By Lynn Gold, PhD, vice-president of CMC services and Kenneth V. Phelps, president and CEO, both with Camargo Pharmaceutical Services, and Peter R. Joiner, CEO of Madeira Therapeutics.
Overview of pediatric drugs. There is a profound need for pharmaceutical products that have been tested and approved safe and effective for use by children. From 1973–1997, the percentage of approved drugs that contained no labeling information for children remained fairly stable at 71–81% (1). Of the 33 new molecular entities approved in 1997, 27 had potential for pediatric use, but only nine contained any pediatric labeling information (2). Two-thirds of the drugs that currently are prescribed to children have not been studied and labeled for pediatric use (3).
With so few medicines containing adequate labeling information to guide their use, off-label use of medicines has become, unfortunately, a necessary and accepted part of pediatric medical practice (4). Off-label prescribing includes the use of drugs for unapproved indications, in a different age group, or with a different dosage, frequency, or route of administration. Off-label prescribing also includes the administration of extemporaneous formulations (e.g., oral suspensions made from adult tablets) with untested bioavailability and stability.
Legislative activity. Recognizing the need to have a determination of pediatric applicability and adequate labeling instructions for children, Congress included incentives for conducting needed studies in the Food and Drug Administration Modernization Act of 1997 (FDAMA). Due to slow progress, Congress added additional incentives in the Best Pharmaceuticals for Children Act (BPCA) in January 2002. In essence, this act provided the innovator a six-month extension of exclusivity if adequate pediatric studies were performed and allowed FDA to formally request that such studies be performed. In 2003, Congress passed the Pediatric Research Equity Act (PREA), which provided FDA with the authority to use bridging data from adult studies in approving pediatric medicines. These three acts, together with continuing enabling legislation through the Prescription Drug User Fee Act (PDUFA) renewals, encourage the development of pediatric drugs. The Food and Drug Administration Amendments Act (FDAAA) of 2007 extended and amended BPCA and PREA.
Until these acts (BPCA, PREA, and FDAAA) were passed, the approach in pediatric drugs was first to develop a drug for adults and then adjust the dose to suit children. The thinking was if a drug were safe enough for adults, it would be safe enough for children. The three acts (BPCA, PREA, and FDAAA) make the development of an "age-appropriate formulation" a legal requirement if the drug under development is appropriate for children.
Penicillamine is a good example of a less-than-optimum formulation for pediatric use. Penicillamine tablets are too large for children and have to be crushed to administer them to children, leading to uncertainty of the actual dose delivered. Dosing of penicillamine is also required for extended time periods. The crushed tablet is foul smelling, and the taste and odor are unpalatable (5).
Pediatric drug development . The goal for any new drug product is a safe, effective dosage form that facilitates maximum compliance through the course of treatment. Formulations for pediatrics usually must cover a broad age range. Drugs that must be dosed based on body weight or endocrine status (e.g., puberty) require either solid doses that are scored or different doses. Children under 12 years of age often have difficulty swallowing capsules and/or chewing tablets. A liquid formulation, therefore, is often chosen for pediatric administration. Liquid formulations facilitate dose titration and are easily administered. Liquid formulations, however, have certain constraints. Taste is an important issue for pediatric formulations, and the more frequent the dosing, the more critical this issue can be. Stability of the liquid in multiple-dose bottles must be maintained, often by using preservatives. Taste-masking agents, preservatives, and solubilizing excipients must have an acceptable safety profile in pediatrics.
Special considerations must be taken to reformulate currently approved adult drugs to be a pediatric friendly product. As an example, Madeira Therapeutics is developing a pediatric formulation of a marketed statin for a population with an inherited cholesterol gene that often leads to early heart disease (6). This product requires flexibility in dosing as the amount of drug required can be variable. To meet the requirements of a flexible dose level and integrate the characteristics of the active pharmaceutical ingredient (API), an oral syrup formulation was identified as the target formulation. As expected, many of the formulation steps are the same as with any drug-development program. The physical and chemical properties, such as solubility, salt form, stability, and the taste of the API must be known or established.
The major difference for a pediatric formulation compared with an adult formulation is an added layer of investigation when choosing excipients. The traditional sources, the generally regarded as safe (GRAS) list (i.e., 21 CFR Parts 182, 184, and 186) and FDA's Inactive Ingredients Guide are based on the safety obtained primarily in adult subjects. Investigation into the safety data in the pediatric population available for the potential excipients to be used should be performed. The specific excipients chosen must be determined based on the drug under development as well as the pediatric product profile under consideration.
