Pediatric Formulations

It has long been recognized that the therapeutic needs of children are sufficiently different than those of adults as to require specific studies of medications in children. Since most children are healthy and do not suffer of many diseases as do adults, the market of drug for children is small relative to the market of medications for adults. Market forces continue to be de driver for research and development of new medications. Since those market forces are small in children, the pediatric population was at a disadvantage before the laws providing pediatric exclusivity were approved. Historically, many children have been treated with medications for which there is not sufficient information in their labels, the so call off-label use [1]. According to the American Academy of Pediatrics, “Unapproved use does not imply an improper use and certainly does not imply an illegal use [2].” Often these drugs are used by means of an extemporaneous formulation that facilitates intake [3,4]. However, it has been recognized that off-label use and extemporaneous formulation use is not ideal. For this reason, the US government in 1997 and more recently the European Union in 2006, approved laws creating incentives for companies to do the necessary research in children. For the most part, these laws have been successful in generating new scientific data in the appropriate usage of medications in children [5,6,7]. One key ingredient in the generation of new data is to have the appropriate formulation. The appropriate formulation allows children to participate in clinical trials for dose finding, efficacy and safety. Children are a very heterogeneous population that includes newborns (term or pre-term), infants, toddlers, pre-schoolers, school-age children, and adolescents [8]. Therefore, there is a need to develop for the same active drug, different formulations for appropriate testing in clinical trials and eventually the production of distinct drug products appropriate for all the pediatric subpopulations that will use the products.

Ideally, pediatric formulations should be bioequivalent to the formulation used in adults, typically a solid in the form of a tablet or capsule. Achieving bioequivalence is not always possible but remains an important aim in order to make the formulations interchangeable. However, if bioequivalence is not possible, appropriate pediatric formulations may still be appropriate [9]. In this case, appropriate labeling will inform the prescriber how to transition from one to another formulation. Fortunately, many children, school-age and adolescents, can swallow tablets or capsules. Therefore, no special formulation may be necessary for them as long as the solid form has a dosage that is appropriate for their stage of development. For younger children or for those not able to swallow solid forms, alternative formulations are necessary. Liquid formulations (solutions, suspension, syrups, etc) have been popular because of the ease of administering them to children of different ages and the ease of dosing more precisely according to body weight or body surface area. Unfortunately, liquid formulations tend to be less stable over time than solid ones. The relative scarcity of appropriate solvents makes the development of a liquid formulation very challenging. Liquid formulations also require appropriate taste masking, which is extremely important to optimize patient’s compliance. There are formulations other than liquid that are appropriate for young children: chewable tablets, fast dissolving tablets, sprinkles, powders, and other oral forms. There are also formulations with alternative routes of administration: transdermal, suppositories, and parenteral.

Since pediatric drug development is now an integral part of the development of any new drug, it is important that formulations suitable for children are considered and explored early in the development of the drug [10]. Initial clinical testing of a pediatric formulation may need to be done in adults to demonstrate acceptable bioavailability and palatability. Once a formulation is chosen based on preliminary testing in adults, initial clinical trials in children may occur once the safety and efficacy of the drug product in adults has been demonstrated. It would not be appropriate to expose children to experimental drugs without a good understanding of the risk and benefits data from adults [11].

For a given drug, it may be necessary to develop more than one formulation to provide appropriate access to all pediatric groups in which research will be conducted. Eventually all these pediatric subpopulations may need access to those formulations if the benefit-risk is found to be acceptable. Efforts are made to optimize the number of formulations to study and eventually market. It would be preferable to find one formulation to cover the entire pediatric age in order to minimize potential dosing errors that occur when multiple formulations of the same active ingredient exist. If a more concentrated formulation is necessary, typically for younger pediatric patients, a distinct formulation needs to be developed to differentiate it from the other formulation(s) used in another, typically older, pediatric population.

Formulations are also developed for different populations of the world with different preference on taste, color and texture. There are parts of the world in which refrigeration is not readily available and climates have extreme temperatures and high levels of humidity that may have an impact on the chemical and physical stability of the formulation. Therefore, formulation development for children should satisfy the needs of patients of different ages and the preferences of patients in different parts of the world. A single formulation may not be able to satisfy all these needs. Therefore, the development of several formulations may be necessary. This may have financial implications for the entire program. Because the financial implications are significant, companies try to protect their investment by ensuring intellectual property rights to their formulations. The economical challenges of developing a new pediatric formulation are probably best illustrated in a paper by Milne and Bruss in which they discussed the financial implications of developing pediatric formulations for off-patent drugs [12].

