Overcoming Challenges to Formulation Development for Pediatric Medicines

Creating pediatric formulations with appealing taste and appearance has been a challenge since drugs were developed specifically for children. With regulations in the United States and Europe now requiring that palatability be addressed by pharma companies during clinical development of pediatric formulations, this issue has grown in importance. Patient adherence must be top of mind when formulating pediatric dosage forms, which cannot be achieved simply by reducing the size of an adult dose. Variables such as the age and weight range of the patient population, speed of symptom onset, liver enzyme function, swallowing capabilities, and ease of administration must be considered.

The most desirable attributes of pediatric formulations, says Joao Marcos Assis, global technical marketing manager at BASF Pharma Solutions, include acceptable taste and dosage form (typically oral), dosing flexibility, convenient and reliable administration, minimal manipulation needed by healthcare givers, minimal dosing frequency, minimum use of nontoxic excipients, and simple manufacturing processes that generate affordable and stable products (1).

Ultimately, an understanding of how to formulate for appropriate dose flexibility and patient compliance, along with an awareness of global regulatory changes regarding excipients, is needed to ensure a successful pediatric product, states Adam Hopper, president of the drug product business unit at Cambrex.

Unique formulating challenges

Pediatric drug formulations pose several unique challenges compared to adult drug formulations. These challenges arise due to the physiological and developmental differences between children and adults, according to Assis. In addition, age-appropriate pediatric-specific formulations and dosage forms that fit children’s needs at different ages are of the uttermost importance, adds Philip Schäfer, head of process and formulation materials at the Life Science business of Merck KGaA, Darmstadt, Germany. Furthermore, acceptance and preferences highly vary between children and are strongly influenced by several individual factors such as their socialization (2).

Dosage form selection can be particularly difficult, as children often have trouble swallowing tablets and capsules, Assis observes. The task is made more difficult for liquid dosage forms or formulations that disintegrate within the mouth due to the bitter taste of many APIs. “Drug size, texture, mouthfeel, smell, taste, and for liquids, viscosity and color, play an essential role in the child’s acceptability and adherence to treatment,” he notes.

Furthermore, precise dosing must be achieved based on age, weight, and body surface to reduce the risk of medication errors, which can be challenging due to the significant variability in drug absorption, distribution, metabolism, and excretion children exhibit compared to adults. Small volumes may be needed, such as for parenteral formulations administered to neonates, and potential modification of dosage forms in the home setting (crushing tablets, mixing with food, etc.) must also be factored into formulation designs, Schäfer comments.

Excipient selection must also be carefully considered, as there are excipients tolerated and widely used in adult formulations that can cause adverse effects in the pediatric population, according to Schäfer. He adds that impurities in excipientsmust also be controlled, as some have been known to cause severe consequences for children. To ensure safety and efficacy, Assis points out that pediatric formulations may therefore require additional studies to establish safety profiles and optimal dosing regimens.

Palatability a primary challenge

Regulatory agencies require pharma companies to develop age-appropriate formulations. For oral dosage forms—solutions, suspensions, orally disintegrating tablets, and multipartculates (powders, granules, minitablets)—palatability remains the primary challenge, states Jeff Worthington, president and founder of Senopsys.

Taste is particularly important to children. Assis points to a survey conducted by the American Association of Pediatrics in 2023 that found unpleasant taste to be the most significant barrier to completing treatment for pediatric patients (3). “Acceptability, palatability, and ease for the caregiver to administer the medicine contribute to whether or not a child will ultimately take a medicine,” he says. Palatability includes not only taste, but the size of a tablet, the pH, texture, and volume of a liquid formulation, Hopper adds.

Many drugs are known to be bitter, some extremely so, or have other aversive sensory attributes including malodor and irritation, Worthington remarks. Each have fundamentally different perception pathways and importantly, require different amelioration approaches or technologies. “There are more technology approaches for managing a low or moderate taste masking challenge than a difficult one. For an extremely bitter drug active, it may be necessary to ‘sequester’ the API from taste receptors via particle coating, complexation, encapsulation, or other means,” he explains.

While product appearance is generally of minor concern for drug products unless required for placebo color matching or masking an aversive API color, it can be important in pediatric applications, according to Schäfer. “It is important that the appearance of medications is clearly distinguishable from candy in order to avoid mix-ups which could expose children to a high safety risk,” he explains. In the case of bitter-tasting APIs, Schäfer contends that formulators should ensure that the taste does not attract children too much; the final taste of pediatric formulations should thus be more neutral than sweet.

Prediction of bitterness a top issue

Bitterness is not only a challenge with respect to overcoming this undesirable taste experience. There are also significant challenges to predicting if new compounds are bitter, according to Assis. He does note, however, that the process for identifying bitter APIs has rapidly progressed in the past few years.

