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Reflection on the Pharmaceutical Formulation Challenges Associated with a Paediatric Investigation Plan for an Off-Patent Drug

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  • Theme: Pediatric Drug Development and Dosage Form Design
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Abstract

In Europe, the development of pediatric medicines for new patent protected products is mandatory and applicants are required to submit a Paediatric Investigation Plan (PIP) to the regulatory authorities. The process is voluntary for off-patent medicines and despite the availability of incentives, there is still a huge unmet need for the development of off-patent pediatric medicines. The aim of the EU grant funded “Labeling of Enalapril from Neonates to Adolescents” (LENA) project is to develop a new pediatric dosage form of the off-patent drug enalapril, for the treatment of heart failure in patients aged from birth to 18 years. This article provides an overview of some of the key formulation challenges that were faced during the product development programme and PIP process, including selection of dosage form and excipients, methodology for administration of the product and evaluation of patient acceptability.

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Notes

  1. Mini tablets are defined as tablets with a diameter of up to 3 mm. van Riet-Nales et al. evaluated the acceptability of 4 mm “mini tablets”.

References

  1. CHMP EMEA, Reflection paper: formulation of choice for the paediatric population. 2006. Available at: http://www.emea.europa.eu/pdfs/human/paediatrics/19481005en.pdf.

  2. Kimland E, Odlind V. Off-label drug use in pediatric patients. Clin Pharmacol Ther. 2012;91:796–801.

    Article  CAS  PubMed  Google Scholar 

  3. Corny J, Lebel D, Bailey B, Bussieres J-F. Unlicensed and off-label drug use in children before and after pediatric governmental initiatives. J Pediatr Pharmacol Ther. 2015;20:316–28.

    PubMed  PubMed Central  Google Scholar 

  4. European Commission Guideline on the format and content of applications for agreement or modification of a paediatric investigation plan and requests for waivers and deferrals and concerning the operation of compliance check and on criteria for assessing significant studies. 2014/C 338/01. Available at: http://ec.europa.eu/health/files/eudralex/vol-1/2014_c338_01/2014_c338_01_en.pdf.

  5. EMA Report on the Expert Group Meeting of Paediatric Heart Failure, London 29 November 2010. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2011/04/WC500105356.pdf.

  6. EMA Report on the survey of all paediatric uses of medicinal products in Europe (EMA/794083/2009). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/01/WC500101006.pdf.

  7. Richey RH, Shah UU, Peak M, Craig JV, Ford JL, Barker CE, et al. Manipulation of drugs to achieve the required dose is intrinsic to paediatric practice but is not supported by guidelines or evidence. BMC Pediatr. 2013;13:81.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sam T, Ernest TB, Walsh J, Williams JL. A benefit/risk approach towards selecting appropriate pharmaceutical dosage forms—an application for paediatric dosage form selection. Int J Pharm. 2012;435:115–23.

    Article  CAS  PubMed  Google Scholar 

  9. Wang S. Formulations in paediatric investigation plans (PIPs): introduction to PIP quality section and regulatory framework. Int J Pharm. 2015;492:332–4.

    Article  CAS  PubMed  Google Scholar 

  10. PubChem Compound Summary for CID 5388961 Enalapril Maleate. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/Enalapril_maleate.

  11. Stanisz B. Evaluation of stability of enalapril maleate in solid phase. J Pharm Biomed Anal. 2003;31:375–80.

    Article  CAS  PubMed  Google Scholar 

  12. Saulnier L, Schlatter J. Stability of enalapril solutions prepared from tablets in sterile water. Aust J Hosp Pharm. 1997;27(5):395–7.

    Article  Google Scholar 

  13. CHMP: Guideline on pharmaceutical development of medicines for paediatric use 2012 (EMA/CHMP/QWP/805880/2012 Rev. 2). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/07/WC500147002.pdf.

  14. Taji S, Seow WK. A literature review of dental erosion in children. Aust Dent J. 2010;55:358–67.

    Article  CAS  PubMed  Google Scholar 

  15. Xavier AFC, Moura EFF, Azevedo WF, Vieira FF, Abreu MHNG, Cavalcanti AL. Erosive and carcinogenicity potential of pediatric drugs: study of physicochemical parameters. BMC Oral Health. 2013;13:71.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Thomson SA, Tuleu C, Wong ICK, Keady S, Pitt KG. Minitablets: new modality to deliver medicines to preschool-aged children. Pediatrics. 2009;123:e235–8.

    Article  PubMed  Google Scholar 

  17. Van de Vijver E, Desager K, Mulberg AE, Staelens S, Verkade HJ, Bodewes FA, et al. Treatment of infants and toddlers with cystic fibrosis-related pancreatic insufficiency and fat malabsorption with pancrelipase MT. J Pediatr Gastroenterol Nutr. 2011;53:61–4.

