International Journal of Molecular Sciences Review How to Modify Drug Release in Paediatric Dosage Forms? Novel Technologies and Modern Approaches with Regard to Children’s Population Monika Trofimiuk 1,2, Katarzyna Wasilewska 1 and Katarzyna Winnicka 1,* 1 Department of Pharmaceutical Technology, Medical University of Bialystok, Mickiewicza 2c, 15-222 Bialystok, Poland 2 Department of Clinical Pharmacy, Medical University of Bialystok, Mickiewicza 2a, 15-222 Bialystok, Poland * Correspondence: [email protected] Received: 11 June 2019; Accepted: 28 June 2019; Published: 29 June 2019 Abstract: In the pharmaceutical technology, paediatric population still presents the greatest challenge in terms of developing flexible and appropriate drug dosage forms. As for many medicines, there is a lack of paediatric dosage forms adequate for a child’s age; it is a prevailing practice to use off label formulations. Children need balanced and personalized treatment, patient-friendly preparations, as well as therapy that facilitates dosing and thus eliminates frequent drug administration, which can be ensured by modified release (MR) forms. MR formulations are commonly used in adult therapy, while rarely available for children. The aim of this article is to elucidate how to modify drug release in paediatric oral dosage forms, discuss the already accessible technologies and to introduce novel approaches of manufacturing with regard to paediatric population. Keywords: modified release; drug delivery; paediatric formulation development; paediatric dosage forms 1. Introduction Creating an appropriate dosage form designed exactly for children still appears as an outgoing challenge for pharmaceutical technology and the distinction between adults and children pharmacokinetics should be considered. The statement that children can be treated as “small adults” is obviously incorrect, particularly in determining the therapeutic doses in individual age groups [1–4]. In paediatric pharmacotherapy, many factors regarding a convenient dosage form (e.g., age-suitable formulations in proper strength, off label use, and palatability) have to be included. Creating paediatric dosage forms is associated with many difficulties. Therefore, the main goal raised by regulations of European Medicines Agency (EMA) or paediatric scientific network groups is increasing the safety and efficiency of paediatric therapy by the enhancement the quality of clinical studies for children in various age groups (from birth to 18 years old) with better availability of pharmacokinetic data [5,6]. Scientific and governmental initiatives (The Best Pharmaceuticals for Children—BPCA, Paediatric Investigation Plan—PIP) are focused on the development of paediatric dosage forms adjusted to the child’s age and as a consequence of enhancing the efficiency and safety of paediatric therapy [7,8]. The main directives implemented in the appropriate paediatric dosage forms development point basic difficulties connected with paediatric therapy. A special guideline concerning formulation and administration of suitable dosage forms and detailed information on how to use the medicines with regard to children was proposed (State of paediatric medicines in the European Union 10 report) [9]. Due to the special attention focused on the safety of excipients used in the paediatric formulations, the Step and Toxicity of Excipients for Paediatric Patients database has been created (STEP database) [10]. Additionally, EMA Int. J. Mol. Sci. 2019, 20, 3200; doi:10.3390/ijms20133200 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, x 2 of 22 Int. J. Mol. Sci. 2019, 20, 3200 2 of 22 Toxicity of Excipients for Paediatric Patients database has been created (STEP database) [10]. Additionally, EMA gave a support in providing clinical trials with children to promote and gave a support in providing clinical trials with children to promote and harmonize existing paediatric harmonize existing paediatric guidelines [7,11–18]. As a result of these acts, the percentage of guidelines [7,11–18]. As a result of these acts, the percentage of clinical trials included children (where clinical trials included children (where only one participant was under 18 years at least) has only one participant was under 18 years at least) has increased from 8.3% in 2007 to 12.4% in 2016. increased from 8.3% in 2007 to 12.4% in 2016. Therefore, it still remains an outgoing problem as Therefore, it still remains an outgoing problem as there is constantly not enough clinical trials with there is constantly not enough clinical trials with children compared to the numbers of clinical trials children compared to the numbers of clinical trials carried out in adults [9]. Challenges associated with carried out in adults [9]. Challenges associated