The revival of the mini-tablets: Recent advancements, classifications and expectations for the future.

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 60 s 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 2000 s 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.