As stated by Thompson, “the objective of formulation development is providing formulations that have sufficient bioavailability, safe excipients, acceptable palatability, acceptable dose uniformity and stability. The defined formulation has guidance for easy and safe administration with precise and clear product information including clinical data to support use in the target patient population [3].” We will elaborate on some of these objectives.

The vast majority of pediatric formulations are for oral administration. McNally and Railkar state that 90% of pediatric dosage forms are for oral administration [13]. The majority of these, are liquid dosage forms. Liquid formulations for oral administration can be solutions, suspensions, syrups, elixirs and emulsions. These are formulations suitable for children who cannot swallow oral solid forms. The dose volume is an important consideration for the appropriateness of a liquid formulation. According to Breitkreutz, Tulue, and Solomonidou, the target dose volumes for pediatric liquid formulations are < 5 ml for children under 5 years of age and < 10 ml for children 5 years or older. These volumes are not only important for the palatability of the formulation but for the ability to accurately measure the appropriate volume to administer [14]. Solutions are preferred over suspension because they provide a homogeneous mixture which allows for more accurate dosing. Water is the most common solvent used but many active ingredients are not readily soluble in water. Therefore, other solvents such as alcohols, glycerin, polyethylene glycol and propylene glycol are also used. However, alcohols are typically avoided in pediatric formulations because of their toxicity especially to the very young. The majority of active ingredients have a bitter or otherwise unpleasant taste. Turning a bad-tasting formulation into a medicine acceptable to children is one of the biggest tasks in pediatric formulation development [15,16]. Newborns have fully developed taste buds, but the analytical skills of young children are not yet fully developed and they have greater difficulties to recognize tastes in mixtures than adults. Avoiding unusual flavors and complex taste mixtures therefore increases the probability that a formulation will be acceptable [10]. This can be achieved by avoiding the oral route of administration or by applying various ways of “masking” the bad taste. These may include coating of the active pharmaceutical ingredient (API) or, more easily achieved, of granules containing the API, or by adding sweeteners and flavors to the formulation. Sweeteners can be added in small quantities (e.g. aspartame) or larger amounts when also used as bulking agent (e.g. sucrose, high fructose corn syrup, sorbitol, maltitol, and xylitol). Considerations should be given on the amount of calories when larger volumes are to be administered over an extended period of time. When selecting a flavor for a pediatric formulation, the following should be considered: i) type of basic sensation to cover, e.g. acid, alkaline, bitter, salty, ii) type of disease, and iii) regional preferences. While “bubble gum” and “grape” are favorites in the US, “citrus” and “red berries” may be better accepted in Europe. McNally and Railkar described various coating techniques that have been applied to successfully reduce bad or bitter taste [13]. The selection of a taste masking concept should be further validated with a test panel, ideally made up with children. Since such palatability tests are considered clinical studies, approvals by an ethical review boards and consent from parents/guardians are required. Although there is a general desire to develop single, worldwide acceptable products, regional differences and preferences for flavor and color may result in the need for different formulations, should a product be intended for worldwide markets.

Table 1 - Example of Pediatric Formulations: Oral Solution & Suspension [McNally & Railkar, Ref 13]

