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This Funding Opportunity Announcement (FOA) encourages grant applications to address different and complementary research needs for the development and acceptability of pediatric drug formulations in different age groups. Development and testing of novel pediatric drug delivery systems are also part of this initiative.
Investigators are encouraged to explore approaches and concepts new to the area of pediatric formulation development and testing and use newly developed techniques superior to the ones currently used in the field.
The lack of appropriate pediatric formulations has been identified as a major obstacle for the study and use of drugs in children. Pediatric formulations may be inappropriate for different reasons. Children under 12 years of age often have difficulty in swallowing capsules, while those under 4 years generally cannot swallow tablets. Liquid formulations facilitate dose adjustments and are easily administered and recommended for infants and younger children. The production of formulations may be limited by the solubility and stability of drugs, require taste-masking agents, preservatives and other excipients. Liquid formulations may also not be optimal for the developing world, where clean water and refrigeration may not be available.
In general, there is a need in pediatrics to develop flexible dosage forms that are oro-dispersible or can be prepared as oral liquid formulations. There is an increased recognition that for medicines requiring precise dosage and titration, the development of a universal technology platform could allow for "tailored dosages" and a range of dosage forms appropriate for children at different developmental stages, or for other populations with swallowing difficulties.
The Biopharmaceutics Classification System (BCS), the scientific framework for classifying drug substances based on their intestinal permeability and solubility/dissolution rates, is widely used to assure bioequivalence of drug products in adults. Its application in pediatrics has been challenged because the tools used to measure intestinal permeability may not be applicable to young children, as the intestinal mucosa of infants and young children is more permeable than that of adults. In addition, the effects of developmental factors such as gastrointestinal pH, gastrointestinal motility, gastric emptying times and intestinal transport systems on drug bioavailability have not been systematically studied in children.
Driven by federal legislation that now requires evaluation of most drugs in children, renewed attention has been focused on the active pharmaceutical ingredients (APIs). Much less attention has been devoted to the excipients that render these formulations feasible, palatable and stable.
Many APIs are extremely bitter, which can make the development of palatable formulations extremely difficult. Adult formulations are frequently taste masked by coating the tablet or by producing a capsule formulation, techniques which are generally not useful for young children. Because the primary market for most pharmaceuticals is in the adult population where palatability has not been a major consideration, taste masking techniques have not been well developed.
Three broad approaches have been used: 1) to create a barrier between taste receptors and drug (physical coatings, capsules); 2) make chemical or solubility modifications; and 3) to overwhelm the unpleasant taste by adding flavors and sweeteners. A new approach has been the development of bitter blockers based on the biology of taste.
There are significant age-related differences in how children and adults respond to flavors. Therefore, adult sensory panels may not be able to predict flavors that children prefer and those they will reject. The use of taste sensing analytical devices (electronic tongues) for initial screening of foods and beverages in children is still in its infancy. The advantages of this approach include its speed, relatively low cost, and lack of risk. The use of this technology has so far not been validated in children.
Implications for psychophysical testing as well as sensory evaluation methods for children have been published in standard guides and review articles. There are, however, no peer-reviewed research studies that systematically determined the validity of many of these methods among children of varying ages. Cultural groups also differ in their sensitivity and preference for bitter tastes and other flavors. The lack of acceptable and palatable dosage forms is a major reason for the low rates of adherence in children, and has been implicated as a major factor in pediatric hospital readmissions for treatment failures.
In addition to orally administered drugs, other routes of administration are being used in children with varying degrees of success. With the advent of needle-free injections, devices for parenteral drug delivery can now be grouped into invasive and non-invasive categories. Neonates require the use of invasive delivery systems and formulations providing appropriate concentrations and volumes. It is anticipated that the increased availability of biotechnology-based drugs will require the development of reliable delivery systems using the subcutaneous route. In addition to topically applied pediatric medicines, transdermal patches and iontophoresis technologies have been used in children with limited success. However, transdermal patches may in the future be used for non- invasive delivery of vaccines.
