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Advanced Drug Delivery Reviews (v.58, #1)
Challenges in pediatric drug delivery: the case of vaccines
by Alessio Fasano Theme editor; Hamidreza Ghandehari Theme editor (pp. 1-3).
Pharmacological research in pediatrics: From neonates to adolescents by Natella Y. Rakhmanina; John N. van den Anker (pp. 4-14).
The data guiding the dosing, efficacy and safety of medicines for children have lagged substantially as compared to the information available for adults. As a consequence, pediatricians faced with the prospect of confining their practice to medicines with adequate information have frequently resorted to prescribing medicines for unapproved uses (different dose, frequency, age group, route, indication or formulation). Although a long time in coming, the past decade, have witnessed a new era in drug development for children — an era that is still in its infancy, but which is currently showing signs of maturation. This review will give some of the history and current progress in pharmacological research and pediatric drug development.
Keywords: Drug therapy in pediatrics; Off-label prescriptions; Drug metabolism in pediatrics; Phase I enzymes; Phase II enzymes
Tight junction modulation and its relationship to drug delivery by Noha N. Salama; Natalie D. Eddington; Alessio Fasano (pp. 15-28).
In order for therapeutic agents to exert their pharmacological effects, they have to cross the biological membranes into the systemic circulation and reach the site of action. Drugs cross the membranes by one of two pathways; paracellular or transcellular. Most drugs are transported transcellularly depending on their physiocochemical properties, however the paracellular route is usually the main route of absorption for hydrophilic drugs (proteins, peptides, etc.). The paracellular pathway is governed by the tight junctions (TJs). The modulation of the TJs by absorption enhancers for paracellular drug transport enhancement and hence drug delivery improvement has been hampered for so many years by lack of comprehensive understanding of the structure and function of the TJs. The TJs are a multiple unit structure composed of multiprotein complex that affiliates with the underlying apical actomyosin ring. TJ proteins identified include transmembrane proteins; occludin and claudin, and cytoplasmic plaque proteins; ZO-1, ZO-2, ZO-3, cingulin, and 7H6. Among the new absorption enhancers that evolved in the past few years is Zonula Occludens toxin, Zot. In vivo and in vitro studies have shown that Zot and its biologically active fragment ΔG could be effectively used to increase the transport/absorption of paracellular markers and low bioavailable drugs across the intestinal epithelium. Above all, the transient opening of the TJs by Zot suggests that it could be used as a novel approach for the safe drug delivery of therapeutic agents.
Keywords: Zonula Occludens toxin; Paracellular permeability; Blood borne barrier; Oral delivery; Zonulin
Novel approaches to pediatric vaccine delivery by Derek T. O'Hagan; Rino Rappuoli (pp. 29-51).
Although currently available vaccines represent an outstanding success story in modern medicine and have had a dramatic effect on morbidity and mortality worldwide, it is clear that improvements in vaccine delivery are required. Vaccine delivery improvements may include the addition of novel injectable adjuvants, or the use of novel routes of delivery, including mucosal immunization. Mucosal delivery may be required to provide protection against pathogens that infect at mucosal sites, including sexually transmitted diseases. Alternatively, novel approaches to delivery, including mucosal administration, may be used to improve compliance for existing vaccines. Of particular interest for safer mass immunization are needle-free delivery devices, which would avoid problems due to needle re-use in many parts of the world, or needle-stick injuries.
Keywords: Vaccine delivery; Vaccine adjuvants; Needle-free immunization; Topical immunization
Mucosal delivery of vaccine antigens and its advantages in pediatrics by Maria Teresa De Magistris (pp. 52-67).
The delivery of vaccines through the mucosal route is very practical, non-invasive and efficacious for the induction of mucosal and systemic immune responses. Appropriately formulated mucosal vaccines can stimulate all arms of the immune system and could be exploited for protection against pathogens that infect the host through the mucosal surfaces as well as those acquired through other routes. There are few available mucosal vaccines so far and these are mainly based on whole microorganisms. The development of new generation mucosal vaccines based on purified protective antigens has been hampered for a long time by the low immunogenicity of soluble antigens and by the lack of safe and efficacious mucosal adjuvants. However, we have now several promising candidate adjuvants and delivery systems for mucosal immunization. In this review I will illustrate the advantages of mucosal vaccination and I will discuss what we still need to develop safe and efficacious mucosal vaccines that would be beneficial especially for young children.
