebec, mixed the ingredients together with vinegar in a waxed paper
bag and after the resultant explosion, labeled the concoction a “maudite poutine”
— a blasted mess. Most aficionados report the “best” poutine includes very fresh
cheese curds, crisp French fries, and homemade brown gravy-preferably one that
would do justice to a fine rib roast. Recently, restaurateurs have begun exper-
imenting with all sorts of additional ingredients, but classic poutine has only
three. Regardless of the quality of the ingredients, however, the dish is certainly
not light. Still, it is a wonderful guilty pleasure that I partake of at least once
a summer. Now I will not have to travel to a particular small town in upstate New
York or Montreal, my traditional spots for poutine, but can savor the dish right
here in my own town.
Noted by WVR, MD

372 IVANOVSKA et al
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 Pediatric Drug Formulations: A Review of Challenges and Progress
Verica Ivanovska, Carin M.A. Rademaker, Liset van Dijk and Aukje K.
Mantel-Teeuwisse
Pediatrics 2014;134;361
DOI: 10.1542/peds.2013-3225 originally published online July 14, 2014;

Updated Information & including high resolution figures, can be found at:
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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: .

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 Pediatric Drug Formulations: A Review of Challenges and Progress
Verica Ivanovska, Carin M.A. Rademaker, Liset van Dijk and Aukje K.
Mantel-Teeuwisse
Pediatrics 2014;134;361
DOI: 10.1542/peds.2013-3225 originally published online July 14, 2014;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/134/2/361

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: .

Downloaded from http://pediatrics.aappublications.org/ by guest on February 5, 2018