Pediatric Formulations: Technical and Regulatory Considerations - Pharmaceutical Technology

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Pediatric Formulations: Technical and Regulatory Considerations
Leading experts share their perspective on the specialized requirments when developing a pediatric formulation and examine dosage forms that can be used for this patient class in this roundtable moderated by Patricia Van Arnum.

Pharmaceutical Technology

Section references

1. J.T. Wilson et al., "Pediatric Labelling Requirements. Implications for Pharmacokinetic Studies," Clin. Pharmacokinet. 26 (4), 308–325 (1994).

2. N.Y. Rakhmanina and J.N. van den Anker, "Pharmacological Research in Pediatrics: From Neonates to Adolescents," Adv. Drug Deliv. Rev. 58 (1), 4–14 (2006).

3. US Government Accountability Office (GAO), "Pediatric Drug Research: Studies Conducted under Best Pharmaceuticals for Children Act," GAO-07-557, March 2007.

4. R.L. Smyth and A.D. Edwards, "A Major New Initiative to Improve Treatment for Children," Arch. Dis. Child. 91 (3), 212–213 (2006).

5. D.P. Lombardi, "Novel Organizational Strategies for Advancing Pediatric Products: Business Case Development," in Pediatric Drug Development: Concepts and Applications, A.E. Mulberg, S.A. Silber, and J.N. van der Anker, Eds. (Wiley–Blackwell, April 2009), p. 74.

6. B.W. McCrindle, "Screening and Management of Hyperlipidemia in Children," Pediatr. Ann. 29 (8), 500–508 (2000).

Development of palatable formulations for children

By Jeff Worthington, president, and David Tisi, technical director, both with Senopsys, and Susan Lum, principal scientist of pharmaceutical development services (PDS) and pharmaceutics, and Kwok Chow, PhD, senior director of global PDS technology and alliances, both with Patheon.

Figure 1: A typical development program for a pediatric formulation. GCP is good clinical practices; API is active pharmaceutical ingredient. (FIGURE 1 IS COURTESY OF PATHEON AND SENOPSYS)
Many existing medicinal formulations are not designed as suitable for children. Therefore, the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act were introduced in the United States, and legislation governing the development and authorization of medicines for use in children was also recently introduced in the European Union to stimulate pediatric formulation development through a combination of market incentives and regulatory requirements (1–3). The goals of these initiatives, however, are difficult to reach if the challenges in pediatric formulation and taste optimization are not well managed (4). A majority of formulations for children have complex compositions in a less desirable physical state, (e.g., liquid state) to provide dose flexibility and facilitate dose administration (e.g., ease-of-swallowing). These formulations are more susceptible to taste, physical, chemical, microbiology, and pharmacokinetics issues than those of conventional solid oral dosages for adults. Advanced knowledge in formulation (e.g., reaction kinetics, physical chemistry of drug solubility and forms, and special technologies for taste-masking), taste assessment/optimization, and biopharmaceutics are required.

A hallmark of many successful pediatric formulation development programs is an integrated team of formulation and sensory scientists. As illustrated in Figure 1, a typical development program for pediatric formulations involves:

  • An exploratory and preparation stage for the development team consisting of formulation and sensory scientists to provide interdisciplinary input on formulation composition, and sensory characteristics (e.g., basic tastes, aroma, texture, mouthfeel, and aftertaste) to clearly define the development strategy
  • An experimental stage for the development team to establish viable options
  • An optimization stage to finalize the formulation and establish product, process, and design space; for example such as for preservative levels
  • A confirmatory stage to verify the flavor quality (i.e., palatability) of formulations (e.g., on aged products) and conduct stability/clinical/bioavailability programs in preparation for product registration.

