Skip to main content
SpringerLink
Log in

Size and Taste Matters: Recent Progress in the Development of Age-Appropriate Medicines for Children

  • Review Article
  • Published:
Pharmaceutical Medicine Aims and scope Submit manuscript

Abstract

Drug therapy for children is one of the cornerstone developments that have sharply reduced childhood mortality. Despite this, many challenges remain in ensuring that children receive safe and effective drug therapy. There are unique issues in treating children with oral medication relating to development, existing formulations and medication acceptability. Medication acceptability in children is complex relating to a wide range of factors, including drug palatability. Over the past decade there has been an increasing interest in and research as to how to improve and enhance child-specific drug formulations including the development of specific instruments for assessing drug palatability in children and new approaches to teaching medication literacy to families. Approaches to enhancing drug acceptability have also included organoleptic (taste masking) strategies as well as the creation of a number of innovative taste-blocking strategies and new technologies for formulation preparation. Polymer coating, microencapsulation and heat melt technologies have resulted in drug formulations that are now being assessed in children while soft melt and gel formulations are now commonly used. Mini-tablets offer the potential of using solid delivery systems in even very young infants. This work has resulted in a number of highly promising developments that are being evaluated for clinical use as well as providing insights into new directions in pursuit of the common goal of effective and safe drug therapy for children. On-going challenges include the need for drug regulatory agencies to work closely with drug regulatory agencies in facilitating innovation in formulation design and approval.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Derived from Rieder [2], Baguley et al [25], Zajicek et al [27], Tuleu et al [51] and Mistry et al [58]

Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Weinshilboum R. The therapeutic revolution. Clin Pharmacol Ther. 1987;42:481–4.

    Article  CAS  PubMed  Google Scholar 

  2. Rieder MJ. If children ruled the pharmaceutical industry: the need for pediatric formulations. Drug News Perspect. 2010;23:458–64.

    PubMed  Google Scholar 

  3. Rieder MJ, Matsui DM, MacLeod S. Myths and challenges—drug utilization for Canadian children. Paediatr Child Health. 2003;8(Supple A):7A–8A.

    Google Scholar 

  4. Chai G, Governale L, McMahon AW, et al. Trends of outpatient prescription drug use in US children, 2002–2010. Pediatrics. 2012;130:23–31.

    Article  PubMed  Google Scholar 

  5. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology—drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349:1157–67.

    Article  CAS  PubMed  Google Scholar 

  6. Lu H, Rosenbaum S. Developmental pharmacokinetics in pediatric populations. Pediatr Pharmacol Ther. 2014;19:262–76.

    Google Scholar 

  7. Brouwer K, Aleksunes LM, Brandys B, Pediatric Transporter Working Group, et al. Human ontogeny of drug transporters: review and recommendations of the Pediatric Transporter Working Group. Clin Pharmacol Ther. 2015;98:266–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rieder MJ. Novel approaches to adverse drug reactions in children. Pediatr Clin N Am. 2012;59:1001–4.

    Article  Google Scholar 

  9. Kauffman RE. Status of drug approval processes and regulation of medications for children. Curr Opin Pediatr. 1995;7(2):195–8.

    Article  CAS  PubMed  Google Scholar 

  10. Shirkey HC. Editorial comment: therapeutic orphans. J Pediatr. 1968;72:119–20.

    Article  CAS  PubMed  Google Scholar 

  11. Bleicher EW. Encouraging research and development of pediatric medical devices through legislative and regulatory action: the Pediatric Medical Device Safety and Improvement Act of 2007 in context. Food Drug Law J. 2009;64(3):531–64.

    PubMed  Google Scholar 

  12. Waisel DB. Moral responsibility to attain thorough pediatric drug labeling. Paediatr Anaesth. 2009;19:989–93.

    Article  PubMed  Google Scholar 

  13. Hawcutt DB, Smyth RL. Drug development for children: how is pharma tackling an unmet need? IDrugs. 2008;11(7):502–7.

    PubMed  Google Scholar 

  14. Rodriguez W, Selen A, Avant D, et al. Improving pediatric dosing through pediatric initiatives: what we have learned. Pediatrics. 2008;121(3):530–9.