There are other technical challenges that need to be considered in the development of an appropriate pediatric formulation. Active Pharmaceutical Ingredient: At the time of pediatric formulation development, the general quality attributes, specifications and corresponding acceptance limits of the active pharmaceutical ingredient have most likely been established and even approved by a health authority for use in the adult population. As a first step, the formulation developer has to assess the appropriateness of the API quality for the intended pharmaceutical formulation and use in a pediatric population. Depending on the intended route of administration and/ or type of formulation to be developed, different physical properties may be required, e.g. micronized API for oral suspension formulation. In certain cases, even a different salt form may have to be developed to obtain the desired characteristics, e.g. increased solubility in aqueous media. However, the gains from such improvements for formulation development may have to be balanced against the need to repeat the toxicological assessment program when a new salt form is selected. Particular attention may have to be given to impurities derived from the synthesis process, such as residual solvents, traces of heavy metals (from catalytic reactions in the synthesis steps) and potentially genotoxic impurities for which limits in the ppm range have to be established. Typically, an array of preclinical juvenile animal studies is conducted prior to conducting clinical studies in the pediatric population [17]. Excipients: The selection of appropriate inactive ingredients (excipients) is a critical step in pediatric formulation development. As mentioned before, pediatric formulations are often more complex and contain a larger number of excipients than formulations for adults. For illustration, two examples are given in Table 1. Achieving a good acceptance by young patients and their caregiver is key for good compliance, and ultimately for a formulation to be successful. This often requires a broad range of excipients that need to be carefully selected, e.g. to achieve taste masking. When dealing with oral liquids, several excipients may be needed as solvents, bulking agents, viscosity modifiers, wetting agents etc. to make a solution or suspension suitable for volumetric dosing. This may result in a higher potential for drug/excipient and for excipient/excipient incompatibilities and, thus adds to the complexity of preformulation studies. Also, excipients may contain (or develop over time) trace amounts of their own degradation products that may negatively impact the stability of the API, the color and/or the level of taste masking in the formulation. Examples are aldehydes and peroxides. Modern concepts of “design of experiment” (DoE) and “quality by design” (QbD) need to be applied to understand the robustness of such formulation and to establish the critical quality attributes of excipients to be used for routine manufacturing of the pediatric product. However, the low volume forecast for most pediatric products may limit the ability to negotiate with a supplier a special quality of an excipient, beyond what is commonly acceptable for other non-pharmaceutical customers. Certain excipients, acceptable in adult formulations, may not be adequate for pediatric use at all, e.g. ethanol in oral liquids or benzyl alcohol in intravenous formulations for neonates. Also, attention needs to be given to residual solvents and other “carry-overs”from excipients that may be ending up in pediatric products. ICH limits on residual solvents may not be acceptable for certain solvents (e.g. ethanol residue from a film coating process) when dealing with pediatric formulations. Certain excipients may be considered “functional excipients” when they are responsible for a critical product property, e.g. providing enteric coating (protecting the active ingredient from stomach acids) or defining the rate of release of the active ingredient from an “extended release” formulation. In such cases, additional tests may have to be developed to assure adequate quality of incoming raw materials used in manufacturing and consistent performance of the resulting drug product. In addition, if an excipient has not already been accepted for use in pediatric formulations, toxicological qualification (in juvenile animals) has to be considered.

Packaging/Dosing: Pediatric products need to be appropriately packaged to guarantee chemical and physical stability, to protect from microbial and other types of contamination, and to make storage and handling easy for care givers. Child-resistant packaging is also required, even though the product is intended for children. In the case of liquid formulation, the use of appropriate dosing devices is important to support accurate dosing by volume. Dosing devices (droppers, measuring cups, graduated pipettes etc.) should be part of the pediatric product and provided by the manufacturer to avoid the use of household spoons and other inappropriate measuring devices [13].

Many pediatric products are reconstituted with diluents or mixed with foods prior to administration. This requires that clear and very specific instructions are provided in the packaging insert and that the compatibility and stability with diluents and foods has been studied during formulation development.

The development of an appropriate pediatric formulation is a complex task that requires multiple considerations. Therefore, it is appropriate that drug developers consider possible pediatric formulations early in the drug development process. A natural point in time would be at the same time a solid oral form is being considered for adults. This will allow for an appropriate consideration of adolescents and pre-adolescents as potential users of such a solid oral form. It is also important to assess all the possible formulations that will be needed for the entire spectrum of the pediatric population. By developing appropriate pediatric formulations, we can make off-label use of drugs and use of extemporaneous formulations things of the past.

