Mini-tablets have recently raised huge interest in pharmaceutical industry. The present review aims to identify the rational, the opportunities and challenges of this emerging small solid drug dosage form by a structured literature review following the PRISMA algorithm. In total, more than 5,000 literature and patent sources have been found starting with the very first in the 60s of the past century, followed by the first multiparticular products using mini-tablets with pancreatin (Panzytrat® by the former BASF subsidiary Knoll/Nordmark) authorized in 1985. There seems to be a second boost of common interest in the 2000s when clinical studies demonstrated that one or more mini-tablets could enable superior drug administration even in very young patients including neonates over the former gold standard, a liquid drug preparation. Several pharmaceutical companies immediately started clinical development programs using the mini-tablet concept and the first products have been recently authorized by the competent authorities. Superiority was given as the mini-tablets ease the swallowing procedure compared to conventional tablets, enable various modified drug release opportunities including taste-masking by film-coating technology and provide excellent drug stability compared to liquid oral dosage forms. Due to these product attributes they are particularly beneficial to children and their caregivers. Furthermore, there is potential for precise individual drug dosing by counting adequate amounts of the multiple drug carriers. Most recently, two novel products with different concepts were authorized by the EMA and entered the market which are highlighted in this review: the first orodispersible mini-tablet with enalapril maleate for congenital heart failure (Aqumeldi® from Proveca Pharma) and the first single unit mini-tablet with matrix-type controlled melatonin release for insomnia (Slenyto® from Neurim Pharmaceuticals). Our review reveals, that the majority of the published scientific papers use co-processed, ready-to-use excipients for the orodispersible mini-tablet formulations. However, traditional fillers such as microcrystalline cellulose or lactose have also been used for immediate release mini-tablets after adding a (super)disintegrant and a lubricant. The manufacturing of mini-tablets is conducted on conventional rotary tablet presses, predominantly equipped with multi-tip toolings to improve the yield or production speed. Scaling-up has been successfully realized from compaction simulators to pilot and production scale. Film-coatings enabling gastric resistance, taste masking or sustained-release properties have been realized in both fluid-bed and drum coaters using the same polymers as for conventional tablets. There is still a significant lack in regulatory guidance despite the recent success of the mini-tablet concept, starting from suitable characterization methods in the pharmacopoeias up to the design and conduct of clinical studies on mini-tablets.

This single-centre, open-label, randomised, parallel-group study assessed the acceptability, swallowability, palatability, and safety of film-coated, 3 mm diameter mini-tablets in children aged ≥2–<7 years. In total, 300 participants were randomised (2:2:1:1) to receive a single oral administration of 16 (group A) or 32 (group B) mini-tablets with soft food or 16 (group C) or 32 (group D) mini-tablets with water. Children in each group were stratified by age group (2–<3 years; 3–<4 years; 4–<5 years; 5–<6 years; and 6–<7 years). Groups C and D were pooled for statistical analyses. The rates of acceptability (swallowed ≥80% of the mini-tablets with or without chewing), swallowability (swallowed all mini-tablets without chewing or any leftover), and palatability (positive/neutral responses) were ≥80.0%, ≥42.0%, and ≥82.0%, respectively, across the study groups. No marked differences were observed between groups or across age groups. No adverse events or issues of clinical relevance with deglutition were reported. Mini-tablets taken with soft food or water provide a suitable method for administering medicines to children aged ≥2–<7 years. This study was registered in the German Clinical Trial Register (No. DRKS00024617).

Introduction: A medicine’s acceptability is likely to have significant impact on pediatric adherence. The importance is underlined in EMA and FDA guidance on this topic where investigation of acceptability is stated as a regulatory expectation. Demonstrating acceptability can be challenging given there is no globally recognized definition and no standardized testing methodology or assessment criteria. Palatability and swallowability are generally recognized as important elements of acceptability, and this work proposes a definition of acceptability using these elements to give a composite endpoint for acceptability for pediatric subjects across all age ranges. Methods: This composite acceptability endpoint is based on validated assessment methods for swallowability and palatability in children of different age groups using different galenic placebo formulations, in line with criteria proposed by EMA for assessing acceptability in children from newborn to 18 years of age. Data from two studies investigating mini-tablets, oblong tablets, orodispersible films, and syrup were analyzed to establish the validity, expediency, and applicability of the suggested composite acceptability assessment tool. Results: The new composite endpoint is an efficient and suitable way to distinguish preferences of oral formulations: Mini-tablets and oblong tablets had significantly better acceptability than syrups and orodispersible films. Conclusion: Since the suggested acceptability criteria takes both swallowability and palatability into account as composite endpoint, it is highly sensitive to detect acceptability differences between oral formulations. It is a well-defined valid approach, which meets regulatory requirements in an appropriate and comprehensive manner and may in future serve as a pragmatic, standardized method to assess and compare acceptability of pediatric formulations with active substances.

Although medicine acceptability is likely to have a significant impact on the patient’s adherence in pediatrics and therefore on therapy success, there is still little data even for common therapeutic areas. For analgesics/antipyretics, healthcare professionals face a wide variety of products and need knowledge to select the best adapted product for each patient. We investigated acceptability of those products most used at the University Children’s Hospital Düsseldorf, Germany. Based on 180 real-life observer reports of medicine intake, we used the acceptability reference framework to score acceptability of six distinct medicines. Both ibuprofen and paracetamol tablets, mainly used in adolescents, were positively accepted. This was not the case for the solution for injection of metamizole sodium. Regarding syrups, mainly used in children under 6 years of age, ibuprofen flavored with strawberry and provided with an oral syringe was positively accepted, while paracetamol flavored with orange and provided with a measuring cup was not. Suppository appeared to be an alternative to oral liquids in infants and toddlers with palatability and administration issues. Differences appeared to be driven by dosage forms and formulations. These findings improve knowledge on acceptability drivers and might help formulating and prescribing better medicines for children.