    Article  PubMed  Google Scholar 

  15. Lau C. Development of suck and swallow mechanisms in infants. Ann Nutr Metab. 2015;66(suppl 5):7–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. LaMantia AS, Moody SA, Maynard TM, et al. Hard to swallow: developmental biological insights into pediatric dysphagia. Dev Biol. 2016;409(2):329–42.

    Article  CAS  PubMed  Google Scholar 

  17. Delaney AL, Arvedson JC. Develop disabilities. Res Rev. 2008;2008(14):105–17.

    Google Scholar 

  18. Meltzer EO, Welch MJ, Ostrom NK. Pill swallowing ability and training in children 6 to 11 years of age. Clin Pediatr (Phila). 2006;45:725–33.

    Article  CAS  Google Scholar 

  19. Chandrashekar J, Hoon MA, Ryba NJ, Zuker CS. The receptors and cells for mammalian taste. Nature. 2006;444:288–94.

    Article  CAS  PubMed  Google Scholar 

  20. Chaudhari N, Roper SD. The cell biology of taste. J Cell Biol. 2010;190:285–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mennella JA, Beauchamp GK. Optimizing oral medications for children. Clin Ther. 2008;30:2120–32.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gaynes BJ, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use. Drug Saf. 2002;25:233–50.

    Article  CAS  PubMed  Google Scholar 

  23. Chiu HY, Tsai TF. Topical use of systemic drugs in dermatology: a comprehensive review. J Am Acad Dermatol. 2011;65:e1–22.

    Article  Google Scholar 

  24. Sears MR, Taylor DR, Lake DC, et al. Regular inhaled beta-agonist treatment in bronchial asthma. Lancet. 1990;336:3191–6.

    Article  Google Scholar 

  25. Baguley D, Lim E, Bevan A, Pallet A, Faust SN. Prescribing for children—taste and palatability affect adherence to antibiotics: a review. Arch Dis Child. 2012;97:293–7.

    Article  PubMed  Google Scholar 

  26. Kozarewicz P. Regulatory perspectives on acceptability testing of dosage forms in children. Int J Pharm. 2014;469:245–8.

    Article  CAS  PubMed  Google Scholar 

  27. Zajicek A, Fossler MJ, Barrett JS, et al. A Report from the Pediatric Formulations Task Force: perspectives on the state of child-friendly oral dosage forms. AAPS Pharm Sci Tech. 2013;15:1072–81.

    CAS  Google Scholar 

  28. Sunakawa K, Akita H, Iwata S, et al. Rational use of oral antibiotics for pediatric infections. Infection. 1995;23(Suppl 2):S74–8.

    Article  CAS  PubMed  Google Scholar 

  29. Al-Shammari SA, Khoja T, Al-Yamani MJ. Compliance with short-term antibiotic therapy among patients attending primary health centres in Riyadh, Saudi Arabia. J R Soc Health. 1995;115:231–4.

    Article  CAS  PubMed  Google Scholar 

  30. Lin D, Seabrook J, Matsui D, et al. Palatability, adherence and prescribing patterns of antiretroviral drugs for children with human immunodeficiency virus infection in Canada. Pharmacoepidemiol Drug Saf. 2011;20(12):1246–52.

    Article  PubMed  Google Scholar 

  31. Rieder M. How sweet it isn’t: a new formulation of sodium phenylbutyrate and the challenge of palatability for medicines in children. Arch Dis Child. 2012;97:1080.

    Article  PubMed  Google Scholar 

  32. Wax PM. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med. 1995;122:456–61.

    Article  CAS  PubMed  Google Scholar 

  33. Jamesa C, Lainga DG, Orama NA. Comparison of the ability of 8–9-year-old children and adults to detect taste stimuli. Physiol Behav. 1997;62:193–7.