Assis points to BitterDB, a free database with more than 1000 naturally bitter and synthetic compounds available to formulators, as one example (4). Machine learning algorithms trained with these known bitter API molecules are leveraged to predict the bitterness of new compounds. Based on such predictions and additional physiochemical API properties, pharmaceutical formulators can proactively select taste-masking technologies. In addition to advanced digital technologies, trained human panels are still employed to test and optimize taste-masked formulations.

Not just a bitter problem

Another important issue in formulation of pediatric medicines is the need to maintain bioavailability while formulating to mitigate bitter taste or undesirable appearance, notes Hopper. “Successfully achieving this goal requires balancing solubility, molecular size, lipophilicity, and overall acidic strength—all of which impact the overall bioavailability,” he comments. Another consideration is how different patients may respond to medications, as liquid and tablet formulations can be held in the mouth for varied times.

In fact, palatability is comprised of four elements—basic tastes (sweet, sour, salty, bitter, and umami); aroma (fishy, oxidized oil, orange, grape, mint), trigeminal irritation (chemesthesis or mouthfeel); and texture (hardness, fracturability, grittiness), according to Worthington. “Each have different biological perception pathways that require tailored approaches to overcome,” he explains.

Bitterness is, as a result, not the only challenge in creating palatable, patient-accepted drug products. Senopsys compiled data from 150 API taste-assessment studies the company completed (excluding over-the-counter drugs). The primary taste masking challenge was bitterness for nearly 70% of the APIs (mostly new chemical entities) (5). Of the other basic tastes, sour and salty were problematic for 3% and 4% of APIs, respectively.

Aversive odors (“aromatics”) were the primary sensory challenge for approximately 7% of APIs, according to Worthington. Some descriptors of these malodors included “phenolic” (like Band-Aids), “sulfidy” (overcooked cruciferous vegetables), “oxidized oil” (like old paint), and “solventy” (e.g., acetone, or ether-like).

The primary challenge for another 4% of the APIs was a strong intensity trigeminal irritancy such as oral or throat burning, numbing, and tongue sting. Finally, 16% of APIs were fundamentally tasteless, but their challenge was driven by the negative sensory attributes of the excipient system (e.g., surfactants, co-solvents, and solubilizers).

Worthington also notes there is a general misconception that most APIs have a single aversive attribute, but that is not the case. Secondary taste masking challenges for those same 150 APIs are heavily represented by aromatics (malodor), followed by trigeminal irritancy, sour and salty basic tastes, “other” (e.g., aversive mouthfeels and textures), and bitter basic taste (5).

High-dosage drugs, meanwhile, are more challenging than low-dose formulations and typically require a combination of more advanced and efficient taste-masking strategies, such as particle film coating, Assis contends.

It is also worth noting, according to Assis, that previous approaches relying on the use of sweeteners or viscosity-modifying agents to suppress API bitterness generally have not been preferred by patients, as they generally require high concentrations of sweeteners, leading to a metallic taste. “Patients are even more opposed to both sweet-bitter sensations on the tongue, and many viscosity-modifying agents are not entirely tasteless or can provide an unpleasant texture,” he adds.

Mechanisms for taste masking

Addressing the palatability challenge for pediatric formulations, says Worthington, depends on the physical and chemical properties of the API, the dosage form, and the specific taste masking needs. He outlines five broad taste-masking approaches that are employed to improve palatability, including signal interruption, using flavor systems, altering the form of the drug substance, complexing the API, and physically encapsulating the API.

Still in the research stage, signal interruption uses an antagonist to inhibit taste via ligand binding, according to Worthington. Taste masking via the use of flavor systems is a common approach, but can be insufficient for particularly challenging actives. Modifying the active molecules as a prodrug, freebase or salt can be effective, but extends development timelines, may cause pharmacokinetic changes, and may still require the use of masking technologies. Complexation traps the API in a chemical matrix to hide it from the taste buds, but generally results in decreased drug loadings, may also cause pharmacokinetic changes and is generally limited to solid forms. Application of a physical barriervia encapsulation has similar limitations.

Assis reiterates that the taste of an API is pronounced if the drug is solubilized in saliva and able to interact with the taste buds, and thus less soluble APIs have a lower aversive taste than highly soluble ones. In addition, he notes that micronized drugs have more chance to interact with the taste receptors within the mouth. For such APIs, “using a more palatable prodrug or salt and a less soluble polymorph or unionized form to reduce drug-taste bud interactions can be alternative,” he says. He also points out that pharmacokinetic and bioavailability properties might be negatively impacted, and thus changes must be made with careful consideration to the effects they may have on other drug-substance attributes.

