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Advanced Drug Delivery R

Preface

Challenges in pediatric drug delivery: the case of vaccinesB

The identification of potent macromolecules or

effective biotechnology derived therapeutic agents is

increasing at a staggering rate. The primary objective

of the drug development process is to identify drug

candidates with structural and molecular character-

istics that permit optimal interaction between the

macromolecule and its target receptor. However,

rational drug design may not necessarily result in

successful drug delivery. The drug development

process aided by biotechnology and the design of

drugs based on gene-related targets has yielded

numerous potent macromolecules, drugs, genes, and

vaccines that are promising in the treatment of chronic

and/or life-threatening diseases. Unfortunately, many

of these potent macromolecules never reached thera-

peutic concentrations at their intended target sites.

This may be due to adverse physico-chemical or

physiological factors. These therapeutic setbacks are

magnified in the pediatric population that represents

the primary target of treatment interventions that

aimed at correcting congenital diseases (e.g., gene

therapy) or preventing serious infective conditions

(e.g., vaccines). There is clearly a disconnect between

the tremendous progress made by capitalizing on the

genomic and proteomic revolution to engineer new

therapeutic molecules and the limited number of

strategies to effectively deliver these molecules.

Characteristics of drugs and macromolecules that

pose delivery challenges include solubility limitations,

minimal permeability, low oral bioavailability, insta-

0169-409X/$ - see front matter D 2006 Published by Elsevier B.V.

doi:10.1016/j.addr.2006.01.001

B This preface is part of the Advanced Drug Delivery Reviews

theme issue on "Challenges in Pediatric Drug Delivery: the Case of

Vaccines", Vol. 58/1, 2006.

bility in the gastrointestinal (GI) tract or blood stream,

significant first pass metabolism, limited distribution

to the target tissue and subcellular compartments, or

efflux by the multi-drug resistant proteins. Additional

challenges posed by protein-based vaccines is their

limited capability to stimulate an immune response

when mucosally delivered: i) because they are unable

to cross the epithelial barrier and, ii) because of the

suppressive mucosal environment (oral tolerance).

Thus, mucosal adjuvants that augment antigen passage

through the mucosal barrier and that favor stimulation

of an antigen-specific immune response are central to

the successful development of mucosal vaccines.

The goal of drug delivery is to develop approaches

to target drugs to specific cell types at the right time

and for the proper period of time. Achieving this goal

would be of particular importance in the pediatric

population, in which acceptance and compliance to

invasive methods of drug administration (e.g., paren-

teral delivery) are obviously sub-optimal and poorly

accepted. This drawback is particularly important for

vaccines, since the vast majority of the pediatric

population is subjected to several vaccinations (up to

12 injections) by school age. The challenges of drug

delivery in the pediatric population are amplified by

the wide age range (newborn to 21 year old), spanning

different stages of maturity of organs and biological

systems. These disparities translate into different

pharmacokinetic and pharmacodynamic characteris-

tics that are only partially defined. The development

of alternative methods of drug administration, includ-

ing transdermal, sublingual, nasal, rectal, and oral,

could decrease discomfort and increase compliance in

the pediatric population. However, a word of caution

eviews 58 (2006) 1–3

Preface 58 (2006) 1–32

is necessary in light of proliferation of reports

describing boff-labelQ routes of administration, i.e.,

routes currently not approved by the Food and Drug

Administration (FDA). This practice is the conse-

quence of initiatives of health care professionals

aimed at developing better, more reliable, and less

painful methods of drug administration. However,

without appropriate controlled studies in children,

these routes of administration could lead to undesir-

able side effects even for drugs that have been proved

safe when administered parenterally. This issue is

important because children have typically not been

included in clinical research aimed at obtaining FDA

approval of a drug. For approval of new drugs, the

FDA requires the identification of potential uses in

children, and approval may be subjected to the

conduct of pediatric studies. Obviously, these regu-

lations may not solve the problem for previously

approved drugs or new routes of drug administration.

