The Development of Minitablets for a Pediatric Dosage Form for a Combination Therapy

Minitablets are an appealing option for an age-appropriate pediatric dosage form. In particular, for combination therapies where multiple active ingredients are dosed simultaneously, the use of minitablets will enable independent adjustments of each dose. The work presented describes the development of Compound A and Compound B minitablets for a combination therapy. Since both actives are formulated as spray dried amorphous solid dispersions (ASDs) due to low solubility of their crystalline forms, the choice of minitablets for the pediatric dosage form allows the application of the same formulation strategy across different age groups. To address the potential need for taste-masking, an ethylcellulose-hydroxypropyl cellulose coating system was developed. In-vitro performance testing was conducted to guide coating development and to ensure proper taste-masking without slowing down API dissolution in the GI tract that can negatively impact exposures. As a result, the exposure of orally dosed coated tablets was comparable to those of uncoated minitablets in the canine model. The work presented can serve as a case study on how minitablets can be designed and developed as an appropriate pediatric dosage form for a combination therapy comprised of ASD of active ingredients. Continue reading on The Development of Minitablets for a Pediatric Dosage Form for a Combination Therapy

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Materials
Compound A and Compound B were produced in-house by Merck & Co. Inc., Kenilworth, New Jersey, USA. Polyvinylpyrrolidone/vinyl acetate co-polymer (PVPVA, Kollidon® VA64) and sodium lauryl sulfate (SLS) were obtained from BASF (Ludwigshafen, Germany). Vitamin E TPGS was obtained from Isochem (Vert-le-Petit, France), and hypromellose (HPMC) 2910 was obtained from Shin-Etsu Chemical Co., Ltd (Tokyo, Japan). Acetone, which was used as a solvent during spray-drying, was obtained from Thermo Fisher Scientific (Bridgewater, New Jersey).
The following tableting ingredients were also used to prepare the minitablets: mannitol (Pearlitol® SD 100, Roquette America Inc., Keokuk, Iowa), microcrystalline cellulose (Avicel® PH102, DowDuPont Inc., Midland, Michigan), croscarmellose sodium (AcDiSol SD-711, DowDuPont Inc., Midland, Michigan), colloidal silicon dioxide (CabOSil® M 5P, Cabot Corp., Boston, Massachusetts), sodium chloride powder (Morton Salt Inc., Chicago, Illinois; NaCl added for helping disintegration, and magnesium stearate (Avantor Performance Materials, LLC., Center Valley, Pennsylvania)

Conclusion
The work presented in this paper describes the development of robust Compound A and Compound B minitablets. It was found that the high tensile strength required by the minitablets did not impact the drug release due to the high surface area available for dissolution. The intergranular addition of excipients helped to decrease segregation during compression to achieve content uniformity. In the development of functional coating for taste-masking, both invitro and in-vivo tools were developed to help select a coating level that would strike a balance between providing adequate
taste-masking and minimizing the delay of API dissolution. The data showed rapid release of both APIs for minitablets with 15% coating both in-vitro dissolution and in a canine model for bioperformance. Concomitantly, the coating retarded API dissolution in the soft food, achieving taste-masking benefit. Although ultimately a human taste panel study showed that coating the minitablets was not necessary to increase the palatability of the minitablets, a coating system comprised of Surelease:HPC at 75:25 wt% ratio could delay the release of potentially unpalatable API without adversely impacting the exposure of Compound A and Compound B. The work presented serves as a case study for the design and development of minitablets as an appropriate pediatric dosage form of a combination therapy with ASD APIs.