pharmaceutics Review Polymeric and Lipid Nanoparticles: Which Applications in Pediatrics? Noelia Nieto González 1, Antonella Obinu 2, Giovanna Rassu 2,* , Paolo Giunchedi 2 and Elisabetta Gavini 2 1 PhD Program in Chemical Science and Technology, Department of Chemistry and Pharmacy, University of Sassari, Via Muroni 23/a, 07100 Sassari, Italy; [email protected] 2 Department of Chemistry and Pharmacy, University of Sassari, Via Muroni 23/a, 07100 Sassari, Italy; [email protected] (A.O.); [email protected] (P.G.); [email protected] (E.G.) * Correspondence: [email protected]; Tel.: +39-079228735 Abstract: This review aims to provide the state of the art on polymeric and lipid nanoparticles, used or suggested to approach pediatric diseases’ problems and needs, and to inspire new researches in this field. Several drugs are currently not available in formulations suitable for pediatric patients. The United States Pediatric Formulation Initiative suggested applying new technologies to pediatric drug formulations, for instance, nanotechnology. The literature analysis showed that polymeric and lipid nanoparticles have been widely studied to treat pediatric diseases, and albumin nanoparticles and liposomes are already used in clinical practice. Nevertheless, these studies are focused almost exclusively on pediatric cancer treatment. Although nanomedicine may solve many needs of pediatric diseases and medicines, the unavailability of data on pharmacokinetics, safety and efficacy of both drugs and nanoparticles in pediatric patients limits the development of new pediatric medicines based on nanoparticles. Therefore, nanomedicine applied in pediatrics remains a significant challenge in the near future. Citation: Nieto González, N.; Obinu, A.; Rassu, G.; Giunchedi, P.; Gavini, E. Keywords: nanomedicine; polymeric nanoparticle; lipid nanoparticle; pediatric disease; pedi- Polymeric and Lipid Nanoparticles: atric medicine Which Applications in Pediatrics? Pharmaceutics 2021, 13, 670. https:// doi.org/10.3390/pharmaceutics 13050670 1. Introduction The European Union’s (EU) Paediatric Regulation took effect in 2007. It aimed to Academic Editor: César Viseras encourage research in age-appropriate formulations and to raise high-quality information on pediatric medicines. This Regulation was inspired by United States (US) Pediatric Received: 16 April 2021 Legislation, whose legislative approaches have been developed since 1997 [1]. Since the Accepted: 5 May 2021 1980s, it has been argued that pediatric patients deserve the same level of health care as Published: 7 May 2021 the rest of the population [2,3] (Figure1). The report published in 2017 by the European Commission (EC), on the 10th anniversary of the EU Regulation, shows an increase in Publisher’s Note: MDPI stays neutral children’s medicines. The most significant advances have been made in the treatment of with regard to jurisdictional claims in diseases common in adult and pediatric patients. published maps and institutional affil- Nevertheless, in the context of rare or exclusive children’s disease (e.g., some forms iations. of tumor), the impact was minor [4]. However, since the Regulation’s implementation, from 2007 to 2015, 238 new medicines for pediatric patients and 39 new formulations appropriate for this population were authorized in the EU [2]. The Paediatric Committee at the European Medicines Agency (PDCO) has established an inventory that defines Copyright: © 2021 by the authors. the requirements for various pathologies and drug formulations in different age groups Licensee MDPI, Basel, Switzerland. in the pediatric population to promote their investigation [5]. The European Paediatric This article is an open access article Formulation Initiative (EuPFI) was founded in 2007 to study the different needs related distributed under the terms and to pediatric formulation development in order to formulate better drugs for children [6]. conditions of the Creative Commons On 20 March 2018, in a workshop organized by the EC and European Medicines Agency Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ (EMA), one of the topics discussed was again identifying pediatric medical needs [4]. 