(T1330-08-52) Developing a Minitablet Formulation for an NCE to Enable Dose and Administration Flexibility in Pediatric Clinical Trials

Purpose: To develop a flexible minitablet formulation supporting a broad dose range (0.2–30 mg) for pediatric patients (ages 3–12 years old), enabling precise dose titration and adaptable administration via sprinkle capsules.

Methods: The API was formulated to 2.0 mm diameter minitablets with an 7.1 mg image. To meet the requirement of flexible dosing regimen, the 0.05 and 0.5 mg potency minitablets, respectively, were developed and filled into sprinkle capsules at different counts to achieve the 0.2, 2.0, 3.0, and 5.0 mg dose strengths, respectively (Figure 1). This strength design enables precise dose titration from 0.2 to 30 mg with 0.2 mg as the minimum increment, accommodating the diverse weight and age requirements of pediatric patients. The formulation presented significant content uniformity challenges due to the extremely low drug loading (0.70%) and the image as low as 28.4 mg for 4 minitablets in a single capsule. To address these challenges, the formulation mainly contained microcrystalline cellulose (Avicel PH-102) and mannitol (Pearlitol 200 SD) to improve powder flow properties. The roller compaction process condition plus the use of 0.63 mm fine milling screen effectively mitigated segregation risks while ensuring uniform drug distribution and granule flow characteristics. For tablet compression, high-precision tablet press equipped with 2.0 mm diameter multi-tip punches were employed, maintaining tight control over compression parameters. The powder flowability was assessed by Flodex measurements, and the segregation potential for the lowest dose (0.7% drug load) was evaluated by segregation index. Tablet weight during compression process and content uniformity were also tested. To ensure precise dosing, the exact number of minitablets are filled into the capsules by counting using precision counting mechanism specially equipped on the encapsulators. The low image (28.4 mg for 4 minitablets encapsulated in a sprinkle capsule) requires particularly high encapsulation precision. Encapsulation speed with adequate minitablet feeding rate was optimized. Prior to encapsulation, all capsule shells underwent weight sorting. Encapsuled capsules were 100% weight checked against the acceptance criteria of the target weight ± 3.0 mg. Minitablets were film coated to improve the palatability and were designed for flexible administration either directly or mixed with soft foods, making them particularly suitable for infants and preschool-aged children. In vitro compatibility study of minitablets with common soft foods was performed, including assay and stability monitoring under simulated use conditions, and biorelevant dissolution testing to evaluate potential food effects on drug release characteristics.

Results: The final lubricated blends for the two doses showed good flow characteristics with Flodex values of 18 and 22 mm, respectively. The segregation potential is low with a segregation index value of 0.03 for the 0.05 mg potency minitablet. The weight variation RSD was < 4.0% for a single minitablet and < 2.0% for four-tablet units whose content uniformity acceptance value (AV) was < 4.0 (Figure 2). The encapsulation process optimization and weight check approach ensured high accuracy across all batches based on the 100% weight sorting results. CLASSY KISS Yogurt and Mott’s apple sauce were selected as the soft food for dosing. Minitablet is compactible with the soft food with no significant assay change when mixed in for up to 60 minutes. As illustrated in Figure 3, biorelevant dissolution studies revealed consistent dissolution profiles between minitablets administered alone and those mixed with either soft food. These in vitro findings suggest a minimal likelihood of food-induced alterations to the in vivo pharmacokinetic performance when administered with these commonly used pediatric food vehicles.

Conclusion: A robust minitablet pediatric formulation with precise dosing was developed to support multi-age clinical studies. By optimizing composition and manufacturing process, the formulation achieved excellent weight control and content uniformity for the 0.05mg potency with extremely low drug loading (0.70%) and the lowest dose with only 4-tablet/capsule. Importantly, the formulation's compatibility with common soft foods enhances its acceptability in pediatric populations. The IND filing of the minitablet formulation has recently been approved by China NMPA.

Minitablet doses and images. a）Minitablet images; b) Information of capsule strength and encapsulated minitablets

Minitablet weight and content uniformity. a) 0.05 mg minitablet weight variation; b) 0.5 mg minitablet weight variation; c) Content uniformity of the lowest dosage unit (4 tabs/capsule)

Biorelevant dissolution of minitablet and minitablet-vehicle mixtures