Parenteralni preparati za primenu u pedijatrijskoj populaciji: izazovi izbora ekscipijenasa
Sažetak
Potreba za razvojem lekova koji su prilagođeni uzrastu pacijenata mlađih od 18 godina je važna da bi se obezbedila adekvatna terapija kada se lekovi primenjuju različitim putevima primene. Primena lekova parenteralnim putem u pedijatrijskoj populaciji česta je kod hospitalizovanih pacijenata, u urgentnim stanjima ili u situacijama kada nije moguć (per)oralni put primene. Pri razvoju formulacije leka za parenteralnu primenu kod dece neophodno je uzeti u obzir put primene leka (povezan sa fiziološkim razlikama između dece i odraslih), mesto delovanja i dužinu trajanja farmakološkog efekta aktivne supstance, zapreminu preparata i opšte zdravstveno stanje pacijenta. Veliki izazov u formulaciji ovih preparata predstavlja izbor ekscipijenasa koji treba da obezbede odgovarajući kvalitet proizvoda i podnošljivost od strane pacijenta. U radu je dat prikaz razmatranja vezanih za formulaciju parenteralnih preparata za primenu u pedijatrijskoj populaciji. Navedeni su regulatorni zahtevi koji se odnose na primenu ekcipijenasa sa potvrđenim dejstvom i obeležavanje preparata koji ih sadrže. Takođe, razmotreni su savremeni pristupi (baze podataka i alati) koji mogu biti od koristi pri izboru odgovarajućih ekscipijenasa.
Reference
Redfern WS, Braby JE. Pediatric Infusion Therapy. In: Weinstein SM, Hagle ME, editors. Plumers Principles & Practice of Infusion Therapy. 9th ed. Philadelphia: Wolters Kluwer Health; 2014; p. 687–742.
Batchelor HK, Marriott JF. Formulations for children: problems and solutions. Brit J Clin Pharmacol.2015;79(3):405–18.
European Medical Agency (EMA) [Internet]. Guideline on pharmaceutical development of medicines for paediatric use; 2013 [cited 2025 Aug 10]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-pharmaceutical-development-medicines-paediatric-use_en.pdf.
Ivanovska V, Rademaker CM, van Dijk L, Mantel-Teeuwisse AK. Pediatric drug formulations: a review of challenges and progress. Pediatrics. 2014;34(2):361–72.
Agrawal A, Salunke S, Rumondor A, Thompson K, Caivano G, Walsh J, et al. Paediatric excipient risk assessment (PERA) tool and application for selecting appropriate excipients for paediatric dosage forms - Part 2. Eur J Pharm Biopharm. 2024;203:114447.
Malkawi WA, AlRafayah E, AlHazabreh M, AbuLaila S, Al-Ghananeem AM. Formulation challenges and strategies to develop pediatric dosage forms. Children. 2022;9(4):488.
Food and Drug Administration (FDA) [Internet]. Pediatric Drug Development: Regulatory Considerations — Complying With the Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for Children Act Guidance for Industry. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER); 2023 [cited 2025 Aug 10]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/pediatric-drug-development-regulatory-considerations-complying-pediatric-research-equity-act-and.
Food and Drug Administration (FDA) [Internet]. Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans Guidance for Industry. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER); 2020 [cited 2025 Aug 10]. Available from: https://www.fda.gov/media/86340/download.
Food and Drug Administration (FDA) [Internet]. E11 Clinical Investigation of Medicinal Products in the Pediatric Population. U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER); 2000 [cited 2025 Aug 10]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e11-clinical-investigation-medicinal-products-pediatric-population.
European Union (EU) EUR-Lex [Internet]. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004; 2006 [cited 2025 Aug 10]. Available from: https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32006R1901.
European Medical Agency (EMA) [Internet]. Reflection paper: Formulations of choice for the paediatric population; 2006 [cited 2025 Aug 10]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-formulations-choice-paediatric-population_en.pdf.
Fabiano V, Mameli C, Zuccotti GV. Paediatric pharmacology: remember the excipients. Pharmacol Res. 2011;63(5):362–5.
