The differences in physiologies and development between subgroups within the pediatrics population add to the challenge in creating a single appropriate dosage form for all young patients. While older children and adolescents may be both capable of and happy to swallow a tablet or capsule, this is certainly not always the case for younger children. A single product may require several different dosage forms and different excipients, as well as a range of dose sizes to cater for everyone. As the pediatric population is smaller than for adults, there are limited financial returns of any marketed product; extending and adapting formulations for different pediatric groups can escalate research and development costs to a point where it may not be an economical option for the brand owner. This is more pronounced when a disease is not particularly prevalent, making it even harder to make a sound economic case for the development of a specific pediatric dosage form.
The commercial realities and constraints of the pharma business, in terms of time and cost, must be balanced against the risk that clinical trials fail to show efficacy, and this is well understood by the regulatory authorities. Therefore, the pharmaceutical industry uses regulatory frameworks to make business decisions regarding pediatric clinical trials, and additional incentives may further motivate the pharmaceutical industry to develop pediatric drugs.1
Regulatory authorities are concerned about pediatric drug safety, and their rules provide essential guidance for the industry when researching pediatric formulations. Their recommendations and guidelines have received multiple revisions over the years, both to clarify guidance and to incentivize companies to carry out specific research and development of drugs for children.
The regulatory requirements are designed to ensure that products are available for infants and children in different age groups that have an acceptable risk-benefit profile, rather than physicians and pharmacists being left to guess how they might scale down a product designed for adults.
The European Union’s Paediatric Regulation came into force in 2007, which means that no new drugs can now be registered within the EU without the European Medicines Agency’s (EMA’s) approval of a detailed pediatric investigation plan. In the U.S., the 2012 FDA Safety and Innovation Act (FDASIA) enshrined the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) into permanent law. Both had previously been subject to reauthorization every five years.
The EMA’s Guideline on Pharmaceutical Development of Medicines for Paediatric Use, issued in 2014, addresses dosage form and route of administration, as well as dosing frequency, modified release, excipient safety, and adaptation of formulations to meet the specific needs of children.2 It also instituted a public consultation in 2016 on the addendum to International Conference on Harmonisation’s (ICH’s) guideline E11 on Clinical Investigation of Medicinal Products in the Pediatric Population, which was designed to clarify a range of topics relevant to pediatric populations such as regulatory requirements for pediatric study plans, and on how pediatric clinical trials are to be conducted. Of interest, additional considerations for pediatric formulations should include age-appropriate dosage forms, ease of preparation and instructions for use for caregivers, acceptability (e.g., palatability, tablet size), and choice and number of excipients. Alternative delivery systems and appropriate packaging have also been recommended. This addendum first came into effect in February 2018, and provides an update to the current regulations.3
Differences in in vivo behavior
As a human grows from baby to adult through infant, child and adolescent phases, many changes occur that can affect drug pharmacokinetics (PK) and pharmacodynamics (PD). The differences in PK/PD behavior between children and adults are largely a result of the physiological, metabolic and physical processes involved in the growth process. Alternative drug delivery technologies may be required to meet bioavailability requirements, and different excipients or levels could be necessary to meet safety profile requirements.
Gastric pH, for example, changes dramatically in the first few weeks of life, and alters further as the baby’s diet shifts from milk to solids. Intestinal fluid volume and composition grows and changes, as does intestinal transit time. These changes, as well as the changes in bile and pancreatic fluid secretion, impact drug exposure.
The rate of permeation through the epithelial layer of the gastrointestinal tract is usually lower in children and in some cases, the formulation design for pediatrics will have to account for that difference. However, this must always be investigated on a case-by-case basis, as individual APIs behave differently.
Clearance issues must also be addressed. Many factors vary as a human grows and matures, such as plasma protein binding, metabolic enzymes and total body water. Other concerns include differences in the first pass effect, glomerular filtration, and in both renal secretion and absorption.
Current dosage form limitations and solutions
The biggest challenge facing those developing pediatric oral solid formulations is the creation of easy-to-administer dosage forms where the dose is sufficiently flexible to allow titration for different children’s needs. It is also important to ensure that the dosing frequency is minimal. Ideally, they will also include taste-masking technology, if needed, to increase palatability and acceptance.