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.
- 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.
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., www.medicinescomplete.com.
14. FDA, Inactive Ingredients Guide, Rockville, MD, www.accessdata.fda.gov/scripts/cder/iig/index.cfm.
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).
By Martha S. Sloboda, business manager with ARx LLC, a subsidiary of Adhesives Research.
The oral thin film (OTF) platform is a proven and accepted form of drug delivery for pediatric products. Its premeasured format provides an accurate and easily ingested dose without water that allows for portable and convenient "give and go" administration by a parent or caregiver. Patient compliance can be improved because of an OTF's ease of administration and subsequent difficulty in expectoration. The dosage format offers flexibility in base chemistry and base formulation development from raw material selection to final packaging configurations as well as an established and well-understood manufacturing path. Based on the continuous nature of production, formulators can also approach pediatric films as either unique, single-product formulations, or as a dosage modification of a preexisting product.
Tolerability and disintegration. Beyond efficacy, most OTF development for pediatric products focuses on two key attributes: tolerability and disintegration. Depending on the age range, region, and marketing needs, formulators can uses various flavors and compendial excipients to create a child-friendly formula. They can also choose to develop dye-free and alcohol-free products, add sensory components such as heating or cooling sensations, and/or modify texture. Different taste-masking approaches can be incorporated, and the dosage unit area can be modified to hit specific taste and disintegration profiles ranging from less than five seconds to multiple minutes. Additionally, dissolvable films may be formulated to demonstrate adhesion properties for use with other devices currently used by younger populations to deliver medications or vitamins. With a standard active pharmaceutical ingredient (API) loading level of 50% of the final unit mass and an adjustable final unit area, formulators have a lot of latitude in both how much API can be loaded and how other product attributes can be tailored for each product.
Oral thin-film delivery via a pacifier
By Theodore Clemente, Jr., vice-president of business development with MonoSol Rx.
The pediatric population represents one of the most challenging patient groups for administering drugs as compliance, proper dosing, and safety are difficult to manage with most standard modes of drug delivery. Thin-film dosage-form technology has become more prominent in pediatrics because it provides an accurate, convenient, and effective way to deliver medications to infants and young children. Thin films are easy to administer and fast-acting and does not require the patient to actively swallow or chew the dosage unit as is required with a liquid or chewable tablet. Thin film is a highly flexible drug-delivery technology. The strips can be manufactured to different sizes and tastes, can carry various drugs, and be applied to a host of surfaces within the oral cavity to enable the desired drug delivery outcomes.
An infant's natural propensity to suckle makes pacifiers and bottle nipples useful devices for administering medication and vitamins. MonoSol Rx has developed a patented technology for administering film dosage units to infants and young children using this approach.
The system relates to the delivery of drugs and/or vitamins contained in a thin film that is attached or placed inside of a pacifier or porous nipple member such as the tip of a baby bottle. Affixing a quick dissolving thin film into the porous nipple of a bottle or pacifier ensures that the active ingredient is immediately released into the oral cavity upon contact with saliva or liquid from the bottle. Delivery of a complete and accurate dose is confirmed as the thin film dissolves and disappears from the inside surface of the pacifier or porous nipple.
Distinct attributes of the thin-film dosage also make it advantageous for pediatric use without the pacifier or nipple member delivery method. Since the polymeric films are very thin (i.e., typically 50 to 150 microns), the technology ensures rapid disintegration due to a larger surface area for wetting and subsequent dissolution. It is virtually impossible for a film strip to be swallowed intact when placed on the tongue because the rapid wetting of the film generally causes adhesion to the tongue or other oral mucosal surface immediately. The film quickly dissolves and is ingested along with the saliva into the gastrointestinal tract.
Thin-film drug-delivery also offers the potential for reduction of dosing errors in a healthcare-provider setting because the dosage forms are usually supplied in printed individual pouches. The thin quick-dissolving film and low-dosage mass also allow for a shorter residence time in the oral cavity, which eliminates the possibility of the child spitting out the medication.
Thin film is likely to play a larger role in pediatric drug delivery in the future. Likely applications will include the delivery of prescription drugs, oral vaccines, nutritional supplements, and over-the-counter medications .