    Article  Google Scholar 

  34. Gie Liem D, de Graaf C. Sweet and sour preferences in young children and adults; role of repeated exposures. Physiol Behav. 2004;83:421–9.

    Article  Google Scholar 

  35. Guffon G, Kibleur Y, Copula W, Tissen W, Breitkreutz J. Developing a new formulation of sodium phenylbutyrate. Arch Dis Child. 2012;97:1081–5.

    Article  PubMed  Google Scholar 

  36. Matsui D, Barron A, Rieder MJ. Assessment of the palatability of antistaphylococcal antibiotics in pediatric volunteers. Ann Pharmacother. 1996;30:586–8.

    Article  CAS  PubMed  Google Scholar 

  37. Matsui D, Lim R, Tschen T, Rieder MJ. Assessment of the palatability of β-lactamase-resistant antibiotics in children. Arch Pediatr Adolesc Med. 1997;151:599–602.

    Article  CAS  PubMed  Google Scholar 

  38. Angelilli ML, Toscani M, Matsui DM, Rieder MJ. Palatability of oral antibiotics among children in an urban primary care center. Arch Pediatr Adolesc Med. 2000;154:267–70.

    Article  CAS  PubMed  Google Scholar 

  39. Dagnone D, Matsui DM, Rieder MJ. Assessment of the palatability of vehicles for activated charcoal in paediatric volunteers. Pediatr Emerg Care. 2002;18:19–21.

    Article  PubMed  Google Scholar 

  40. Hames H, Seabrook J, Matsui D, Rieder MJ, Joubert G. Palatability study of a flavored dexamethasone preparation versus prednisolone liquid in children with asthma exacerbation in a Pediatric Emergency Department. Can J Clin Pharmacol. 2008;15:e95–8.

    PubMed  Google Scholar 

  41. Goldberg SL, Giardina PJ, Chirnomas D, et al. The palatability and tolerability of deferasirox taken with different beverages or foods. Pediatr Blood Cancer. 2013;60:1507–12.

    Article  PubMed  Google Scholar 

  42. Bastiaans DT, Immohr LI, Zeinstra GG, et al. In vivo and in vitro palatability testing of a new paediatric formulation of valaciclovir. Br J Clin Pharmacol. 2017;83:2789–97.

  43. Kodish E. Ethics and research with children: a case-based approach. New York: Oxford University Press; 2005.

    Google Scholar 

  44. Sammons HM, Malhotra J, Choonara I, et al. British and Canadian views on the ethics of paediatric clinical trials. Eur J Clin Pharmacol. 2007;63:431–6.

    Article  CAS  PubMed  Google Scholar 

  45. Dove ES, Avard D, Black L, Knoppers BM. Emerging issues in paediatric health research consent forms in Canada: working towards best practices. BMC Med Ethics. 2013;14:5.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Rieder MJ. (Member, Expert Panel): improving medicines for children in Canada. Council of Canadian Academies; 2014.

  47. Davies EH, Tuleu C. Medicines for children: a matter of taste. J Pediatr. 2008;2008(153):599–604.

    Article  Google Scholar 

  48. Wizenburg G, Desset-Brethes S. Industry perspective on palatability testing in children—two case studies. Int J Pharm. 2012;435:131.

    Article  Google Scholar 

  49. Abdel-Rahman SM, Amidon GL, Kaul A, Lukacova V, Vinks AA, Knipp GT. Members of the BCS Task Force. Summary of the National Institute of Child Health and Human Development-best pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics Classification System Working Group. Clin Ther. 2012;34:S11–24.

  50. Committee for Medicinal Products for Human Use, Paediatric Committee. Guideline on pharmaceutical development of medicines for paediatric use. European Medicines Agency, London, UK, 2013.

  51. Tuleu C, Breitkreutz J. Education paper: formulation issues in pediatric clinical pharmacology. Eur J Pediatr. 2013;172:717–20.