Keywords: Vaccines; Mucosal immune system; Adjuvants; Delivery systems; Mucosal vaccines; Pediatric vaccines; Mechanism of action of adjuvants
Needle-free vaccine delivery by Erin L. Giudice; James D. Campbell (pp. 68-89).
The search for methods of vaccine delivery not requiring a needle and syringe has been accelerated by recent concerns regarding pandemic disease, bioterrorism, and disease eradication campaigns. Needle-free vaccine delivery could aid in these mass vaccinations by increasing ease and speed of delivery, and by offering improved safety and compliance, decreasing costs, and reducing pain associated with vaccinations. In this article, we summarize the rationale for delivery of needle-free vaccines and discuss several methods currently in use and under development, focusing on needle-free injection devices, transcutaneous immunization, and mucosal immunization. Jet injectors are needle-free devices that deliver liquid vaccine through a nozzle orifice and penetrate the skin with a high-speed narrow stream. They generate improved or equivalent immune responses compared with needle and syringe. Powder injection, a form of jet injection using vaccines in powder form, may obviate the need for the “cold chain.� Transcutaneous immunization involves applying vaccine antigen and adjuvant to the skin, using a patch or “microneedles,� and can induce both systemic and mucosal immunity. Mucosal immunization has thus far been focused on oral, nasal, and aerosol vaccines. Promising newer technologies in oral vaccination include using attenuated bacteria as vectors and transgenic plant “edible� vaccines. Improved knowledge regarding the immune system and its responses to vaccination continues to inform vaccine technologies for needle-free vaccine delivery.
Keywords: Needle-free vaccine; Jet injectors; Transcutaneous immunization; Mucosal immunization; Oral vaccine; Nasal vaccine; Aerosol vaccine
Clinical trials in pediatrics: The drug delivery dimension by Bankole Osuntokun (pp. 90-105).
The medical and drug delivery devices needs of children are quite different and unique when compared to that of adults. The practice of off label use and modification of adult devices for pediatric use is widespread. Attendant risk and adverse effects of such practices are poorly documented.Lack of pediatric age appropriate drug formulations constitutes a major impediment to pediatric drug labeling. While novel drug delivery system can help circumvent some of the pediatric formulations issues, the inherent high cost of development, the small size of the pediatric market, and the ethical dilemma of enrolling children in non-therapeutic clinical trials continue to militate against pediatric drug labeling as well medical devices development.Over the past four decades, major breakthroughs and achievements in basic biomedical science have supplied unprecedented potential information for improving human health. The need for properly designed and conducted pediatric clinical trials along with new drug delivery devices has never been greater. However major issues, like slow transition of promising basic scientific discovery into clinical applications, heavy regulatory burden, limited pediatric pharmacology research infrastructure, spiraling costs of health care, disproportionate governmental funding of basic science research over clinical research, conflicts of interest, and shortage of properly trained clinical investigators and willing study subjects continue to constitute major impediments to pediatric clinical trials clinical trials. This paper will seek to review among other things, the current state of affairs and the structure of the pediatric academic research enterprise along with their relationship with the pharmaceutical industry. Impediments to successful implementation of clinical trials in the academic setting will also be closely examined.
Keywords: Pediatric drug delivery devices; Pediatric clinical trials; Pediatric medical devices; Clinical trial office; Pediatric academic health center; Parental consent
The evolution of legislation to regulate pediatric clinical trials: Present and continuing challenges by Kathleen R. Gans-Brangs; Paul V. Plourde (pp. 106-115).
Children suffer from many of the same diseases as adults and are often treated with the same agents. However, it was not until 1997 that legislation mandating studies in children was introduced in the United States. A 2000 International Conference on Harmonisation (ICH) Guidance on the Clinical Investigation of Medicinal Products in the Pediatric Population intended to encourage and facilitate timely pediatric clinical trials detailed critical issues in pediatric drug development and ways to ethically study the safety and efficacy of drugs in the unique and vulnerable pediatric population. In 2005, there is draft legislation in Europe. In Japan, pediatric data are not currently required although studies in pediatric populations are encouraged. This chapter describes the history of legislation on the study of drugs in the pediatric population and details present and continuing challenges for the child, parent/guardian, manufacturer and health authority.
Keywords: Pediatric clinical trials; Legislation; Assent; Consent