Time to focus on pediatric-friendly formulations

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.

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.

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.

Follow the PediatricSuperSite.com on Twitter.