    Article  PubMed  Google Scholar 

  18. Spomer N, Klingmann V, Stoltenberg I, Lerch C, Meissner T, Breitkreutz J. Acceptance of uncoated mini-tablets in young children: results from a prospective exploratory cross-over study. Arch Dis Child. 2012;97:283–6.

    Article  PubMed  Google Scholar 

  19. van Riet-Nales DA, de Neef BJ, Schobben AFAM, Ferreira JA, Egberts TCG, Rademaker CMA. Acceptability of different oral formulations in infants and preschool children. Arch Dis Child. 2013;98:725–31.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Klingmann V, Spomer N, Lerch C, Stoltenberg I, Frömke C, Bosse HM, et al. Favorable acceptance of mini-tablets compared with syrup: a randomized controlled trial in infants and preschool children. J Pediatr. 2013;163:1728–32.

    Article  PubMed  Google Scholar 

  21. Klingmann V, Seitz A, 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 

  22. Tissen C, Woertz K, Breitkreutz J, Kleinebudde P. Development of mini-tablets with 1 mm and 2 mm diameter. Int J Pharm. 2011;416:164–70.

    Article  CAS  PubMed  Google Scholar 

  23. Rancé F, Deslandes B, Decosta P. Acceptability and tolerance of prednisolone metasulfobenzoate in orally dispersing tablets in 2 to 12-year-old children. Arch Pediatr. 2004;11:1127–30.

    Article  PubMed  Google Scholar 

  24. Stoltenberg I, Breitkreutz J. Orally disintegrating mini-tablets (ODMTs)—a novel oral dosage for paediatric use. Eur J Pharm Biopharm. 2011;78:462–9.

    Article  CAS  PubMed  Google Scholar 

  25. Hermes. Kindgerechte, niedrigdosierte Zubereitung mit Enalaprilmaleat. 2012. Göttingen: Cuvillier Verlag. Available at: http://www.cuvillier.de/flycms/en/html/30/-UickI3zKPS3xcE0=/Buchdetails.html.

  26. Kaye JL. Review of paediatric gastrointestinal physiology data relevant to oral drug delivery. Int J Clin Pharm. 2011;33:20–4.

    Article  PubMed  Google Scholar 

  27. Strollin-Benedetti M, Whomsley R, Baltes EL. Differences in absorption, distribution, metabolism and excretion of xenobiotics between the paediatric and adult populations. Expert Opin Drug Metab Toxicol. 2005;1:447–71.

    Article  Google Scholar 

  28. CHMP: Guideline on the investigation of medicinal products in the term and preterm neonate. 2009. (EMEA/536810/2008). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003750.pdf.

  29. EC 2003 NOTICE TO APPLICANTS VOLUME 3B Guidelines Medicinal products for human use Safety, environment and information Excipients in the label and package leaflet of medicinal products for human use July 2003. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003412.pdf.

  30. Salunke S, Giacoia G, Tuleu C. The STEP (Safety and Toxicity of Excipients for Paediatrics) database. Part I—a need assessment study. Int J Pharm. 2012;435:101–11.

    Article  CAS  PubMed  Google Scholar 

  31. Salunke S, Brandys B, Giacoia G, Tuleu C. The STEP (Safety and Toxicity of Excipients for Paediatrics) database. Part 2—the pilot version. Int J Pharm. 2013;457:310–22.

    Article  CAS  PubMed  Google Scholar 

  32. Salunke S, Tuleu C. The STEP database through end-users eyes—USABILITY STUDY. Int J Pharm. 2015;492:316–31.

    Article  CAS  PubMed  Google Scholar 

  33. de Diego M, Godoy G, Mennickent S, Godoy R. Chemical stability of enalapril maleate drug substance and tablets by a stability-indicating liquid chromatographic method. Quim Nova. 2011;34(3):450–4.

    Article  Google Scholar 

  34. Al-khattawi A, Mohammed AR. Compressed orally disintegrating tablets: excipients evolution and formulation strategies. Expert Opin Drug Deliv. 2013;10(5):651–63.

    Article  CAS  PubMed  Google Scholar 

  35. Chen M-L, Sadrieh N, Yu L. Impact of osmotically active excipients in bioavailability and bioequivalence of BCS class III drugs. AAPS J. 2013;15(4):1043–50.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Grabitske HA, Slavin JL. Gastrointestinal effects of low-digestible carbohydrates. Crit Rev Food Sci Nutr. 2009;49(4):327–60.