    Article  CAS  PubMed  Google Scholar 

  52. Batchelor H, Rayner O, Nickless J, et al. Children with cystic fibrosis: understanding issues related to oral administration of liquid flucloxacillin. Arch Dis Child. 2016;101:e2.

    Article  Google Scholar 

  53. Aljebab F, Alanazi M, Choonara I, Conroy S. Observational study on the palatability and tolerability of oral prednisolone and oral dexamethasone in children in Saudi Arabia and the UK. Arch Dis Child. 2017;102:1–6.

    Article  Google Scholar 

  54. Cohen R, de La Rocque F, Lecuyer A, et al. Study of the acceptability of antibiotic syrups, suspensions, and oral solutions prescribed to pediatric outpatients. Eur J Pediatr. 2009;168:851–7.

    Article  PubMed  Google Scholar 

  55. Anand V, Kataria M, Kukkar V, Saharan V, Choudhury PK. The latest trends in the taste assessment of pharmaceuticals. Drug Discov Today. 2007;12:257–65.

    Article  CAS  PubMed  Google Scholar 

  56. Bai S, Dormer N, Shoults C, Meyer A, Carol D, Pierce CD, Neville KA, Kearns GL. Palatability of a novel oral formulation of prednisone in healthy young adults. J Pharm Pharmacol. 2017;69:489–96.

    Article  CAS  PubMed  Google Scholar 

  57. Ali AA, Charoo NA, Abdallah DB. Pediatric drug development: formulation considerations. Drug Dev Ind Pharm. 2014;40:1283–99.

    Article  CAS  PubMed  Google Scholar 

  58. Mistry P, Batchelor H. Evidence of acceptability of oral paediatric medicines: a review. J Pharm Pharmacol. 2017;69:361–76.

    Article  CAS  PubMed  Google Scholar 

  59. Allen LV Jr. Dosage form design and development. Clin Ther. 2008;30:2102–11.

    Article  PubMed  Google Scholar 

  60. Klovrova S, Zahalka L, Matysova L, Horak P, Sklubalova Z. Pediatric oral solutions with propranolol hydrochloride for extemporaneous compounding: the formulation and stability study. Ceska Slov Fam. 2013;62:35–9.

    Google Scholar 

  61. Ferrarini A, Biachetti AA, Fossali EF, et al. What can we do to make antihypertensive medications taste better for children? Int J Pharm. 2013;457:333–6.

    Article  CAS  PubMed  Google Scholar 

  62. Sohi H, Sultana Y, Khar RK. Taste-masking technologies in oral pharmaceuticals: recent developments and approaches. Drug Dev Ind Pharm. 2004;30:429–48.

    Article  CAS  PubMed  Google Scholar 

  63. Ayenew Z, Puri V, Kumar L, Bansal AK. Trends in pharmaceutical taste-masking technologies: a patent review. Recent Pat Drug Del Formul. 2009;3:26–39.

    Article  CAS  Google Scholar 

  64. Ranmal SR, Cram A, Tuleu C. Age-appropriate and acceptable paediatric dosage forms: insights into end-user perceptions, preferences and practices from the Children’s Acceptability of Oral Formulations (CALF) Study. Int J Pharm. 2016;514:296–307.

    Article  CAS  PubMed  Google Scholar 

  65. Vaillancourt R, Truong Y, Karmali S, et al. Instructions for masking the taste of medication for children: validation of a pictogram tool. Can Pharm J (Ott). 2016;150:52–9.

    Article  Google Scholar 

  66. Al-kasemi B, Alsirawan B, Bashiman M, El-Zein H. Mechanical microencapsulation: the best technique in taste masking for the manufacturing scale—effect of polymer encapsulation on drug targeting. J Control Release. 2017;260:134–41.

    Article  Google Scholar 

  67. Münster M, Schoch C, Schmidt C, Breitkreutz J. Multiparticulate system combining taste masking and immediate release properties for the aversive compound praziquantel. Eur J Pharm Sci. 2017;109:446–54.

