News & Press
By Dr. Brittany L. Hayes
Director, Highly Potent & Oncology Platform
Developing oral solutions for paediatric patients can be difficult, for a variety of reasons. What can mini-tablets do to help overcome these issues?
The development of pediatric medicine poses numerous challenges to pharmaceutical formulators, particularly products intended for infants and very young children. Conducting adequate and well-controlled clinical trials in pediatrics has always been a difficult process. Fear of permanent damage to developing bodies and interference of physiological changes throughout pediatric development have raised ethical concerns. This has led to issues in recruitment and small population sizes. These factors have proven to constrain the development of medications for specific pediatric applications.1 Faced with such difficulties, clinicians have grappled with the issue of how to effectively treat children with medications designed for adults.
But the focus on developing drugs specifically for children and infants has also led to innovation, especially in dose forms more suitable to this patient demographic. In this article, we take a close look at mini-tablets, a practical Oral Solid Dose (OSD) technology with great potential to create patient-centric therapeutics for this underserved market.
The EU Regulation 1901/2006 on medicinal products for pediatric use rightly states that children are not simply small adults and that pediatric treatments must thus be tailored to the specific needs of children in various age groups. This means that developers must carefully select a dosage form that is appropriate for young patients in terms of administration and palatability, especially in the case of highly potent medicines used for various indications such as oncology.
The FDA has issued guidance several times during this period of pediatric drug development as well, including:
The regulatory framework has ensured pediatric trials continue to be conducted to generate labeled, approved pediatric therapeutics. Today there are more than 840 small molecule and biologic products with pediatric labeling from the results of these acts. Many of these are being developed into OSD forms.
Most patients prefer swallowing tablets and capsules versus injections or infusions.2 Inherently patient-friendly and convenient, OSDs can be dispensed easily and sent home with patients to self-administer their prescriptions instead of having to travel to a clinical setting. In addition, they are generally simple and more stable, flexible, and cost-effective to produce compared to other dose forms and modalities.
Additionally, 70-90% of Active Pharmaceutical Ingredients (APIs) in development are highly insoluble and suffer from bioavailability issues. This trend is expected to increase over the next few years, requiring efficient formulation strategies and enabling manufacturing technologies to solve this issue. Demand has expanded for processing and manufacturing to cope with these issues relative to OSD formulation issues. These include an array of technologies such as spray drying, hot melt extrusion, nanomilling, and micronization.
When drug companies are determining the best child-friendly delivery mechanism for their pediatric formulation, finding a combination that works for the pediatric market is mandatory. Mini-tablets truly stand out in this regard. Presented as compressed round or cylindrical tablets, mini-tablets are a fraction the size of conventional doses (2.5 mm in diameter or smaller) and offer a wide variety of advantages.
Size isn’t the only factor that enhances mini-tablets’ pediatric profile. Because they’re pressed tablets from powdered formulations, the tabletted OSD delivery route offers flexibility and therapeutic performance in a variety of ways, including sublingual administration. Orodispersible mini-tablets, for example, are a particularly child-friendly format because they disintegrate rapidly (within ~30 seconds) in the mouth, and are thus safe for patients as young as six months old.
Similarly, mini-tablets can be dispersed easily in water, juice, and baby formula or sprinkled on food, depending on the needs and preferences of the patient.
Flexible, more accurate dosing
Dosing of mini-tablet formulations according to the child’s age, weight and body surface area is significantly more flexible than with fixed-dose adult systems. Formulators can control optimal dosing by parsing the number of mini-tablets according to a patient’s specific age and weight. For example, trial and analytical data might indicate a single dose of 5 mini-tablets for children of one given weight range, and 10 mini-tablets for another weight range.
Simple incremental dosing of mini-tablets offers benefits to many applications, including therapeutic applications designed for smaller patient populations. This is because it can be cost-prohibitive to offer a variety of finely adjusted fixed-dose forms, particularly highly potent compounds that require advanced containment solutions.
For years pediatric developers have relied on liquid formulations such as syrups, emulsions, suspensions, and solutions as the go-to delivery mechanism for children’s drugs. While liquid formats certainly have benefits for pediatric patients, they also have limitations. One, in particular, is the possibility of inaccurate dosing arising from the fact that some amount of medication inevitably remains in the cup or oral syringe after consumption or dribbles down children’s chins. These challenges are particularly problematic when dosing life-saving medications with a low therapeutic index.
Conversely, mini-tablets offer excellent dosing accuracy, which is enhanced through dose-counting devices and stick packs that assist greatly with dispensing accuracy.
Masking bitter-tasting APIs is, of course, another important consideration for manufacturing effective pediatric dosage forms. Poor taste and texture often confront younger patients and remain a common complaint of liquids. Mini-tablets can easily accommodate various typical excipients for taste masking such as sweeteners (e.g., sucralose), bitter blockers, cyclodextrins and fruit flavors. In fact, several studies suggest that both children and caregivers find mini-tablets more palatable than other dosage forms, which benefits the patient, as well as associated compliance concerns.3,4
Selecting effective excipients for pediatric drugs is an important and often undervalued aspect of the formulation’s overall therapeutic effectiveness as well. At this stage, formulators must carefully consider whether the therapeutic is intended for short or long-term use, and that includes the excipient’s safety profile for the targeted age group based on single or daily exposure. In this case, it can be very expedient and efficient to transfer compatibility knowledge from existing adult formulations.
One key methodology that improves both therapeutic performance and patient-centricity is a modified release dosage form. Modified release drug products enable actives to be released over a defined period of time, or at specific locations within the GI tract for prolonged or targeted drug delivery. OSD formulators understand that modifying and controlling API release can allow for less frequent dosing and other benefits that can increase patient compliance. For example, reducing the peaks and troughs of actives in blood levels can decrease side effects over time. This often represents a huge therapeutic advantage for younger patients with low body mass – especially if the debilitating effects of a disease appear quickly once the drug concentration falls out of the therapeutic window.
Drug developers must demonstrate they have the means to transition their traditional adult tablet formulation into pediatric mini-tablets. Fortunately, developers can draw upon much of the data gained from stability and other similar studies of the adult formulation to support its pediatric investigation plan. For example, the excipients used in both formulations may be similar.
Some level of reformulation work will often be necessary to accomplish successful compression of mini-tablets. Ideally, the manufacturing technologies used to make both traditional and mini-tablets are in a practical sense quite similar. While the same conventional tablet presses may be used to produce both traditional and mini-tablets, multi-tip tooling enables these machines to achieve a higher throughput without increasing speeds.
In particular, when using multi-tip tooling, flowability of the powder blend is essential to allowing the adequate filling of the dies, thereby ensuring low mass variation and good content uniformity. Another area where drug developers may run into challenges when transitioning from a traditional to a mini-tablet is with standard tablet tests.
Challenges transitioning from tablets to mini-tablets6
The development of pediatric formulations requires special considerations to ensure compliance. Depending on the Target Product Profile (TPP) mini-tablets are an elegant way of delivering APIs not only to pediatric patients, but also other groups like geriatric patients that would benefit from mini-tablet’s distinct dose delivery advantages, such as age-appropriate and accurate dosing and better patient acceptability. This delivery system, however, requires special expertise in terms of developing a suitable tableting process and analytical methods to analyze these mini, yet mighty tablets.