The following is a summary of a Q&A with two formulation and bioavailability experts from Catalent addressing some common formulation challenges for pediatric populations.
Uwe Hanenberg, Ph.D., Director Product Development and Oral Solids, Catalent. A well-known industry expert on formulation and analytics of oral solids dosage forms.
Pascale Clement, Director, Project Management, Catalent. An expert on bioavailability enhancement techniques for challenging molecules.
Q1 - What are the special challenges in the development of medicines for pediatric use?
Recognizing the fact that physiological changes happen from birth through the adolescent years – leading to differences in pharmacokinetics (PK) and pharmacodynamics (PD) - the task to develop medicines for the various pediatric age groupings can be challenging. This can require different formulations, different dosage forms and strengths, or different routes of administration to ensure proper treatment of children of all age groups.
Looming over this scenario are limitations of the various dosage forms and their possible adverse impact on patient’s safety, acceptability as well as swallowability.
For example, oral solid dosage forms are associated with limited dose flexibility and risk of aspiration or choking, depending on the size and shape of the tablet or capsule. Oral liquids have challenges in terms of physical, chemical, and microbiological stability. Both oral solids and liquids have to deal with palatability issues. Measurement and administration of oral liquid and oral solid dosage forms can lead to improper dosing and potential toxicity concerns.
Non-oral routes of drug administration are limited by the difficulty in application or administration and the potential for local site irritation. Like for adults, the parenteral and topical administration also faces challenges in measuring and administrating small dose volumes that have the potential to cause dose variation and error. Special attention must also be given on the use of appropriate excipients for children from different age groups to avoid the consequences of excipient toxicity.
The potential drug-food or vehicle interaction in children adds to the complexity. It is quite common for medication to be mixed with or dissolved in food or liquids to improve delivery and palatability. Quantity and composition of food required to generate a food effect in children are not clear at the moment, and there is no guidance to support in vitro or in silico risk assessment to understand food effect.
Oral solid dosage forms are gaining favor over oral liquids for use in pediatric patients. Mini-tablets have been shown to be an acceptable dosage form for toddlers. Granules and multiparticulates with taste masking technologies may be appropriate dosage forms for infants.
Arguably the biggest challenge in pediatric oral solid formulation development is to develop flexible dosage forms with measurable and easy to administer dosage, preferably formulated with taste-masking properties for better acceptance of the drug formulation in children.
Despite these challenges, the industry is nevertheless committed to providing safe and effective age-appropriate medicine to children. Many initiatives within industry, regulators, and academia have been spurred related to the development of medicines for pediatric age groups and to the improved availability of information on the use of medicines in children.
For example, the European Pediatric Formulation Initiative (EuPFI), a group composed of pediatric formulation experts from industry, academia, and clinical pharmacy, was founded with the aim to raise awareness of pediatric formulation issues and provide recommendations for formulation development plans. Other network such as the European Network of Pediatric Research (Enpr-EMA) was established by the European Medicines Agency to encourage collaboration with academic and industry members from within and outside the European Union.
Q2 - You mentioned PK/PD differences between adults and children – can you please explain?
The differences in PK/PD are caused by the physical, metabolic and physiological processes inherent to growth and reveal that children can’t be regarded as small adults.
Let’s have a look at the differences to better understand this:
From birth to adulthood several important factors driving the PK/PD values are changing constantly: gastric pH (first three years, especially first weeks), intestinal fluid volume and composition, immaturity of secretion of bile and pancreatic fluid, and intestinal transit time can have a significant impact on the exposure of the drug.
A further significant difference between children and adults can be the permeation of the drug through the epithelial layer of the gastrointestinal tract, which has often a smaller value in children compared to adults – the permeability of APIs can, but must not, be lower. In some cases, (e.g. Dolasetron, Ketoprofen or Voriconazole) this leads to a switch in the BCS class from 1 (adult) to 3 (children) or from 2 (adult) to 4 (children) with related impact on formulation and bioavailability enhancement requirement of the pediatric formulation.
Differences related to total body water, plasma-protein binding, metabolic enzymes, first pass effect, glomerular filtration, renal secretion, and renal absorption are leading to differences in the clearance between adults and children.
Q3 - Does the regulatory body reflect the specifics of pediatric medicines in their regulations?
The fine nuances of specifics of pediatric medicine are definitely reflected in the current foundation of drug regulatory environment. Generally, pediatric legislations in the US and EU are welcomed for the guidance provided for the pharmaceutical industry.
The underlying principles of pediatric regulatory requirements are that pharmaceutical substances and products intended for children should be manufactured to ensure that children in the target age groups will have access to consistent quality and age-appropriate formulations with an acceptable risk benefit profile.
The past 10 years have seen enormous changes in the legislation of pediatric medicine. For example, in the US, the Best Pharmaceuticals for Children Act and Pediatric Research Equity Act that were previously subjected to reauthorization every 5 years, were made permanent under Food and Drug Administration Safety and Innovation Act in 2012.