The recent advances in nanoscience and nanotechnology have resulted in the development of nanoparticle-based diagnostic and therapeutic approaches for the treatment of adult cancers, infections, asthma and other conditions. Nanoparticle-based drug delivery has advantages over conventional formulations, including increased solubility of poorly water soluble drugs, sustained release and delivery of drugs to specific targets tissues, and potential minimization of toxic effects. There is a need to test new drug delivery systems in pediatrics using nanoparticle-facilitated delivery. Targeted therapy using anti-cancer and anti-infective drugs encapsulated in nanoparticles, for example, holds considerable promise to reduce toxicity and improve the efficacy of drugs given to children.
The rapid advances in peptide and protein pharmacology have fueled great interest in these types of compounds. Although initial attempts have failed (e.g., insulin delivered by inhalation), novel experimental smart polymer-based drug delivery systems have been developed to deliver drugs at a controlled rate over long periods of time. Smart polymers are macromolecules that display significant physicochemical changes in response to small changes in the environment. Major advantages of smart polymer based systems include delivery for site specific action and decrease total body exposure.
In vivo nano-device-based platforms, which improve efficacy of treatment when combined with diagnostics in one construct (theranostics), are being tested in children with cancer.
The delivery of drugs to the lungs or for systemic delivery using inhalers has been limited by the different physiology of children compared with adults (e.g., airway diameter, short respiratory cycle time, and small tidal volume). There is a need for versatile, efficient devices given the variety of treatment modalities needed and the developmental and behavioral characteristics of young children.
Specific areas of research interest under this FOA include, but are not limited to, the following:
- Development of innovative technologies and platforms for oral pediatric formulations for poorly soluble drugs, unpalatable drugs, and for drugs requiring reconstitutable dosage forms. These technologies include taste masking and the use of novel excipients;
- Use of a materials science approach to overcome solubility limitations of pediatric drugs, increase bioavailability, decrease excipient exposure, and provide effective taste masking;
- Use of modeling and computational analysis of drug molecules and application of chemometric analysis to determine correlations with experimentally determined values of solubility, stability and taste and to establish the predictive value of computer simulations of new pediatric formulations;
- Development of animal models for taste assessment with comparison to electronic tongue, as well as more traditional sensory analysis in current use;
- Evaluation of methods in current use for taste testing in children including their validity and reliability;
- Development of standardized methods for testing drug formulations in pediatric and adult panels;
- Studies to evaluate the value of electronic tongue to quantify bitterness and taste masking efficiency in the development of pediatric formulations;
- Study of effect of different textures, granularity and smell of dosage forms in the acceptability of pediatric formulations;
- Application of theranostics in pediatrics;
- Determination of the reliability of the Biopharmaceutical Classification System in newborns and young infants;
- Study of the effect in infancy of the functional ontogeny of the gastrointestinal tract and of feedings on the dissolution, solubilization and absorption of different types of pediatric dosage forms;
- Development of methods to study efficacy of bitter blockers/maskers in reducing bitter taste and increasing acceptance;
- Performance of studies on cross-cultural flavor preferences and bitter taste sensitivity in children;
- Performance of psychophysical research on the chemical senses to determine what types of adult sensory panels and methods are most appropriate for predicting acceptance/compliance in the pediatric population;
- Performance of studies on excipients used in pediatric formulations, assessing interaction of excipients with drugs and with other excipients in different pediatric formulations;
- Development of non-invasive devices for evaluating adherence to chronic therapy in life- threatening conditions (e.g., HIV, diabetes, asthma, solid organ transplant patients);
- Development of novel approaches for oral mucosal, transdermal, nasal , ocular and pulmonary drug delivery systems and device technologies.
- It should be noted that applications using the NIH R01 grant mechanism will require sufficient preliminary data to substantiate the validity of the proposed research and feasibility of new technologies or tools.
For more information and to apply, click here.