    Article  PubMed  Google Scholar 

  68. Pein M, Preis M, Eckert C, Kleine FE. Taste-masking assessment of solid oral dosage forms—a critical review. Int J Pharm. 2014;465:239–54.

    Article  CAS  PubMed  Google Scholar 

  69. Walsh J, Cram A, Woertz K, Breitkreutz J, Winzenburg G, Turner R, Tuleu C. Playing hide and seek with poorly tasting paediatric medicines: do not forget the excipients. Adv Drug Deliv Rev. 2014;73:14–33.

    Article  CAS  PubMed  Google Scholar 

  70. Ibrahim K, Al Ansari K. Flavored intravenous ondansetron administered orally for the treatment of persistent vomiting in children. J Trop Pediatr. 2016;62:288–92.

    Article  PubMed  Google Scholar 

  71. Batchelor H, Maukonen AM, Klein S, Davit B, Ju R, Ternik R, Heimbach T, Lin W, Wang J, Storey D. Food effects in paediatric medicines development for products Co-administered with food. Int J Pharm. 2017. https://doi.org/10.1016/j.ijpharm.2017.05.011.

  72. Neumann U, Whitaker MJ, Wiegand S, Krude H, Porter J, Davies M, Digweed D, Voeet B, Ross RJ, Blankensteing O. Absorption and tolerability of taste-masked hydrocortisone granules in neonates, infants and children under 6 years of age with adrenal insufficiency. Clin Endocrinol (Oxf). 2017. https://doi.org/10.1111/cen.13447.

    Google Scholar 

  73. Preis M, Grother L, Axe P, Breitkreutz J. In-vitro and in-vivo evaluation of taste-masked cetirizine hydrochloride formulated in oral lyophilisates. Int J Pharm. 2015;491:8–16.

    Article  CAS  PubMed  Google Scholar 

  74. Batchelor HK, Fotaki N, Klein S. Paediatric oral biopharmaceutics: key considerations and current challenges. Adv Drug Deliv Rev. 2014;73:102–26.

    Article  CAS  PubMed  Google Scholar 

  75. Klingmann V, Meissner T, Breitkreutz J, Moeltner A, Bosse HM. Acceptability of uncoated mini-tablets in neonates—a randomized controlled trial. J Pediatr. 2015;167:893–6.

    Article  PubMed  Google Scholar 

  76. Kluk A, Sznitowska M, Brandt A, Sznurkowska K, et al. Can preschool-aged children swallow several minitablets at a time? Results from a clinical pilot study. Int J Pharm. 2015;485:1–6.

    Article  CAS  PubMed  Google Scholar 

  77. Peris M. Orally disintegrating films and mini-tablets—innovative dosage forms of choice for pediatric use. AAPS Pharm Sci Tech. 2015;16:234–41.

    Article  Google Scholar 

  78. Hattrem MN, Dille MJ, Seternes T, Ege T, Draget KI. The relative bioavailability of ibuprofen after administration with a novel soft chewable drug formulation. Clin Pharmacol Drug Dev. 2017;0:1–9.

    Google Scholar 

  79. Cutler AJ, Mattingly GW. Beyond the pill: new medication delivery options for ADHD. CNS Spectr. 2017;7:1–12.

    Article  Google Scholar 

  80. Salunke S, Liu F, Batchelor H, European Paediatric Formulation Initiative (EuPFI), et al. European paediatric formulation initiative (EuPFI)—formulating ideas for better medicine for children. AAPS Pharm Sci Tech. 2017;18:257–62.

    Article  Google Scholar 

  81. Ternik R, Liu F, Bartlett JA, Khong YM, Tan DCT, Dixit T et al. Assessment of swallowability and palatability of oral dosage forms in children: report from an M-CERSI pediatric formulation workshop. Int J Pharm. 2017. https://doi.org/10.1016/j.ijpharm.2017.08.088.

