The Feasibility of the Repeated Administration of Acetylsalicylic Acid Mini-Tablets to Children with Kawasaki Disease: A Pilot Study

Ensuring access to appropriate pediatric medicine led the World Health Organization in 2008 to propose solid oral dosage forms as the preferred formulation for pediatric use [1]. In Japan, the most commonly used pediatric dosage forms are syrup, fine granules, dry syrup, and orally disintegrating tablets [2,3]. Saito et al. [3] reported that for patients younger than 10 years (n = 354), powders such as fine granules, granules, and dry syrups are most frequently prescribed (n = 252, 71.2%). For children under 6 years, although powders remain the most common form of prescription, liquids such as syrups and suspensions are the second most frequently prescribed dosage form (n = 60, 21.0%). The frequency of tablet prescriptions increases as children grow, but remains relatively uncommon. In Japan, pharmacists typically dispense a single dose of powder into a sachet. The powder is then consumed by the patient in an unaltered state; alternatively, the parent or caregiver may add a small quantity of water or syrup to create a paste or kneaded syrup for the child to ingest [4]. However, children may refuse to take medication in powder or paste form due to its taste and texture [5], creating challenges for both healthcare providers and caregivers.

Mini-tablets represent a novel pediatric dosage form under development in Europe and the United States. These mini-tablets have the potential to prevent immediate disintegration in the oral cavity and effectively mask the taste of the drug [6,7]. Children under the age of 5 generally lack the ability to safely swallow solid capsules or tablets larger than 10 mm [8]. Moreover, global research on mini-tablets has advanced, and studies in Japan have shown that 2 mm mini-tablets are well accepted by children over 6 months old [9,10]. Similarly, in other countries, mini-tablets are found to be more acceptable for children aged 6 months to 6 years [11,12]. Children aged 2–7 years can ingest film-coated mini-tablets with soft food or water without adverse effects or dysphagia [13].

Additionally, rectangular tablets have been suggested as a safe alternative to liquid formulations and multiple mini-tablets for children aged 1–5 years [14]. Mini-tablets are increasingly seen as a practical option for pediatric patients due to their ability to provide precise dosing and safe ingredients [15]. However, previous studies have primarily investigated placebos, and it remains unclear whether mini-tablets containing active ingredients are equally well tolerated. Recent studies have demonstrated the acceptability of 3 mm mini-tablets in pediatric populations [9,12,13,14]. For example, Klingmann et al. [12] reported a 99% success rate in swallowing 3 mm mini-tablets among children aged 2–7 years, with no adverse events. Münch et al. [14] found that children aged 2–7 years could ingest 3 mm film-coated mini-tablets with soft food or water without experiencing adverse effects or dysphagia. Similarly, Thomson et al. [16] showed that children aged 2–6 years could successfully swallow a single 3 mm mini-tablet, with acceptability increasing with age. However, these studies focused primarily on placebos.

ASA is a white crystalline substance, often formulated in granular or powder form, with a slightly acidic and sour taste when taken orally [17]. Acetylsalicylic acid (ASA) gradually hydrolyzes into salicylic acid and acetic acid, contributing to its strong, distinctive taste. This degradation can occur during storage at medical institutions or in homes. In Japan, it is not uncommon for children with Kawasaki disease (KD) to be prescribed ASA for extended periods [18]. ASA is expected to demonstrate anti-inflammatory effects in the acute phase and inhibit platelet aggregation, making it a cornerstone of treatment. Rapid suppression of the intense inflammatory response during the acute phase is crucial to prevent the formation of coronary aneurysms [19].

KD is an acute, self-limited vasculitis that primarily affects children under 5 years of age. It presents with symptoms such as fever, rash, conjunctival injection, changes in the extremities, oral mucosal changes, and cervical lymphadenopathy. KD is the leading cause of acquired heart disease in children in developed countries, with coronary artery aneurysms being the most serious complication [20,21,22,23]. In Japan, KD is particularly prevalent, with an annual incidence of approximately 330 per 100,000 children under five [20]. The etiology of KD remains unknown, but it is thought to involve a complex interplay between genetic factors and environmental triggers. Early diagnosis and prompt treatment with intravenous immunoglobulin and ASA are crucial for reducing the risk of coronary artery complications [18,19].

We previously created mini-tablets capable of masking the taste and odor of ASA and conducted a pharmacokinetic study in healthy adults. This study confirmed that the mini-tablets demonstrated comparable dissolution properties and bioequivalence to ASA powder and mini-tablets [24]. However, data on the long-term administration of ASA mini-tablets in Japanese pediatric patients are lacking. This case series aimed to evaluate the clinical feasibility of the repeated administration of ASA mini-tablets in children with KD. Rather than conducting a full clinical trial, this pilot study serves as an initial evaluation of the feasibility of repeated ASA mini-tablet administration in a pediatric population. This study presents an initial evaluation of the acceptability of mini-tablets containing active ingredients in Japanese pediatric patients, addressing the unique challenges of medication administration to children with KD.

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