The complexities of developing paediatric oral doses

Dr Anthony Qu, vice president of scientific affairs at Cambrex and Dr Yanjun Zhao, market intelligence manager examine the complexities of developing oral doses for the paediatric market.

Infants, children and adolescents require different oral dosage forms depending on their swallowing abilities, taste preferences and dosage requirements. The development of tailored solutions that are practical to manufacture increases medication adherence and provides a competitive advantage.

Growing Paediatric Market

Currently there are nearly 1,300 paediatric clinical trials underway investigating the safety and efficacy of over 600 drug substances for the treatment of various cancers, central nervous system disorders, infectious diseases and other ailments.

In the US, paediatric drugs based on new molecular entities (NMEs) must be evaluated in paediatric clinical trials. Existing drugs marketed for adults only can, if proven safe and effective for children, receive approval from the FDA as paediatric medications with six months of marketing exclusivity. Similarly, existing drugs proven safe and effective as paediatric medications for different indications can also benefit from marketing exclusivity.

Need for Age-Appropriate Dosage Forms

Consequently, developing paediatric dosage forms for both new and existing drug substances provides an effective means for expanding market reach and improving the lifecycle management of many different products. The paediatric population includes children ranging from infants to teenagers, and each age subgroup has different pharmacokinetic responses, dosage requirements, swallowing abilities and taste preferences. Therefore age-appropriate formulations are essential.

Liquids are ideal for newborns, infants and toddlers. They are also effective for pre-school children, along with mini-tablets. Chewable tablets may be the best solution for school children, but traditional capsules and tablets work as well, as do liquid dosage forms. Adolescents prefer capsules, chewable tablets and mini tabs. For all children, the palatability of medication can have a direct impact on treatment success. For many younger children, easy-to-swallow formulations are equally necessary.

Choosing the Right Dosage Form

Once the age-appropriate dosage form options are identified, the next step is to determine the most appropriate dosage form for the specific API in question. The first consideration is whether a measurable dosage form is required, such as dosing based on milligram (mg) of drug per kilogram (kg) of body weight. If yes, then liquid formulation will be suitable. Tablets and capsules would not be suitable in this case. Next, it is important to consider whether taste masking is needed and effective in the drug products. If it is not effective, then sprinkle powders or granules, tablets or capsules are the best choice because taste masking can be effective and achieved via coating technology in solid dosage forms. For liquid formulations, drug products must be chemically stable over a two-year period.

Formulation Design Requirements

Overall design requirements for paediatric oral dosage forms are primarily based on the age, body size and swallowing ability of the target population. In addition to liquid and solid forms such as tablets and capsules, multiparticulate formulations like granules and mini-tabs, and alternative oral delivery pathways such as dose-sipping technology are available.

Liquid dosage forms are ideal for patients with trouble swallowing, allow for flexible dosing and are more rapidly absorbed than solid dosage forms, but they often have shorter expiration periods; require special storage conditions (i.e., refrigeration); require careful dosage measurement; have unpleasant tastes and can be difficult to administer.

Traditional oral solid dosage forms leverage the most established manufacturing technologies with control costs, have long-term stability, do not require dosage measurement and are relatively easy and effective to taste mask via coating. They can, however, be difficult or young children to swallow and do not afford and dose flexibility.

Fast-dissolving tablets allow absorption of the tablets in 60 seconds or less. They are appropriate for smaller molecule weight of APIs with no bitter taste that are delivered at doses of less than 20 mg and can diffuse into the epithelium of the upper GI tract and permeate oral mucosal tissues. However, they do not work for APIs that have a bitter taste, short half-lives and for formulations requiring sustained or controlled release.

Chewable tablets provide fast absorption and better bioavailability through bypass disintegration and tend to have high paediatric patient acceptance. They also offer convenience to caregivers because no water is required for swallowing. On the other hand, these formulations contain sorbitol, which can cause diarrhea and flatulence. Due to their hygroscopicity, they must be kept dry and may require specialised packaging and storage conditions. The formulation must also have the right flow, lubrication, disintegration organoleptic and compressibility properties.

Multiparticulate formulations are popular for paediatric populations because as a solid dosage form they have long-term stability; several options are available; they provide maximum dose flexibility; modified release formulations are possible; and taste masking is generally effective.

Mini-tablets are small tablets averaging 1.5-3mm in diameter that can be filled into capsules, compressed into bigger tablets or loaded into sachets or stick packs. They not only provide flexible dosing (by simply increasing the number of mini-tabs) and sustained/timed release options with coating but are easy to swallow, can be effectively taste-masked and allow different incompatible APIs to be formulated into a single dosage form. If APIs are unstable in liquid forms, mini-tablets can also be reconstituted and dosed as a suspension.

Modified feeding bottles allow delivery of medication while the baby drinks its formula. Dose-sipping technology, which consists of a specially designed straw, enables the delivery of a single dose of small-sized pellets.

Specialised Expertise is Often Required

The choice of formulation type for paediatric patients is often dictated by the physiochemical properties and the taste of the active drug substance, along with the intended dose for different age groups. Each formulation must be appropriate for the child in terms of dose, convenience and acceptability to ensure compliance.

Expertise in the wide range of possible oral dosage forms is essential for ensuring the most age-appropriate, efficacious and cost-effective option is selected for any given API. Collaboration with contract development and manufacturing organisations with long-term experience and demonstrated success developing and producing right-sized dosage forms tailored for children from infants to teens at clinical to commercial scale can provide competitive advantage, reduce time to launch and ensure market success.