    Article  CAS  PubMed  Google Scholar 

  37. EFSA Panel on Dietetic Products, Nutrition and Allergies. Scientific opinion on the appropriateness of the food az-colours Tartrazine (E102), Sunset Yellow FCF (E110), Carmoisine (E122), Amaranth (E123), Ponceau 4R (E124), Allura Red AC (E129), Brilliant Black BN (E151), Brown FK (E154), Brown HT (E155) and Litholrubine BK (E180) for inclusion in the list of food ingredients set up in Annex IIIa of Directive 2000/13/EC. EFSA J. 2010;8(10):1778.

    Article  Google Scholar 

  38. EFSA Panel on Dietetic Products, Nutrition and Allergies. Scientific opinion on the re-evaluation Tartrazine (E102). EFSA Journal. 2009;7(11):1331.

    Article  Google Scholar 

  39. EFSA. Refined exposure assessment for Amaranth (E123). EFSA J. 2013;11(10):3442.

    Article  Google Scholar 

  40. EFSA Panel of Food Additives and Nutrient Sources added to Food. Reconsideration of the temporary ADI and refined exposure assessment for Sunset Yellow FCF (E110). EFSA J. 2014;12(7):3765.

    Article  Google Scholar 

  41. EFSA. Refined exposure assessment for Allura Red AC (E129). EFSA J. 2015;13(2):4007.

    Article  Google Scholar 

  42. EFSA. Refined exposure assessment for Ponceau 4R (E124). EFSA J. 2015;13(4):4073.

    Article  Google Scholar 

  43. Egger C, Schoneker D, Tiwari S. Iron oxides. In: Rowe RC, Sheskey PJ, Cook WG, Fenton MW, editors. Handbook of pharmaceutical excipients. London: Pharmaceutical Press; 2012. p. p389–90.

    Google Scholar 

  44. Walsh J, Cram A, Woertz K, Breitkreutz J, Winzenburg G, Turner R, et al. 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 

  45. Roberts IF, Roberts GJ. Relation between medicines sweetened with sucrose and dental disease. BMJ. 1979;2:14–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Aleksovski A, Dreu R, Gasperlin M, Planinsek O. Mini-tablets: a contemporary system for oral drug delivery in targeted patient groups. Expert Opin Drug Deliv. 2015;12:65–84.

    Article  CAS  PubMed  Google Scholar 

  47. van Riet-Nales DA, Ferreira JA, Schobbena AFAM, de Neef BJ, Egberts TCG, Rademaker CMA. Methods of administering oral formulations and child acceptability. Int J Pharm. 2015;492:261–7.

    Article  Google Scholar 

  48. Venables R, Batchelor H, Hodson J, Stirling H. 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 

  49. Ponrouch MP, Sautou-Miranda V, Boyer A, Bourdeaux D, Montagner A, Chopineau J. Proton pump inhibitor administration via nasogastric tube in pediatric practice: comparative analysis with protocol optimization. Int J Pharm. 2010;390:160–4.

    Article  CAS  PubMed  Google Scholar 

  50. Ruzsikova A, Souckova L, Suk P, Opatrilova R, Kejdusova M, Sramek V. Quantitative analysis of drug losses administered via nasogastric tube—in vitro study. Int J Pharm. 2015;478:368–71.

    Article  CAS  PubMed  Google Scholar 

  51. Kozarewicz P. Regulatory perspectives on acceptability testing of dosage forms in children. Int J Pharm. 2014;496:245–8.

    Article  Google Scholar 

  52. Liu F, Ranmal S, Batchelor HK, Oru-Gul M, Ernest TB, Thomas IW, et al. Patient-centred pharmaceutical design to improve acceptability of medicines: similarities and differences in paediatric and geriatric populations. Drugs. 2014;74:1871–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Jenny Walsh Consulting Ltd, BioCity Nottingham, Pennyfoot Street, Nottingham, NG1 1GF, UK

    Jennifer Walsh

  2. on behalf of Ethicare GmbH, Haltern am See, Germany

    Jennifer Walsh

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  1. Jennifer Walsh
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Correspondence to Jennifer Walsh.

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Funding

The research leading to these results has received funding from the EU’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA). The author has provided consultancy support to the LENA project, but received no financial support for the creation of this manuscript.

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Guest Editors: Maren Preis and Jörg Breitkreutz

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Walsh, J. Reflection on the Pharmaceutical Formulation Challenges Associated with a Paediatric Investigation Plan for an Off-Patent Drug. AAPS PharmSciTech 18, 250–256 (2017). https://doi.org/10.1208/s12249-016-0527-x

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  • DOI: https://doi.org/10.1208/s12249-016-0527-x

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