Figure 2: A decision tree for selecting the formulation and technology for a pediatric drug. (FIGURE II IS COURTESY OF PATHEON AND SENOPSYS)
It is important for the project team to define the strategies to address excipient compatibility, physical and chemical stability, taste, preservative, bioavailability, regulatory, and packaging issues as early as possible (5). A decision diagram for the selection of formulation and technology for pediatric formulations is provided in Figure 2. For excipient compatibility, it is unlikely that all combinations of excipients can be tested. To reduce technical risk and late-stage setbacks, an approach based on drug substance chemistry, drug/excipient sensory characteristics, excipient properties, and statistical design-of-experiments is recommended to generate data to set the direction for taste-masking and dosage-form selection and development. The excipients, including colorants, sweeteners, and flavors for consideration can be based on several acceptance criteria. These factors include regulatory acceptance; toxicity; function such as mouthfeel, viscosity and taste; disease state (acute versus chronic, and the disease itself); administration (dose strength, volume, and frequency); patient population; market potential; and dosage-form characteristics (6). For example, the use of sucrose may be more suitable for acute therapy than for long-term therapy such as in the treatment of HIV, provided patient compliance is not compromised. The decision in choosing excipients must be balanced and not overly constraining. Trade-offs should be identified and carefully considered by all stakeholders (e.g., clinical, regulatory, pharmaceutical development, and marketing (see Figure 2). For example, pediatric drug products often need more than one type of sweetener and taste modifier to effectively mask the bitterness of the active pharmaceutical ingredient (API) that is strong in intensity and long in duration. Nutritive sweeteners and sugar alcohols alone do not provide lingering sweetness. High-intensity sweeteners do not provide bulk, build viscosity, or provide beneficial mouthfeel effects and as such do not work in most systems by themselves.

The development of palatable drug formulations requires human input for taste assessment and optimization. Sensory analysis methods are applied to create great tasting food products for decades and are increasingly being adopted in the pharmaceutical industry to develop palatable drug products. With qualified taste panels, analytical sensory tests are used to accurately identify and quantify perceived sensory characteristics of APIs, excipients, and products under controlled laboratory conditions to guide development programs (7, 8). To minimize exposure to drug substances, proper precautions, including good clinical practices for investigational new drugs, are taken to ensure the safety of the evaluators. For example, "sip and spit" tasting protocols and the use of surrogates of generally recognized as safe (GRAS) ingredient compositions are employed. Human taste panels require proper calibration, standardized sampling procedures, and reference standards to generate objective and reproducible data. Knowledge of flavor construction is required to properly translate the data to pediatric drug products. Instrumental taste measurement is finding application in quality control to detect lot-to-lot variations and reduce the sample testing burden on human taste panels. However, there are comparatively few applications of these instrumental techniques in formulation development owing to the general lack of API-specific data correlating human taste panel with instrumental output.

Table I: Sensory characteristics of common pharmaceutical excipients used in pediatric formulations. (TABLE I IS COURTESY OF PATHEON AND SENOPSYS)
Excipient selection. Developing a palatable drug product entails considerably more than adding flavors and sweeteners to overcome an unpleasant taste of an API. Excipients often contribute significantly to the palatability of the final product (see Table 1). For example, many excipients such as surfactants and solvents that are used in liquids for low-solubility drugs, are known to create taste-masking challenges. The development of patient-acceptable pediatric drug products need not be left to trial and error. Applying appropriate design-of-experiment techniques, a multidisciplinary team of formulation and sensory scientists with knowledge and understanding of the principles of flavor construction and the sensory characteristics as well as the pharmaceutical applications and properties of excipients can effectively and efficiently develop palatable pediatric drug products.

Many oral liquid products are developed as an afterthought after a solid oral product is developed with the objectives of achieving bioequivalence and identical shelf life. Achieving bioequivalence can be challenging, especially when the drug substance has first-pass metabolism and/or a narrow absorption window. The product stability and impurity profile will likely be affected if the drug substance is sensitive to oxidation, hydrolysis, polymorphic changes, and formation of solvates. The formulation and taste optimization strategies often need to be adjusted to these product performance objectives. For example, a nonaqueous liquid, suspension, or powder for reconstitution may be required to meet the stability or bioavailability requirements. Certain excipients that can influence gastric emptying or gastrointestinal transit such as mannitol, may need to be avoided in taste optimization for drug substances with potential bioavailability issues (9).

Table II: Selection of excipients for oral pediatric formulations, contributions to osmolar laxative effects and carbohydrate content at nominal usage (Section references 10–22). (TABLE II IS COURTESY OF PATHEON AND SENOPSYS)
The choice of excipients for pediatric formulations should also be based upon toxicity concerns, regulatory acceptability, and flavor development. For example, sweeteners and their levels can be judiciously chosen with respect to contribution to osmotic diarrhea and energy intake (e.g., for children with Type I diabetes). Although low-molecular-weight polyols add to osmotic load, they are nonnutritive, noncariogenic, and low in carbohydrate content. The osmotic effects of disaccharide-type alcohols present generally fewer gastrointestinal effects than polyols of lower molecular weight, but they can still be used therapeutically as laxatives (e.g.. lactulose (9). Sucrose is digested by enzymes in the small intestine into fructose and glucose, which are then rapidly absorbed with minimum osmolar laxative effects. The usage level, osmotic contribution, and the energy impacts of a partial list of common excipients are provided in Table II (10-22).