Excipients’ role in solutions

While formulation challenges with respect to taste, palatability, and appearance differ depending on the API and dosage form, all approaches have the same aim, according to Schäfer, and many rely on same or similar excipients.

High-intensity sweeteners such as neotame and sucralose, for example, offer benefits for any formulation type as they are safe, sugar-free, non-cariogenic, and effective in cost and use due to their high sweetness potency in both liquid and solid formulations, Schäfer comments. Mannitol, meanwhile, is also popular in pediatric formulations because it provides superior mouthfeel, which is particularly important for orally disintegrating tablets (ODTs).

There are some disadvantages to using excipients. Often a trial-and-error approach might be needed to identify the best mix of flavors and other additives to hide the bitterness of a particular API in a particular dosage form. In addition, all excipients, Assis says, should be evaluated for potential allergic and other side effects, particularly those that do not provide efficient masking effects and need to be used in large quantities. As a result, formulation development timelines can be extended.

Many advantages of film coating

Functional film coatings are used to prevent direct contact of the drug substance with the tongue, thereby avoiding an unpleasant taste sensation, according to Assis. Reverse-enteric polymers, such as methyl-methacrylate and diethylaminoethyl methacrylate copolymer (from BASF) are used for this purpose. “These film coatings are not soluble in saliva pH (pH 6.2 - 7.0), so they maintain the drug covered by the polymer. After swallowing, the film is immediately solubilized in the stomach for fast API release, allowing drug dissolution out of the coated core and its absorption in the stomach and intestine,” he explains.

These types of polymers can be applied to cover API particles, granules, pellets, tablets, and minitablets. The coating process can be performed using organic solutions or polymeric dispersions or suspensions in standard equipment like fluid beds and drum-coater machines, according to Assis. It is also possible to obtain coated particles through microencapsulation, high-shear granulation, melt coating, and spray drying.

Because the polymers have a high molecular weight, absorption is not expected, ensuring safety. Film-coating technology can be used for very strong APIs at low or high doses. One potential disadvantage is that solid drug formulations with large surface areas may involve lengthy coating processes. Optimization is possible, however, using a well-designed formulation and process parameters, according to Assis.

Lipophilic polymers such as ethyl cellulose and hydrophobic components such as carnauba wax are other alternatives, but they can impact drug absorption due to excipient insolubility and possible delayed release, Assis comments. “In addition to the need to confirm effective drug masking, formulators should guarantee complete drug solubilization and absorption to ensure bioavailability using suitable excipients,” he adds.

There are some potential disadvantages of API sequestration that Worthington notes. “Particle coating results in an increase in particle size that can result in a gritty texture. The presence of particulates can also encourage chewing as part of normal oral processing, which can lead to coating rupture and release of the API into the oral cavity. Multiparticulate formulations, if added to foods with physicochemical properties (e.g., pH, water, sugar, fat, and flavor content) that can interact with pH-sensitive polymers, may also have a negative effect on palatability,” he explains.

Several other advances

New dosage forms are improving the viability of oral solid dosage forms for pediatric use. Hopper points to advances in mini-tablets, multi-layer beads, and ODTs, all of which allow for dose flexibility and improved compliance due to improved palatability and ease of administration. “These new innovation areas make flexible dosing based on age and weight possible, leading to increased dosage form acceptability and safety,” he observes.

Schäfer highlights oral thin films, which he says have become more popular due to their ability to overcome swallowing difficulties associated with traditional oral solid dosage forms while also enabling taste masking. Mini-tablets, he adds, have been shown in some studies to be superior to liquid formulations (6).

Use of titanium dioxide in Europe

Titanium dioxide is widely used in tablet formulation as a white colorant and opacifier to ensure a uniform appearance. Toxicological concerns about nanoparticulate titanium dioxide and its ban from use in foods and nutritional supplements in the European Union have led to increased interest in suitable alternatives to titanium dioxide for use in drug products, Schäfer observes. MilliporeSigma has for this purpose developed a particle-engineered calcium carbonate with a unique morphology and designed particle size distribution that provides uniform tablet finishing and good opacity.

Pilot program for novel excipients

Using novel excipients can be challenging given the lack of a separate approval pathway. Currently, new excipients can only be approved within a drug formulation, and drug developers are generally hesitant to risk approval by using a novel excipient.

FDA’s Center for Drug Evaluation and Research (CDER) has launched a new pilot program for the review of novel excipients. BASF and Senopsys support CDER’s pilot program. “Many pharmaceutical technologies and excipients trace their roots to the food industry. Co-processes, sustained-release flavor and sweetener systems like those used in confectionary and chewing gum products could potentially be used with great effect in drug products, particularly with APIs with long aftertastes, such as clarithromycin and many others. Such excipient developments have been to date hindered by the current lengthy approval pathway,” says Worthington.

