The availability of patient-friendly dosage forms in children lags far
behind those of their adult counterparts. Despite the technological
advancements of novel drug-delivery systems in the past century, several
hurdles still must be overcome if the 80 million children in the United States
and around 1.7 billion more in the world are to receive safe and effective
medications. Currently, pediatric formulations are expensive to produce and not
usually a successful business model.
Mansoor A. Khan, RPh, PhD
There are many challenges associated with pediatric formulation
development, and research and development of pediatric dosage forms are needed.
The goal of any such research must be the unimpeded availability of
pediatric-acceptable dosage forms.
There are physiological and pharmacokinetic challenges resulting from
ongoing development in the child, where the spectrum of ages ranges from
neonates to adulthood. A major problem rests in the use of tablets and capsules
that lack dosing flexibility. Tablets and capsules usually are not uniformly
suitable for children aged 4 years and younger, and adult tablet strength may
not be modifiable for use in older children. Furthermore, portions of tablets
may be administered without ways to control for the actual dose, which changes
with body weight or body surface area. Grinding the tablet and sprinkling it
into fluid or a food vehicle usually results in a dosing variability from one
administration to the next.
William Rodriguez, MD
To facilitate pediatric studies that result in pediatric information in
labeling, and to overcome the reluctance of manufacturers to develop pediatric
dosage forms, Congress enacted legislations with the FDA Modernization Act
(FDAMA 1997), Best Pharmaceuticals for Children’s Act (BPCA 2002),
Pediatric Research Equity Act (PREA 2003), and FDA Amendment
Act (FDAAA 2007). This legislation utilized incentives, as well as
requirements, to provide the FDA with a way to accomplish the goal of improving
the labeling of products with potential use in the pediatric population. The
number of pediatric formulations has increased as a result of BPCA and PREA.
However, most products are available in tablets and capsules intended for adult
dosing.
Pediatric dosages
The ideal oral pediatric dosage form is tasteless/taste-masked with
minimal excipients in flexible dosage increments; orally dissolvable or easy to
swallow; and, heat, humidity and light stable with a good consideration of
physicochemical and pharmacokinetic properties. Dosage forms should be designed
for various pediatric age groups. Syrups and oral solutions are more readily
accepted by some of the youngest children, as opposed to chewable tablets that
are more acceptable for older children. However, particularly in developing
countries, the liquid dosage forms, such as syrups and suspensions, are usually
not amenable to long-term storage or transport under the conditions of extreme
temperatures.
As an example, if there is a pandemic influenza emergency, there would
be an easy availability of oseltamivir capsules (Tamiflu, Genentech) for the
adult population. In 2009, the CDC authorized the emergency use of several
million oseltamivir capsules. Although the adult population had access to these
dosage forms, some pediatric populations had to use compounded products. The
safety and efficacy of compounded products is not easily established and is not
usually approved or labeled by FDA. For compounding of oseltamivir, it was
recommended in labeling that the oseltamivir capsules be mixed with sweetened
liquids such as cherry syrup or Ora-Sweet SF (Paddock Laboratories), and
stability testing was performed. Oseltamivir phosphate is classified as a
biopharmaceutic class system (BCS) III drug. These are the drugs with high
solubility in water but poor permeability across the gastrointestinal tract. In
the event of an emergency, one needs to have prepared pediatric suspensions or
establish what the compounding approaches would be to provide a bioavailable
and stable product.
Potential excipient problems
Chemistry and manufacturing problems include excipient selection, drug
solubility, drug stability and taste-masking for bitter drugs. For adult
products, excipients are based on the stated amount in an FDA database called
“Inactive Ingredients Guide” (IIG). If the excipient doesn’t
have a history of prior use, they need to be qualified by a battery of safety
tests as outlined in the FDA guidance on excipient safety. For pediatric
products, no such IIG database exists. In the absence of safety information, it
becomes very difficult to select an excipient for pediatric formulations.