4.0/). Pharmaceutics 2021, 13, 670. https://doi.org/10.3390/pharmaceutics13050670 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, 670 2 of 20 Pharmaceutics 2021, 13, x FOR PEER REVIEW 2 of 20 Figure 1. Schematic representation of the key milestones in the regulation of pediatric medicines. Figure 1. Schematic representation of the key milestones in the regulation of pediatric medicines. Several drugs areare currentlycurrently not not formulated formulated for for administration administration to to children. children. In hospitals,In hospi- tals,they they are frequently are frequently formulated formulated in galenic in galenic medicines, medicines, using using adult adult dosage dosage forms forms or off-label or off- labeluse. use. Surveys Surveys suggested suggested that that in manyin many therapeutic therapeutic areas, areas, off-label off-label use use was was higherhigher than 50% [3]. [3]. Moreover, thethe useuse ofof extemporaneousextemporaneous preparation preparation may may result result in in an an elevated elevated risk risk of oftoxicity toxicity or lowor low therapeutic therapeutic dose, dose, an uncertain an uncertain bioavailability bioavailability and an and absence an absence of documented of docu- mentedinformation information about the about stability the stability [7]. [7]. The development development of of pediatric pediatric medicines medicines is complex, is complex, because because children children cannot cannot be con- be sideredconsidered small small adults adults and heterogeneous. and heterogeneous. The EM TheA classifies EMA classifies them into them five into groups: five groups: (i) pre- term(i) preterm newborn newborn infants, infants, (ii) term (ii) termnewborn newborn infants infants (0–27 (0–27 days), days), (iii) (iii)infants infants and and toddlers toddlers (1 month(1 month to 23 to months), 23 months), (iv) (iv)children children (2–11 (2–11 years), years), (v) adolescents (v) adolescents (12–16 (12–16 or 18 oryears). 18 years). Each ageEach group age group has different has different requirements requirements consider consideringing the type the of typeformulation of formulation and the andadmin- the istrationadministration route due route to physiological, due to physiological, anatomical anatomical and pharmacokinetic and pharmacokinetic changes changes[7]. The op- [7]. timalThe optimal considerations considerations for pediatric for pediatric formulations formulations are (i) are age-appropriate (i) age-appropriate dosage dosage forms, forms, (ii) facility(ii) facility of preparations of preparations and and instructions instructions for for use use for for careers, careers, (iii) (iii) acceptability, acceptability, (iv) (iv) choice and quantity of excipients, (v) use of alternativealternative delivery systems, and vi) appropriate packaging to improve efficiency efficiency and avoid the risk of dosagedosage errorserrors [[8].8]. Also, excipient choice for for enhancing enhancing drugs drugs is isone one of the of the main main issues issues in the in pediatric the pediatric area. area.Excipients Excipients safely andsafely commonly and commonly used in used formulations in formulations for grown-ups for grown-ups could could be harmful be harmful to children to children [7]. For [7]. example,For example, regarding regarding preservatives, preservatives, the use the of use benzyl of benzyl alcohol alcohol should should be considered be considered care- fully,carefully, and andit is better it is better to avoid to avoid it in young it in young pediatric pediatric patients patients due to duetheir to immature their immature metab- olismmetabolism [9]. Also, [9]. ethanol Also, ethanolshows adverse shows adversesynergis synergistictic effects on effects the central on the nervous central system nervous if combinedsystem if combinedwith other with drugs. other For drugs. example, For example,ethanol and ethanol dextromethorphan and dextromethorphan can cause can an infant’scause an death infant’s [10]. death [10]. The United States Pediatric Formulation Initiative (US PFI) suggested applying new technologiestechnologies forfor pediatricpediatric drugdrug formulations. formulations Nanotechnology. Nanotechnology is is considered considered an an innovative innova- tiveapproach approach for reducingfor reducing drug drug toxicity toxicity and and improving improving drug drug efficacy. efficacy. US USPFI PFI alsoalso argued forfor future applications of polymeric nanoparticles as a controlled drug deliverydelivery system over a a long long period period [11]. [11]. This This review review aims aims to assess to assess the thenanoparticles nanoparticles (NPs) (NPs) used usedor sug- or suggested as drug delivery systems in the pediatric field to tackle pediatric diseases’ needs. gested as drug delivery systems in the pediatric field to tackle pediatric diseases’ needs. Pharmaceutics 2021, 13, 670 3 of 20 Pharmaceutics 2021, 13, x FOR PEER REVIEW 3 of 20 TheThe excipientsexcipients usedused andand the technological and biological properties properties of of the the nanosystems nanosystems areare reported.reported. 2. Nanoparticles as Pediatric Formulations 2. Nanoparticles as Pediatric Formulations NPs are particles with a size range from one to several hundred nanometers. The NPs are particles with a size range from one to several