European Pharmacopoeia. 11th edition, Strasbourg: Council of Europe, 2023.
World Health Organization (WHO) [Internet]. Draft working document for comments: Development of paediatric medicines: points to consider in formulation; 2025 [cited 2025 Avg 10]. Available from: https://cdn.who.int/media/docs/default-source/medicines/norms-and-standards/current-projects/qas24.950_paediatric_medicines.pdf?sfvrsn=59fed2f_1.
Shah, UU, Roberts M. Parenteral liquids for intravenous and transdermal use. In: Bar-Shalom D, Rose K, editors. Pediatric formulations: a roadmap. New York: Springer; 2014; p. 239–52.
Nellis G, Metsvaht T, Varendi H, Toompere K, Lass J, Mesek I, et al. Potentially harmful excipients in neonatal medicines: a pan-European observational study. Arch Dis Child. 2015;100(7):694–9.
Sridharan K, Hasan HM, Al Jufairi M, Al Daylami A, Al Ansari E, Qader AM, et al. Possible effects of excipients used in the parenteral drugs administered in critically ill adults, children, and neonates. Expert Opin Drug Saf.2020;19(12):1625–40.
Breitkreutz J, Tuleu C. Pediatric and geriatric pharmaceutics and formulation. In: Florence AT, Siepmann J, editors. Modern Pharmaceutics, Volume 2: Applications and Advances. 5th ed. Boca Raton: CRC Press; 2010; p. 221–57.
Rouaz K, Chiclana-Rodríguez B, Nardi-Ricart A, Suñé-Pou M, Mercadé-Frutos D, Suñé-Negre JM, et al. Excipients in the paediatric population: A review. Pharmaceutics. 2021;13(3):387.
Ruiz F, Nunn A, Gill A, Clapham D, Fotaki N, Salunke S, et al. A review of paediatric injectable drug delivery to inform the study of product acceptability - an introduction. Eur J Pharm Biopharm. 2023;188:265–70.
Belayneh A, Tadese E, Molla F. Safety and biopharmaceutical challenges of excipients in off-label pediatric formulations. Int J Gen Med. 2020;13:1051–66.
Allegaert K. Propylene glycol in neonates: never prescribed, frequently administered, hardly evaluated. J Clin Toxicol. 2012;2(9). doi: 10.4172/2161-0495.1000e113.
European Medical Agency (EMA) [Internet]. Annex to the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’ (SANTE-2017-11668) - Revision 4. 2017 [cited 2025 Aug 10]. Available from: https://www.ema.europa.eu/en/annex-european-commission-guideline-excipients-labelling-package-leaflet-medicinal-products-human-use.
Alade SL, Brown RE, Paquet A Jr. Polysorbate 80 and E-Ferol toxicity. Pediatrics. 1986;77:593–7.
Martone WJ, Williams WW, Mortensen ML, Gaynes RP, White JW, Lorch V, et al. Illness with fatalities in premature infants: association with an intravenous vitamin E preparation, E-Ferol. Pediatrics. 1986;78:591–600.
Kicker JS, Haizlip JA, Buck ML. Hepatotoxicity after continuous amiodarone infusion in a postoperative cardiac infant. J Pediatr Pharmacol Ther. 2012;17:189–95.
Kriegel C, Festag M, Kishore RSK, Roethlisberger D, Schmitt G. Pediatric safety of polysorbates in drug formulations. Children (Basel). 2019;7(1):1. doi: 10.3390/children7010001.
Murphy A, Campbell DE, Baines D, Mehr S. Allergic reactions to propofol in egg-allergic children. Anesth Analg. 2011;113(1):140–4.
Burbridge MA, Jaffe RA. Excipients in anesthesia medications. Anesth Analg. 2019;128(5):891–900.
Martínez S, Lasa EM, Joral A, Infante S, Perez R, Ibáñez MD, et al. Recommendations for the use of propofol in egg-allergic patients. J Investig Allergol Clin Immunol. 2019;29(1):72–4.
Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations II: Solubilization, binding constant, and complexation efficiency. Drug Discov Today. 2016;21:363–8.
Ferreira L, Campos J, Veiga F, Cardoso C, Paiva-Santos AC. Cyclodextrin-based delivery systems in parenteral formulations: a critical update review. Eur J Pharm Biopharm. 2022;178:35–52.
Gould S, Scott RC. 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD): a toxicology review. Food Chem Toxicol. 2005;43:1451–9.
Musuc AM. Cyclodextrins: advances in chemistry, toxicology, and multifaceted applications. Molecules. 2024;29(22):5319.
European Medical Agency (EMA) [Internet]. Cyclodextrins used as excipients. Report published in support of the ‘Questions and answers on cyclodextrins used as excipients in medicinal products for human use’ (EMA/CHMP/495747/2013); 2017 [cited 2025 Aug 10]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/questions-and-answers-cyclodextrins-used-excipients-medicinal-products-human-use_en.pdf.
Wheeler BJ, Taylor BJ. Successful management of allergy to the insulin excipient metacresol in a child with type 1 diabetes: a case report. J Med Case Rep. 2012;6:263.
European Commission (EC) [Internet]. Excipients in the Labelling and Package Leaflet of Medicinal Products for Human Use; EC: Brussels, Belgium; 2018 [cited 2025 Aug 10]. Available from: https://health.ec.europa.eu/system/files/2018-03/guidelines_excipients_march2018_en_0.pdf.
Food and Drug Administration (FDA) [Internet]. Inactive Ingredients in Approved Drug Products Search: Frequently Asked Questions; 2025 [cited 2025 Sep 20]. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/inactive-ingredients-database-download.
Food and Drug Administration (FDA) [Internet]. Using the Inactive Ingredient Database Guidance for Industry; 2019 [cited 2025 Sep 20]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/using-inactive-ingredient-database-guidance-industry.
Homar M, Kalčič Š, Gorup G. Comparison of excipients in approved parenteral products and their maximum daily exposure values. PDA J Pharm Sci Technol. 2024;78(4):445–64.
Saito J, Nakamura H, Akabane M, Yamatani A. Quantitative investigation on exposure to potentially harmful excipients by injection drug administration in children under 2 years of age and analysis of association with adverse events: a single-center, retrospective observational study. Ther Innov Regul Sci. 2024;58(2):316–35.
Yang S, Aggarwal K, Jurczyszak J, Brown N, Sridhar S. Nanomedicine therapies for pediatric diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2024;16(5):e1996.
Bigini P, Gobbi M, Bonati M, Clavenna A, Zucchetti M, Garattini S, et al. The role and impact of polyethylene glycol on anaphylactic reactions to COVID-19 nano-vaccines. Nat Nanotechnol. 2021;16:1169–71.
Karaaslan BG, Burtecene N, Mustu U, Ocak S, Kasapcopur O, Kıykım A, Cokugras H. Evaluation of pediatric patients with suspected polyethylene glycol and polysorbate allergy before mRNA SARS-CoV2 vaccination. Allergol Immunopathol. 2023;51:174–80.
Buckley LA, Salunke S, Thompson K, Baer G, Fegley D, Turner MA. Challenges and strategies to facilitate formulation development of pediatric drug products: safety qualification of excipients. Int J Pharm. 2018;536(2):563–9.
Salunke S, Tuleu C, European Paediatric Formulation Initiative (EuPFI). The STEP database through the end-users eyes-USABILITY STUDY. Int J Pharm. 2015;492(1–2):316–31.
European Paediatric Formulation Initiative (EuPFI) [Internet]. STEP Database; 2025 [cited 2025 Aug 10]. Available from: https://eupfi.co.uk/.
The STEP Database [Internet]. UCL: Revolutionising Paediatric Medicine; 2024 [cited 2025 Sep 20]. Available from: https://www.ucl.ac.uk/life-sciences/case-studies/2024/oct/revolutionising-paediatric-medicine-step-database.