The aforementioned considerations provided the

rationale for this theme issue in Advanced Drug

Delivery Reviews. This issue begins with a review by

Rakhmanina and van den Anker (Children’s National

Medical Center, Washington DC) on the challenges in

pharmacological research in the pediatric population

encompassing diverse groups such as neonates,

toddlers, pre-school children, and adolescents. While

several drug and macromolecule-related factors un-

doubtedly contribute to the inherent resistance to

effective drug delivery, many acknowledge that

the biological barriers (e.g., skin, intestine, airway

mucosa, blood-brain barrier) may play a key role in

preventing effective levels of therapeutic agents into

the systemic circulation or target tissue. One approach

to minimize the impact of these biological barriers is

to exploit the natural anatomical limiting structures,

such as tight junctions, which exist in intestinal

epithelium. In the second chapter, Salama and

colleagues (University of Maryland, Baltimore, Mary-

land) documented the use of a drug delivery technol-

ogy that transiently and reversibly open tight junctions

to facilitate the paracellular transport of various

macromolecules and allowing for enhanced oral

absorption, distribution to the brain or nasal delivery.

The next three chapters are devoted to vaccine

delivery. The special emphasis placed on this topic is

justified by the fact that every single child is subjected

to vaccination (up to 12 vaccines) and that, with few

exceptions, current vaccines are parenterally delivered

and require multiple doses, creating major challenges

that concern mass vaccination, costs, side effects, and

acceptability. O’Hagan and Rappuoli (Chiron Vac-

cines, Emeryville, California) presented an overview

of existing as well as emerging alternative approaches

for vaccine delivery in pediatrics. These approaches

include needle-free devices for DNA and traditional

vaccines, microparticle delivery systems and immu-

nizations with microneedles. In the next chapter, De

Magistris (Istituto Superiore Sanita’, Rome, Italy)

specifically focused on the advantages of mucosal

vaccine antigen delivery technologies particularly

relevant for the pediatric population. The use of

microparticles, liposomes, immune stimulating com-

plexes and chitosans among other strategies for this

purpose are discussed. Finally, Giudice and Campbell

(University of Maryland, Baltimore, Maryland) fo-

cused on the needle-free vaccine delivery technology

as an innovative way to address the challenge of mass

vaccination, particularly concerning the developing

countries. Unique issues about transcutaneous and

mucosal immunizations are discussed in this chapter.

The final section of this theme issue is on practical

aspects of pediatric drug delivery. Osuntokun (Uni-

versity of Cincinnati, Cincinnati, Ohio) outlined the

challenges of drug delivery trials in the academic

settings and stressed the need for coordinated integra-

tion between academia and industry to fulfill the

mandate of the NIH Roadmap initiative to translate the

great potentials of basic and translational science in

tangible applications that would benefit patients. In

the final chapter, Gans-Brangs and Plourde (AstraZe-

neca LP, Wilmington, Delaware) covered the special

needs and challenges of pediatric clinical trials and the

constant changes in the legislation regulating exper-

imentation in the pediatric population.

Taken together, the seven chapters provide a

perspective on the current understanding of the

specific needs and challenges in drug delivery,

particularly vaccine delivery, in pediatrics. Drug

delivery research in the pediatric population is a

long-neglected area in drug development. Drug

delivery systems developed for the adult population

may not necessarily be suitable for the pediatric

population. New drug delivery systems that meet the

specific requirements in pediatrics is necessary.

Hopefully, this theme issue will provide the

Preface 58 (2006) 1–3 3

intellectual bpushQ to set this process in motion. It

has been our privilege to work with a group of

outstanding authors that took time from their

extremely busy schedule to share their expertise

on a very important area of therapeutics. We would

also like to thank both Dr. Philip Smith (former

Executive Editor) and Dr. Vincent Lee (Editor-in-

Chief) for inviting us to undertake this editorial task

and for providing support and encouragement along

the way. In addition, we wish to express our deep

gratitude to Mrs. Donna Bethke for her invaluable

technical assistance.

Alessio Fasano(Theme Editor)

Mucosal Biology Research Center

University of Maryland School of Medicine

20 Penn Street, Baltimore, MD 21201

USA

Division of Pediatric Gastroenterology and

Nutrition, University of Maryland Baltimore

Baltimore, MD

USA

E-mail: afasano@mbrc.umaryland.edu

Hamidreza Ghandehari

(Theme Editor)

Center for Nanomedicine and Cellular Delivery

University of Maryland Baltimore

Baltimore, MD

USA

Department of Pharmaceutical Sciences

University of Maryland Baltimore

Baltimore, MD

USA

E-mail: hghandeh@rx.umaryland.edu