Technological advancements in minitablet (MT) manufacturing, combined with an improved understanding of their palatability and ease of swallowing for children, are fueling interest in MTs as a preferred pediatric dosage form. Despite their numerous advantages in flexibility and patient compliance, MT production presents unique challenges. Collaborating with a seasoned contract development and manufacturing organization (CDMO) like Mikart is crucial for leveraging these advancements in both new drug development and life cycle management strategies.
Growing Appeal of Minitablets in Pediatric Care
Historically, most drugs were developed with adult patients in mind, often overlooking the unique requirements of children. This oversight has seen a shift in both the United States and Europe, where regulatory frameworks now mandate the development of formulations specifically for pediatric use. These regulations have propelled drug developers to seek versatile solutions that cater to the nuanced needs of children across all age groups, from infants to adolescents.
Minitablets (MTs) have emerged as a particularly promising technology in pediatric targeted formulation. Their development has been spurred by advancements in manufacturing equipment and a deeper understanding of their benefits in pediatric care — especially their ease of swallowing and improved palatability, which are crucial for acceptance by young patients.
The small size of MTs, typically less than 4 mm in diameter, circumvents the challenges faced with traditional oral solid dosage (OSD) forms, which remain the preferred format owing to their stability and ease of administration.1
Traditionally, liquid formulations have often been preferred for infants and toddlers owing to their inability to swallow normal tablets. Cutting and crushing tablets to mix with food presents the potential for inaccurate dosing and can disrupt taste-masking and controlled-release coatings. For children, exposure to the bitter taste of APIs can greatly impact their willingness to take the medicine. The same issue exists with liquids, however, which expose the entire oral cavity. MTs avoid these pitfalls by allowing for precise dosing without the need for modification, and their minute size means they can be administered directly or mixed into food without the child being aware of the medication, thereby maintaining the effectiveness of taste-masking without compromising swallowability. Data suggest that over 90% of children are able to swallow minitablets.2
The adaptability of MTs extends beyond simple administration. They allow for flexible dosing, which is essential in pediatric medicine where dose requirements can vary significantly with age and body weight. Innovations in dosing devices have been developed to dispense exact numbers of MTs, enabling tailored and precise dosing for individual patients.3 Moreover, MTs reduce the risk of dose dumping and can be taken with or without food, offering consistent drug delivery.1
Fixed-dose combination products supporting a range of therapeutic needs are also possible by combining multiple coated MTs with different release profiles, including delayed, extended/sustained, pulsatile, or biphasic release, in a capsule or sachet.3 They allow for the independent adjustment of doses of each active ingredient, which is particularly useful in treatments requiring tight control over drug ratios and interactions.4
This flexibility makes MTs comparable to more complex multiparticulate systems but with the added benefits of easier manufacturability and potentially lower costs. Minitablets include more reproducible size and weight and a smoother surface.5 The latter supports more efficient coating processes, reducing time and material consumption and hence costs and producing more stable products. Furthermore, immediate-release MTs can be formulated using orally disintegrating and orally dispersible, effervescent, and other technologies. MTs can also be designed to be gastroretentive or to target the colon and for vaginal, ocular, sublingual, and buccal delivery.1
Beyond these advantages in formulation, MTs can support more efficient drug development. The flexible dosing capability readily supports clinical dose-finding studies.1 Early-phase development timelines and costs can also be reduced by enabling early performance of stability and other testing (e.g., tabletability, compactability, and compressibility) of potential formulations using minimal amounts of expensive APIs. MTs also serve as a means for extending product life cycles by enabling dosing adjustments for different patient populations. In fact, many big pharma companies pursue development of minitablet formulations as a strategy to limit potential generic competition.
Technical Demands of Minitablet Manufacturing
Manufacturing MTs presents unique challenges, especially given their small size. One of the primary issues is the difficulty in visualizing these tiny tablets, particularly microtablets, which often require magnification to inspect for any defects. This inspection is crucial, as the miniaturization of these tablets can amplify issues typically encountered in traditional tablet production. For example, the multi-tip tools used in standard tableting machines feature delicate die tips that are prone to breakage, yet detecting such damage can be quite challenging.
Proper powder flow is critical, as each MT uses only a minimal amount of material. Any compaction in the feed can lead to inconsistencies in die filling, tablet weight, and drug content, thus demanding powders with optimal properties for consistent production.1 Once the tablets are manufactured, handling them is not straightforward; issues such as dusting and static electricity can interfere with the smooth transition of MTs down the discharge chute. Moreover, accurately determining the weight of individual MTs is impractical; typically, batches of 50 to 100 tablets are weighed multiple times to mitigate counting errors. This necessitates specialized coating processes and precise analytical techniques to maintain quality and consistency.
Another significant consideration is the requirement for excipients with smaller particle sizes (less than 1 mm), to support effective MT formulation. These small particles must have suitable flow properties, requiring a careful balance of particle shape, morphology, density, and size to ensure proper functionality and performance.
A complicating factor in the production of MTs is the absence of specific regulatory guidelines tailored to these formulations. In the United States, manufacturers often refer to the FDA's guidance on Size of Beads in Drug Products Labeled for Sprinkle (revised May 2012) as a general standard for MTs, highlighting the need for more defined regulatory protocols to guide the development and approval of these innovative dosage forms.
Mikart’s Extensive Experience in Minitablet Development and Manufacturing
Mikart boasts over a decade of expertise in developing and manufacturing MT formulations, highlighting a significant track record in this specialized field. Our facility is equipped with advanced multi-tip dies, essential for producing MTs with precision and consistency.
Our capabilities extend to the application of various coating techniques, utilizing both pan and fluid-bed systems. This flexibility allows us to create diverse taste-masking solutions and controlled release profiles tailored to specific therapeutic needs. Mikart's pilot-scale equipment facilitates the seamless transition from small-scale development to larger production scales. This adaptability is crucial for efficiently scaling up operations without compromising product quality and supports the production of smaller-volume batches tailored to niche markets.
Moreover, our team of subject matter experts is adept at rapidly prototyping multiple versions of a product, enabling us to explore various formulation strategies. This rapid prototyping capacity is invaluable for determining the most suitable dosage form — whether MTs, multiparticulates, or orally dispersible tablets — for any given drug, indication, or patient demographic.
Mikart currently has the capacity to support a range of minitablet programs, from development and clinical trials to full-scale commercial production. We are actively seeking collaborations and welcome inquiries from potential clients looking to leverage our specialized capabilities in minitablet formulation and manufacturing.
References
1. Meruva, Saikishore, et al. “Current State of Minitablet Product Design: A Review.” Journal of Pharmaceutical Sciences. 113: 1123-1154 (2024).
2. Thomson, Sarah A. et al. “Minitablets: New Modality to Deliver Medicines to Preschool-Aged Children.” Pediatrics. 123: e235–e238 (2009).
3. Zuccari, Guendalina et al. “Mini-Tablets: A Valid Strategy to Combine Efficacy and Safety in Pediatrics.” Pharmaceuticals (Basel). 15: 108 (2022).
4. Zhang, Dan et al. “The Development of Minitablets for a Pediatric Dosage Form for a Combination Therapy.” Journal of Pharmaceutical Sciences. 109: 3590–3597 (2020).
5. Lura, Ard, Guillaume Tardy, Peter Kleinebudde, and Jörg Breitkreutz. “Tableting of mini-tablets in comparison with conventionally sized tablets: A comparison of tableting properties and tablet dimensions.” International Journal of Pharmaceutics: X. 2: 100061 (2020).