Salunke S, Agrawal A, Walsh J, Nunn A, Hughes K, Kuehl P, et al. Selecting appropriate excipients for paediatric dosage form - paediatric excipients risk assessment (PERA) framework - Part 1. Eur J Pharm Biopharm. 2024;203:114458.
PharmaCirleTM [Internet]. 2025 [cited 2025 Avg 10]. Available from: https://www.pharmacircle.com/info/products/.
Omidian H, Mfoafo K. Exploring the potential of nanotechnology in pediatric healthcare: advances, challenges, and future directions. Pharmaceutics. 2023;15(6):1583.
Medina A, Brown MN, Cox E, Donegan S, Dragulin-Otto S, Flores K, et al. Drug product development and case studies for patient centric pediatric protein-based therapeutics. J Pharm Sci. 2025;114(2):681–9.
García-López I, Cuervas-Mons Vendrell M, Martín Romero I, de Noriega I, Benedí González J, Martino-Alba R. Off-label and unlicensed drugs in pediatric palliative care: a prospective observational study. J Pain Symptom Manage. 2020;60(5):923–32.
Guidi B, Parziale A, Nocco L, Maiese A, La Russa R, Di Paolo M, Turillazzi E. Regulating pediatric off-label uses of medicines in the EU and USA: challenges and potential solutions: Comparative regulation framework of off label prescriptions in pediatrics: a review. Int J Clin Pharm. 2022;44(1):264–69.
Lizano-Díez I, Aldalur-Uranga I, Braza AJ, Figueiredo-Escribá C, Viñas-Bastart M, Mariño EL, et al. Assessment of mandatory declaration excipients in pediatric off label prescriptions in Spain. Sci Rep. 2025;15(1):26293.
Shuib W, Wu XY, Xiao F. Extent, reasons and consequences of off-labeled and unlicensed drug prescription in hospitalized children: a narrative review. World J Pediatr. 2021;7(4):341–54.
British National Formulary for children 2022–2023. British Medical Association, Royal Pharmaceutical Society of Great Britain, the Royal College of Paediatrics and Child Health, and the Neonatal and Paediatric Pharmacists Group. London, 2022.
Chen J, Zhao Z, Alantary D, Huang J. Nanomedicine for pediatric healthcare: A review of the current state and future prospectives. Eur J Pharm Biopharm. 2025;207:114597.
Nieto González N, Obinu A, Rassu G, Giunchedi P, Gavini E. Polymeric and Lipid Nanoparticles: Which Applications in Pediatrics? Pharmaceutics. 2021;13(5):670.
Saito J, Agrawal A, Patravale V, Pandya A, Orubu S, Zhao M, et al. The current states, challenges, ongoing efforts, and future perspectives of pharmaceutical excipients in pediatric patients in each country and region. Children. 2022;9(4):453.
Hirschfeld S, Lagler FB, Kindblom JM. Prerequisites to support high-quality clinical trials in children and young people. Arch Dis Child. 2021;106(5):423–28.
Ward RM, Benjamin D, Barrett JS, Allegaert K, Portman R, Davis JM, et al. Safety, dosing, and pharmaceutical quality for studies that evaluate medicinal products (including biological products) in neonates. Pediatr Res. 2017;81(5):692–711.
- Autori zadržavaju autorska prava i pružaju časopisu pravo prvog objavljivanja rada i licenciraju ga "Creative Commons Attribution licencom" koja omogućava drugima da dele rad, uz uslov navođenja autorstva i izvornog objavljivanja u ovom časopisu.
- Autori mogu izraditi zasebne, ugovorne aranžmane za neekskluzivnu distribuciju članka objavljenog u časopisu (npr. postavljanje u institucionalni repozitorijum ili objavljivanje u knjizi), uz navođenje da je članak izvorno objavljen u ovom časopisu.
- Autorima je dozvoljeno i podstiču se da postave objavljeni članak onlajn (npr. u institucionalni repozitorijum ili na svoju internet stranicu) pre ili tokom postupka prijave rukopisa, s obzirom da takav postupak može voditi produktivnoj razmeni ideja i ranijoj i većoj citiranosti objavljenog članka (Vidi Efekti otvorenog pristupa).