Innovative options

Signal interruption, one of the five main approaches to improving palatability noted by Worthington remains, he says, a “Holy Grail” of taste masking. Bitterness is detected by a family of several dozen receptors (TAS2Rs), and APIs generally activate multiple TAS2Rs simultaneously, making development of signal interruption solutions challenging.Bitter blockers work by biochemically interfering with the taste transduction from the mouth to the brain via an antagonist that inhibits a specific bitter receptor site, blocking the taste cascade (interrupting the G-protein coupled receptor, or GPCR, signal cascade) (3), notes Assis.

This approach is challenged by the large number of different bitter taste receptors and their high genetic diversity. Trial and error is often required to identify compounds that follow the same receptor pathway as the API, leading to longer development times, Assis notes. There are novel compounds under development that act as antagonists to these receptors, Worthington notes, but the technology is still in its infancy, and the regulatory risk is high and commercialization timelines are unknown.

Schäfer is interested in the potential of three-dimensional (3D) printing for the production of pediatric medications, as it offers the opportunity for tailored dosage forms and can be implemented for the manufacture of age-appropriate solutions. Assis adds that 3D-printing technologies enable the manufacture of pharmaceutical dosage forms according to patient requirements, such as dose, release profile, color, texture, and size, which are all highly relevant to pediatric drugs. “With production via direct powder or filament-based extrusion combined with a functional taste-masking polymer or a lipidic, this approach can provide the right taste-masking,” he states.

For parenteral pediatric products administered in a clinical setting, there is a need for technologies that enable the administration of higher doses in smaller volumes to children, according to Schäfer. One new development in this field is MilliporeSigma’s Viscosity Reduction Platform, which allows for highly concentrated, small-volume protein formulations to be administered to patients.

Overcoming swallowing issues

The most challenging topic when formulating a pediatric drug is developing suitable options to overcome swallowing issues with an appropriate taste for better convenience and compliance. Worthington agrees that palatability and swallowability will continue to be a challenge for not only pediatric populations, but increasingly for geriatric and special needs populations as well.

Easier-to-swallow dosage forms, however, increase the opportunity for contact with oral cavity receptors—gustatory (taste buds), smell (olfactory receptors), and irritation (chemoreceptors). “Accordingly,” observes Worthington, “many of these alternative, age-appropriate dosage forms have increased palatability challenge compared to traditional tablets and capsules.”

“Defining the most efficient taste-masking approach to hide or minimize the unpleasant taste of a drug, aiming to improve patient adherence to treatment when taste is the main reason for non-compliance, still needs further understanding and research,” Assis contends. Improvements in taste masking and bioavailability enhancement, Hopper believes, will continue to be critical. “As our understanding of how the pharmacokinetics can change within different age populations, it will make flexible dosing and potentially different release profiles even more important,” he states.

References

1. Litalien, C.; Bérubé, S.; Tuleu, C.; Gilpin, A.; Landry, ÉK; Valentin, M.; Strickley, R,; Turner, MA. From Paediatric Formulations Development to Access: Advances Made and Remaining Challenges. Br J Clin Pharmacol. 2022 Oct; 88(10):4349-4383.
2. Mennella, J. A. and N. K. Bobowski. The Sweetness and Bitterness of Childhood: Insights from Basic Research on Taste Preferences. Physiol Behav 2015 152(Pt B): 502-507.
3. Walsh, J.; Cram, A.; Woertz, K.; Breitkreutz, J.; Winzenburg, G.; Turner, R.; Tuleu, C.. European Formulation Initiative. Playing Hide and Seek with Poorly Tasting Paediatric Medicines: Do Not Forget the Excipients. Adv Drug Deliv Rev. 2014 Jun;73:14-33.
4. Wiener, A.; Shudler, M.; Levit, A.; Niv, MY. BitterDB: A Database of Bitter Compounds. Nucleic Acids Research. January 2012.
5. Senopsys LLC. Taste Masking Challenge of 150 API. April 13, 2023.
6. Klingmann, V., H. Linderskamp, et al. Acceptability of Multiple Uncoated Minitablets in Infants and Toddlers: A Randomized Controlled Trial. J Pediatr 2018 201: 202-207.e201.

About the author

Cynthia Challener, PhD is a contributing editor for Pharmaceutical Technology Group.

Article details

Pharmaceutical Technology
Vol. 47, No. 8
August 2023
Pages: 20–25

Citation

When referring to this article, please cite it as Challener, C. Overcoming Challenges to Formulation Development for Pediatric Medicines. Pharmaceutical Technology, 2023, 47 (8) 20–25.