with conducting clinical trials in children include conducting clinical trials in children include many childhood diseases, heterogeneity of the population many childhood diseases, heterogeneity of the population and ethical problems [18]. Main and ethical problems [18]. Main problems related to paediatric therapy are presented in Figure1. problems related to paediatric therapy are presented in Figure 1. Figure 1. Problems in paediatric pharmacotherapy practice [11,19,20]. Figure 1. Problems in paediatric pharmacotherapy practice [11,19,20]. Traditional dosage forms (e.g., tablets, capsules, and injections) are often not appropriate for children,Traditional hence cutting dosage or forms crushing (e.g., tablets, tablets, splitting capsules, capsule and injections) and then mixing are often with not the appropriate food (solid for or liquid)children, and hence dilution cutting of injections or crushing are tablets, common splitting practice capsule [19–22 ].and Manipulation then mixing with with dosage the food form (solid may or causeliquid) a riskand ofdilution damage of ofinjections formulation are common structure, practice hence [19–22]. side effects Manipulation and changes with in pharmacologicaldosage form may ecauseffect might a risk occur.of damage Despite of formulation significant advances structure, in hence the development side effects ofand drug changes dosage in formspharmacological dedicated especiallyeffect might for children,occur. Despite but unfortunately, significant unlicensedadvances drugsin the are development still used [1– 4of]. drug dosage forms dedicatedOral route especially of administration for children, is but the unfortun most naturalately, way unlicensed of giving drugs medicines are still for us children.ed [1–4]. Regardless, childOral age isroute still theof administration most popular liquidis the dosagemost na forms.tural way Their of main giving advantages medicines are for safety children. and easeRegardless, of swallowing, child age but is thestill most the importantmost popular and liquid most convenientdosage forms. factor Their is the main possibility advantages of drug are administrationsafety and ease in of a swallowing, wide group but of children the most by important volumetrically and most measuring convenient a dose, factor precisely is the possibility adjusted toof adrug child’s administration weight or age. in Liquida wide dosagegroup of forms children are preferred by volumetrically especially measuring for newborns, a dose, infants, precisely and smalleradjusted children, to a child’s avoiding weight the or risk age. of chockingLiquid do andsage enhancing forms are the preferred probability especially of taking for anewborns, full dose ofinfants, the drug. and smaller For older children, children avoiding (above the 6 years), risk of despitechocking liquid and enhancing formulations, the probability solid dosage of formstaking (tablets,a full dose effervescent of the drug. formulations, For older children orodispersible (above tablets, 6 years), films, despite pellets, liquid or minitablets) formulations, could solid be dosage safely administered.forms (tablets, However, effervescent the individualformulations, swallowing orodispersible abilities tablets, should films, be considered pellets, or when minitablets) administering could oralbe safely solid formsadministered. for children. However, Nevertheless, the individual numerous swallowing studies proved abilities that pre-schoolshould be (upconsidered to 6 years when old) andadministering even infants oral (6 monthssolid forms old) for are children. able to safely Nevertheless, swallow particlesnumerous smaller studies than proved 3 mm that (minitablets, pre-school pellets)(up to 6 [ 23years–26 ].old) While and even both infants liquid and(6 months solid formsold) are are able available to safely in swallow paediatric particles therapy, smaller there than are not3 mm many (minitablets, MR formulations pellets) dedicated[23–26]. While for children.both liqu MRid and dosage solid formsformsensure are available drug release in paediatric in the entiretherapy, gastrointestinal there are not tractmany providing MR formulations constant dedi drugcated concentration for children. and MR eliminating dosage forms the necessityensure drug of takingrelease several in the entire doses gastrointestinal a day, hence improving tract provid pharmacotherapying constant drug eff concentrationectiveness [19 and,27]. eliminating Additionally, the itnecessity is worth emphasizingof taking several that utilizingdoses a MRday, technologyhence improving creates apharmacotherapy possibility of increasing effectiveness drug stability. [19,27]. Additionally, it is worth emphasizing that utilizing MR technology creates a possibility of Int. J. Mol.