By making these Acts permanent, the law ensures pediatric medicine will have a permanent place on the agenda for drug research and development in the US. In the European Union, Pediatric Regulation came into effect in 2007 and since then, no new drugs can be registered in the EU without a detailed Pediatric Investigation Plans being approved by the EMA's Pediatric Committee.
Regulatory authorities have published a number of useful guidelines and recommendations. And there has been a considerable amount of revisions on these guidelines, where the authorities have periodically improved regulatory tools to provide clearer guidance as well as to incentivize industry to conduct research and development of drugs in children.
For instance, the EMA has published a guideline for pharmaceutical development in children that came into effect in 2014 that addresses issues in the route of administration and dosage form, dosing frequency, modified release preparations, safety of excipients, and how formulations should be adapted to the needs of children.
Another example would be the 6-month public consultation that was recently launched in October 2016 by the EMA on the addendum to the current ICH E11 (guideline on clinical investigation of medicinal products in the pediatric population). The proposed addendum intends to provide clarification and current regulatory perspective on various topics such as age classification and pediatric subgroups, issues to aid scientific discussions at various stages of pediatric drug development in different regions, just to mention a few.
Q4- What are the specifics for the development of pediatric medicines?
Driven by the previously explained differences between adults and children during development and growth, the following specifics need to be reflected:
- Pediatric medication may need a different drug delivery technology compared to adult medication with the same API.
- Not all excipients suitable for adults can be used in pediatric formulations.
- Selected excipients should be reduced to the minimum needed
- Minimal dosing frequency
- Swallowability needs to be considered
- Risk of choking needs to be considered
- Acceptance of treatment needs to be in strong focus (influenced by age, culture, health status, behavior, social background, route of administration, taste of medication, duration of treatment, convenience of administration)
Q5 - Which oral dose form is preferred by children?
Based on a report released by FDA in 2014, 69% of the approved product labeling for pediatric use is in the form of tablets. However, in general, we knew that the preference towards dosage forms primarily differed based on age and prior use.
About 4 years ago, the EMA specifically recommended that the evaluation of the patient acceptability of a pediatric preparation should be an integral part of the pharmaceutical and clinical development.
Since then, we have acquired more understanding on pediatric drug development and begin to bridge the knowledge gap on the acceptability of dosage forms based on evidence gathered in clinical trials in children.
For example, initial findings revealed that minitablets and syrups were found to be the most acceptable formulation to toddlers and infants. Another study also demonstrated that children of 2 to 3 years old had no difficulty in swallowing multiple units of minitablets that were suspended in a fruity jelly on a spoon.
Subsequently, another clinical trial reported that neonates have a higher level of swallowability of minitablets compared with syrup. Latest data published November last year reported a preference for chewable and orodispersible preparations across ages when compared with multiparticulates such as sprinkles.
There is a trend toward oral solid formulations with a focus on novel preparations, including flexible, dispersible, and multiparticulate oral solid dosage forms. These clinical evidence further confirmed the shift of paradigm from liquid toward small-sized solid drug formulations.
Q6 – How is the industry meeting the requirement of weight or age dependent dosing of oral dose forms?
Industry is addressing the need for easy, reliable, flexible dosing of pediatric oral dose forms by using
- Dosing Mini-tablets with counting device
- Powders for reconstitution; solution to be dosed by volume (e.g. powder in a bottle, powder in a stick pack)
- Liquids/syrups to be dosed by volume
- Conventional solid formulations in different dosage strength (different formulations may be required)
Q7 - With all the challenges in developing a suitable formulation for pediatric use, what are the most promising technologies available today?
There is no single technology that fits perfectly for pediatric drug development. Technologies that offer options for age appropriate formulation would be desirable. Therefore, technologies that produce small oral dosage forms like mini-tablets or pellets, chewables or orally dispersible tablets stand a promising chance for better compliance in the pediatric population.
In Catalent, we have the expertise and capability to develop pediatric-friendly softgels that are small and easy to swallow. For example, the OptiGel™ Mini Technology is capable of producing 30% smaller size than traditional softgels in various shapes for ease of use in children.
In addition, to address issues on formulation that requires dose titration, Catalent’s OptiGel™ Micro Technology can produce spherical form capsules as small as 1mm in diameter. These micro-capsules can then be packaged into a sachet to accommodate for different dosing levels. The Zydis® Orally Disintegrating Tablets (ODT) tablets offer orally disintegrating tablets for children and infants.
Given trends from recent clinical trials that provided some evidence towards rational for solid dosage form design for pediatric use, the technologies that we have in Catalent offers the opportunity to develop and deliver an optimal formulation dosage form that addresses issues such as adherence and acceptability in the pediatric population.