  82. Bahia MS, Nissim I, Niv MY. Bitterness prediction in-silico: a step towards better drugs. Int J Pharm. 2017. https://doi.org/10.1016/j.ijpharm.2017.03.076.

  83. Jaggupulli A, Howard R, Upadhyaya JD, Bhullar RP, Chelikani P. Bitter taste receptors: novel insights into the biochemistry and pharmacology. Int J Biochem Cell Biol. 2016;77:184–96.

    Article  Google Scholar 

  84. Gittings S, Turnbull N, Roberts CJ, Bershkovich P. Dissolution methodology for taste masked oral dosage forms. J Control Release. 2014;173:32–42.

    Article  CAS  PubMed  Google Scholar 

  85. Pöllinger N. Microparticulates as drug carriers for pediatric use. Int J Pharm. 2013;457:337–58.

    Article  Google Scholar 

  86. Caffarel-Salvador E, Tuan-Mahmood TM, McElnay JC, et al. Potential of hydrogel-forming and dissolving microneedles for use in paediatric populations. Int J Pharm. 2015;489:158–69.

    Article  CAS  PubMed  Google Scholar 

  87. Jagani M, Legay H, Ranmal SR, et al. Can a flavoured spray (Pill Glide) help children swallow their medicines? A pilot study. Pediatrics. 2016;136:e20160680.

    Article  Google Scholar 

  88. Nagtegaal MJ, Swen JJ, Hanff LM, Schimmel KJM, Guchelaar HJ. Pharmacogenomics of taste: turning bitter pills sweet? Pharmacogenomics. 2014;15:111–9.

    Article  CAS  PubMed  Google Scholar 

  89. Allen AL, McGeary JE, Knopik VS, Hayes JE. Bitterness of the non-nutritive sweetener acesulfame potassium varies with polymorphisms in TAS2R9 and TAS2R31. Chem. Senses. 2013;38:379–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rieder MJ, Carleton B. Pharmacogenomics and adverse drug reactions in children. Front Genet. 2014;5:1–10.

    Article  CAS  Google Scholar 

  91. Bryson S. Patient-centred, administration friendly medicines for children—an evaluation of children’s preferences and how they impact medication adherence. Int J Pharm. 2014;469:257–9.

    Article  CAS  PubMed  Google Scholar 

  92. Liu F, Ranmal S, Batchelor HK, et al. Formulation factors affecting acceptability of oral medicines in children. Int J Pharm. 2015;492:341–3.

    Article  CAS  PubMed  Google Scholar 

  93. Venables R, Batchelor H, Hodson J, Stirling H, Marriott J. Determination of formulation factors that affect oral medicines acceptability in a domiciliary paediatric population. Int J Pharm. 2015;480:55–62.

    Article  CAS  PubMed  Google Scholar 

  94. Walsh J, Ranmal SR, Ernest TB, Liu F. Patient acceptability, safety and access: a balancing act for selecting age-appropriate oral dosage forms for paediatric and geriatric populations. Int J Pharm. 2017. https://doi.org/10.1016/j.ijpharm.2017.07.017.

Download references

Author information

Authors and Affiliations

  1. Department of Paediatrics, London Health Sciences Centre, Children’s Hospital of Western Ontario, 800 Commissioner’s Road East, London, ON, N6A 5W9, Canada

    Michael Rieder

Authors
  1. Michael Rieder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Rieder.

Ethics declarations

This work was supported by the CIHR-GSK Chair in Paediatric Clinical Pharmacology at the University of Western Ontario. Dr. Rieder has served as a consultant to Health Canada, the National Institutes of Health and the Medical Research Council.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rieder, M. Size and Taste Matters: Recent Progress in the Development of Age-Appropriate Medicines for Children. Pharm Med 32, 21–30 (2018). https://doi.org/10.1007/s40290-017-0218-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40290-017-0218-2

Search

Navigation