The challenge in determining an appropriate method of administration should not be underestimated, because the potential for a child to choke on a large tablet or capsule, or to aspirate a very small tablet is very real. However, therapeutic education sessions for caregivers could make it possible to minimize the risk of choking on selected pills to children aged four or older.4
Dose individualization is easier with an oral liquid formulation, but ensuring both physical and chemical stability is more challenging and the potential for microbial contamination is greater. There is a growing trend away from liquid-based doses to flexible oral solid formulations.5
Another problem, whether it is a solid or liquid dosage form, is ensuring the correct dose is measured and given to the patient by their caregiver. If it is too low then the medication’s efficacy is likely to be sub-optimal; if it is too high then toxicity may become a significant risk. One potential solution to this would require the use of dosing devices to allow measurement of different amounts/volumes of the medication. An age-appropriate administration device (e.g., the solid dosage pen, multi-particulate counters and medicated straws) may improve the acceptability of pharmaceutical products.6
Even the choice of excipient is fraught with difficulties to ensure that there are no adverse events. Excipients that are deemed acceptable for adult use are not always appropriate for use in children because they may have different effects on developing organ systems, depending on age and developmental stage of children.7 Recent consensus from industry, academia, and regulatory agencies recommended that before choosing an excipient, literature and databases such as the Safety and Toxicity of Excipients for Pediatrics (STEP) database should be searched to determine if the safety of the excipient has been established, and to evaluate the need for any additional studies to assess its safety.8
Food effect, how the presence of food in the gastrointestinal tract can influence the direct or indirect rate and extent of absorption, can cause unexpected problems if it is not considered adequately. If a child is resistant to taking their medication, a parent or caregiver may be tempted to dissolve the dose in juice, a flavored drink or milk, or to mix it with food to disguise its taste. But some drugs display significant food effects, and little research has been done to determine which foods a drug can be mixed with, or to quantify the amount that creates a food effect.9 There is still no way to assess the risks of food effect within pediatric populations either in the lab or by computer prediction.9 In addition, stability issues caused by food such as drug degradation or precipitation, dissolution of enteric/protective coatings, and increased/decreased wetting, solubilization, disintegration, dissolution or diffusion may affect the bioavailability of the drug.10
Acceptability of dosage form in children
To encourage adherence, the product should be made sufficiently palatable so that the patient does not reject it because of a bitter taste. If something tastes bitter, a child may try it once, realize it is unpleasant, and refuse to take it again. Several taste masking techniques have been explored to overcome palatability issues, from the simple use of sweeteners and flavors to more complex techniques such as complexation with ion exchange resin and cyclodextrin, polymer film-coating, hot-melt coating, spray congealing, melt extrusion or melt granulation.11
Generally, solid dosage forms have been the formulation of choice within the pharmaceutical industry due to the established advantages of long-term stability, ease of supply chain and low cost of manufacturing.6 However, the ideal dosage form will certainly vary depending on the age of the child, and the EMA recommends that patient acceptability should be evaluated as part of all development projects for pediatric products.2
Oral solid dosage forms are becoming more popular for those children who are old enough to swallow them. The development of mini-tablets that are suitable for toddlers has provided at least one new option. Findings from clinical trials indicate that children as young as two years old are perfectly capable of swallowing a spoonful of fruit-flavored jelly in which are suspended multiple mini-tablets.12-14 Another trial found that mini-tablets can be more successful in newborns than syrups.15
For babies and others who cannot successfully be dosed in this way, multiparticulates or granules that include taste masking technologies to increase their palatability may also help improve adherence.
There are also data suggesting that chewable products and those that disperse in the mouth are preferred by all ages to multi-particulate formulations such as sprinkles.16
As more work is carried out in the pediatric market, there is a growing body of data about the acceptability of different dosage forms, gleaned from experience in clinical trials in children.
Meeting the challenge of variable dosage sizes
The ideal dosage form will also be easy for a caretaker to administer accurately. Accurately measuring a dose of any given medication to meet the needs of different sized patients remains important, even when a suitable dosage form has been established, and a variety of flexible options exist. It is relatively straightforward to change the dose of traditional syrups and other liquid formulations to meet patient requirements by altering the prescribed volume; similarly, powders designed to be reconstituted have in-built flexibility.
For an oral solid dosage form, one way to approach the issue is to create conventional formulations in different dosage strengths, although changes in formulation may be necessary. An alternative is to use a counting device filled with mini-tablets to dispense the appropriate number to meet the prescribed dose.
There is, of course, no single technology that will meet every pediatric drug development challenge. However, some are more flexible than others, and forms such as pellets, mini-tablets, mini-softgels, chewable products, and orally dissolving tablets are inherently more likely to prove acceptable in children.16,17
Safe, effective and age-appropriate medicines remain an important goal for the pharmaceutical industry, along with the provision of clear information about their use. Projects such as the European Paediatric Formulation Initiative, a collaboration between industry, academia and clinical pharmacy, play an important role in raising awareness of the issues, and giving recommendations regarding formulation development plans. Innovators too are collaborating to gain insights and to address the specific challenges of pediatric formulation and drug delivery, and in 2017 the Catalent Applied Drug Delivery Institute announced it had entered into a collaboration with the Department of Pharmacy Practice at Rutgers University to allow for further research into the development and administration of medicines to children.
Careful consideration of all the options, and studying the behavior of individual medicines in the different target age groups, are essential if the needs of pediatric patients are going to be met effectively and safely.
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3. EMA. ICH E11(R1) guideline on clinical investigation of medicinal products in the pediatric population: Step 5. 2017 1 Sept 2017.
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