References

1. Blumer JL. Off-Label Uses of Drugs in Children. Pediatrics 1999;104;598-602
2. American Academy of Pediatrics, Committee on Drugs. Unapproved uses of approved drugs: the physician, the package insert and the Food and Drug Administration: subject review. Pediatrics 1996;98;143-145
3. Thompson KC. Extemporaneous Formulations: Comparison with Labeled Pediatric Formulations. American Pharmaceutical Review, January/February 2010
4. Nahata MC, Allen LV. Extemporaneous Drug Formulations. Clinical Therapeutics 2008;30(11);2112-2119
5. Title V of USA Public Law 110-85, Best Pharmaceuticals for Children Act of 2007.
6. Title IV of USA Public Law 110-85, Pediatric Research Equity Act of 2007.
7. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of December 12, 2006 on medicinal products for pediatric use.
8. International Conference on Harmonization (ICH) – Guidance for Industry: E-11 Clinical Investigation of Medicinal Products in the Pediatric Population
9. Gal P and Gilman J. Therapeutic Drug Monitoring: Theoretical and Practical Issues in Pediatric Pharmacology, Therapeutic Principles in Practice by Yaffe and Aranda. Second Edition, W.B. Saunders Company.
10. Committee for Medicinal Products for Human Use (CHMP), European Medicines Agency (EMEA), 2005. “Reflection Paper: Formulations of Choice for the Paediatric Population.”
11. AAP Committee on Drugs. Committee on Drugs. Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations. Pediatrics. 2010;125(4):850-860
12. Milne C-P and Bruss JB. The Economics of Pediatric Formulation Development for Off-Patent Drugs. Clinical Therapeutics 2008;30(1)2146-2154
13. McNally GP and Railkar AM. Formulation of Pediatric Dosage Forms in Pediatric Drug Development, Concepts and Applications by Mulberg, Silver and van den Anker. 2009 by John Wiley and Sons, Inc.
14. Breitkreuz J, Tuleu C, Solomonidou D. Paediatric Formulations in Guide to Paediatric Clinical Research by K. Rose and J.N. van den Anker. 2007 Karger.
15. Cram A, Breitkreuz J, et. al. Challenges of developing palatable oral paediatric formulations. International Journal of Pharmaceutics. 2009;365:1-3
16. Mannella JA, Beauchamp GK. Optimizing Oral Medications for Children. Clinical Therapeutics 2008;30(11):2120-2132
17. Coogan T. Preclinical Safety Assessment in Pediatric Drug Development, Concepts and Applications by Mulberg, Silver and van den Anker. 2009 by John Wiley and Sons, Inc.

Author Biographies

Sam Maldonado, M.D., M.P.H., FAAP is the Vice President of Pediatric Drug Development Center of Excellence, at J& J PRD. Sam joined J&J in 2000 as Director of Pediatric Drug Development. He received his MD Diploma from the National University of Honduras and his MPH from George Washington University (GWU), Washington, D.C. He trained in pediatrics at Henry Ford Hospital in Detroit, MI, and in pediatric infectious diseases and regulatory medicine at Children’s National Medical Center, George Washington University and the Food and Drug Administration (FDA) in Washington, D.C., respectively. He then joined the FDA as a Medical Officer in the Division of Anti-Infective Drug Products and subsequently in the Division of Antiviral Drug Products. After leaving FDA, he worked in clinical drug development at Boehringer-Ingelheim in Connecticut for 2 years from where he joined J&J. Sam chairs PhRMA’s Pediatric Committee since 2003. Sam also worked with staff members of several US Congressman and Senators on the importance of renewing the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. President Bush signed both pieces of legislation into law in September 2007.

Dr. Maldonado’s experience in pediatric drug development expands over 19 years, of which 8 he served as Medical Officer at the FDA and the last 11 in Industry.

Daniel Schaufelberger is a Global CMC Project Leader, in Pharmaceutical Development and Manufacturing Sciences at Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan NJ. He attended the School of Pharmacy at ETH Zurich, Switzerland and obtained his Ph.D. (Docteur en Pharmacie) at the University of Lausanne, Switzerland. Following post-doctoral appointments in natural product/cancer research at Arizona State University (Grant by the Swiss National Science Foundation) and at the Frederick Cancer Research & Development Center (National Cancer Institute), he joined Analytical Research & Development at Sandoz Pharma AG in Basel, Switzerland. In 1993, he accepted a position at Johnson & Johnson’s Pharmaceutical Research Institute in Schaffhausen, Switzerland, and later relocated to New Jersey. More recently, he has been leading internal and external CMC projects, including partnering with Japanese companies, to develop new products for our youngest patients.