A review of the literature indicates that some excipients have a
questionable safety record. Examples include cyclodextrins (complexing
excipient to solubilize and stabilize poorly soluble or unstable drugs);
polysorbates (surfactant to enhance solubility of poorly soluble drugs);
propylene glycol (cosolvent for solubilizing poorly soluble drugs); parabens
(preservatives used to prevent bacterial or microbial growth); and certain
colors and flavors. The information available on safe dosing of these
excipients in pediatrics is mostly anecdotal, and therefore, robust dose-effect
studies have not been developed by research to ascertain a minimal safe
exposure in pediatrics.
Most new products in development are poorly soluble. It becomes apparent
from the growing list of questionable excipients that there is an urgent need
to understand and address safety concerns. This excipient list is not without
controversy. A formulation scientist might argue that these excipients have
prior use precedence without known problems and their restriction for use in
the absence of newer proven choices is obstructing the opportunities to develop
newer therapies. There are only a few ways by which a poorly soluble drug can
be formulated. Until more definitive information is available on the No
Observed Adverse Effect Level (NOAEL), the approach is not to use these
excipients in pediatric preparations.
Important considerations
It is essential to remember that formulation considerations must include
both the drug dosage form (suspension, chewable, transdermal patch) and its
taste. Taste is a major problem in pediatrics. Children may not like the taste
of masked formulations or may object to the bitter or metallic taste of
non-masked formulations. Additionally, availability of solutions may not be the
answer to the many access issues, which also include issues such as size,
weight, dilutions, devices and methods of delivery.
Several papers in the literature indicate the challenges of
physiological and pharmacokinetic differences between the adult and pediatric
population. Gastric emptying time is variable, gastric pH is variable, and
there are differences in the surface area of the absorptive sites and
gastrointestinal permeability. There are reported changes in the biliary
functions depending upon age, body water and adipose tissue, which may lead to
differences in drug disposition and elimination. Even the transporter
expression differences are well documented. In most cases, especially for
compounded products, a child’s dose is calculated based on the body
weight, whereas a few cases based on body surface area are also in use.
One possible solution to obtain accurate dosing for children might be to
do dose-optimization studies in pediatric patients. Such studies must be
designed to either offer a prospect of direct benefit to the enrolled children
or to present no more than a minor increase over minimal risk, provided that
the studies are done in children with the relevant disorder or condition.
Although the world has dedicated scientists pursuing development of
pediatric products, a lack of serious availability of novel dosage forms and
platforms call for the emergence of more champions. These champions must adopt
a broad-based approach to develop novel platform technologies of the 21st
century. Through the cooperation of toxicologists, pharmaceutical scientists,
pharmacokineticists and clinicians, the field can be advanced. Several new
platforms, such as thin films, minitablets, flash tablets, multiple-scored
tablets for dosing flexibility, lollipops and patches, are well documented in
the literature but are not usually available to pediatric patients as
prescription products. We should have dosage forms that are suitably coated
with safe excipients to mask the bad taste and then suitably flavored to make
it appealing to children. Depending upon the region or the country, these
flavors may need to be different. Once coated, they should be easily formulated
in any of the novel drug-delivery systems or platforms.
More work needed
In conclusion, there is an acute lack of pediatric formulation platform
technology for use for products for pediatric patients. The technical
challenges of excipient formulation selection include toxicology, chemistry and
dosage form/platform development. A multidisciplinary approach and broad-based
platform development need to be pursued as future research to facilitate the
development of pediatric formulations.
Note: FDA and NIH have a new interagency agreement to provide
scientifically feasible information for pediatric formulations platforms (such
as those necessary for oral forms). The program will determine possible
formulations technologies for specific drug categories, depending upon the
physicochemical properties of the drug candidates. It will determine the
scientific feasibility of prototype batches using available technologies. It
will also report and present results in publically available publications and
scientific presentations. The information will be available on the NIH and FDA
websites when completed. It is envisioned that this system will be available to
anyone who wants to utilize the data.
Mansoor A. Khan, RPh, PhD, works in the Division of Product Quality
Research in the Center for Drug Evaluation and Research at the FDA; and William
Rodriguez, MD, works in the Office of Pediatric Therapeutics/Office of the
Commissioner at the FDA. Rodriguez is also a member of the Infectious
Diseases in Children Editorial Board. Disclosures: Drs. Khan and Rodriguez
report no relevant financial disclosures.