A good understanding of the technical, clinical, regulatory and market requirements using a multidisciplinary development approach, with solid scientific principles is critical for developing formulations that meet today's needs in pediatric medicine.

Section references

1. Public Law 107-109, "Best Pharmaceuticals for Children Act," (Washington, DC), 2002.

2. Public Law 108-155, "Pediatric Research Equity Act" (Washington DC), 2003.

3. Regulation No. EC 1901/2006, European Parliament and the Council, European Commission (Brussels), Dec. 12., 2006.

4. EMEA/CHMP/PEG/194810/2005, "Reflection Paper: Formulations of choice for the Pediatric Population," European Medicines Agency, July 28, 2006.

5. R.G. Strickley et al., "Pediatric Drugs: A Review of Commercially Available Oral Formulations," J. Pharm. Sci. 97 (5) 1731–1774 (2008).

6. M. Meilgaard, G. Civille, and B. T. Carr, Sensory Evaluation Techniques (CRC Press, Boca Raton, FL , 3rd edition, 1999).

7. A.J. Neilson, V.B. Ferguson, and D.A. Kendall, "Profile Methods: Flavor Profile and Profile Attribute Analysis," in: Applied Sensory Analysis of Foods, Vol. 1., Moskowitz, H., Ed. (CRC Press, Boca Raton, FL, 1988).

8. A. Cram et al., "Challenges of Developing Palatable Oral Pediatric Formulations," Int. J. Pharm. 365 (1–2), 1–2 (2009).

9. D.A. Adkin et al., "The Effects of Pharmaceutical Excipients on Small Intestinal Transit," Eu. J. Clin. Pharmac. 39 (4) 381–387 (1995).

10. T.E. Edes and B.E. Walk, "Nosocomial Diarrhea: Beware the Medicinal Elixir," South. Med. J. 82 (12), 1497–1500 (1989).

11. M. Gracey and V. Burke, "Sugar Induced Diarrhea in Children," Arch. Dis. Child. 48 (5), 331–336 (1973).

12. T.H. Grenby, Advances in Sweeteners, Blackie Academic & Professional (Chapman & Hall, London, 1996), pp. 288.

13. Handbook of Pharmaceutical Excipients, R.C. Rowe, P. J. Sheskey, S.C. Owen, Eds. (American Pharmacists Association and Pharmaceutical Press, Washington, DC), 2006, for online ed.,

14. FDA, Inactive Ingredients Guide, Rockville, MD,

15. G.A. Koutsou et al., "Dose-Related Gastrointestinal Response to the Ingestion of Either Isomalt, Lactitol or Maltitol in Milk Chocolate," Eu. J. Clin. Nutr. 50 (1), 17–21 (1996).

16. G. Livesey, " Tolerance of Low-Digestible Carbohydrates: A General View," Br. J. Nutr. 85 (Suppl. 1), S7–S16, 2001.

17. H. Mitchell, Sweeteners and Sugar Alternatives in Food Technology (Blackwell Publishing, Oxford, UK, 2006), pp. 413.

18. T. Oku and S. Nakamura, "Threshold for Transitory Diarrhea Induced by Ingestion of Xylitol and Lactitol in Young Male and Female Adults," J. Nutr. Sci. & Vitaminol. 53 (1), 13–20 (2007).

19. T. Oku T. et al. "Maximum Permissive Dosage of Lactose and Lactitol for Transitory Diarrhea and Utilizable Capacity for Lactose in Japanese Female Adults," J. Nutr. Sci. & Vitaminol. 51 (2), 51–57 (2005).

20. A. Ruskone-Fourmestraux et al., "A Digestive Tolerance Study of Maltitol after Occasional and Regular Consumption in Healthy Humans," Eu. J. Clin. Nutr. 57 (1), 26–30 (2003).

21. D.M. Storey et al., "The Comparative Gastrointestinal Response of Young Children to the Ingestion of 25 g Sweets Containing Sucrose or Isomalt," Br. J. Nutr. 87 (4), 291–297 (2002).

22. Y.M. Wang and J. van Eys, "Nutritional Significance of Fructose and Sugar Alcohols," Ann. Rev. Nutr. 1, 437–475 (1981).


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