(T1230-02-11) Formulation Development and In-Use Sprinkle-on-the-Food Stability of Delayed-Release Pellets in Capsules: A Case Study

Purpose: While immediate-release dosage forms are intended to release the active drug immediately after administration to patients and are associated with relatively rapid drug absorption and onset of therapeutic effect, modified-release dosage forms are designed/engineered to alter the release pattern. The modified-release pattern may be in the form of delayed-release, where dosage form dissolution occurs at pH values higher than the gastric pH (small intestine or colon), or extended-release. In both modified-release and extended-release, the rate of drug release is engineered to achieve certain therapeutic or convenience outcomes ^[1]. One of the versatile and complex technologies in the area of modified-release dosage forms is the pellet coating process. In a typical pellet or bead coating process, the drug is layered on a “core” along with certain excipients/polymers with various dissolution characteristics. Unlike conventional tablet or capsule dosage forms, sprinkle-on-the-food dosage forms, including minitablets, granules, pellets or powders, offer several advantages, including flexibility and convenience in administration and improved patient compliance, especially for pediatric and/or geriatric patient populations with dysphagia. One of the important aspects of the sprinkle-on-the-food dosing technique is the stability of the base formulation/dosage form for certain time intervals when mixed with the vehicle/food prior to administration. This study detailed the formulation and manufacturing process of a delayed-release enteric coated pellet of an acid-labile API along with in-use stability studies of the dosage form when sprinkled on apple sauce and apple juice. Assay/impurity and dissolution characteristics of the pellet were studied at certain time intervals upon mixing with the soft food vehicles. The design of the delayed-release coated pellet is presented in Figure 1. Note that due to the proprietary nature of the active ingredient, it is referred to as “Compound X”. The active ingredient was a water-soluble API and highly unstable in gastric pH. Therefore, an enteric coated pellet formulation was developed to achieve target drug release profile and desired stability.

Methods: Core sugar spheres (Suglets 710/850) were first coated with ethylcellulose (Ethocel Standard 10 Premium) using Hüttlin process (Hüttlin HDGC-200). Product temperature was maintained within (20 - 40) °C and spray rate was kept in the range of 0.1-1kg/hr of coating solution (7% solids in ethanol). Upon completion of the base coat, the beads were dried with inlet air temperature of 60°C for fifteen (15) minutes. Drug layering was conducted using 5.9% of Compound X (in salt form), 1.2% magnesium oxide heavy, 1.47% Hypromellose, and Type 2910 (Pharmacoat 606, as binder). Drug feed solution was an aqueous dispersion with 14.6% solids. Fluid bed process was accomplished with product temperature of (20 - 50) °C. Upon completion of the coating process, pellets were dried in fluid bed with 50 °C for five (5) minutes. Third layer seal coat was a Hypromellose, Type 2910 (Pharmacoat 606) coated onto the drug with total weight gain of 6%. Delayed (enteric) coating was done using Hypromellose Phthalate (HPMCP HP-55) with 11.7% weight gain. Coating process was conducted using product temperature of (30 - 50) °C followed by drying at 50 °C for ten (10) minutes. Pellets were filled into capsules to achieve 5mg and 10mg strength final dosage form. For in-use stability assessment, 20 capsules of 5mg strength or 10 capsules of 10mg strength were opened and pellets added to 15mL of apple juice and 15mL apple sauce for 15, 30 and 45 minutes. The pellets were then collected on a wire mesh, washed and tested for assay/impurity and acid dissolution.

Results: Results of the assay test of the pellets (5mg and 10mg) are shown in Figure 1. It was observed that the assay remained unchanged after exposure to both apple sauce and apple juice for 15, 30 and 45 minutes. All the samples met the specification of 90-110% at all time points and exposure to soft food. Impurity assessment of pellets after mixing with apple sauce and apple juice showed no growth in known and unknown impurities. All recovered samples met specification of total degradation products ≤2.0%. Results of the dissolution study showed that at all time points and in both apple sauce and apple juice, not more than 10% of the drug was released in acid stage dissolution, demonstrating the integrity of enteric coating in the tested soft food.

Conclusion: This case study demonstrates that acid-labile Compund X delayed-release pellets remained stable when added to apple juice and apple sauce for 15, 30 and 45 minutes due to multi-layered coating technology.

References: [1] Murugesan, Senthilkumar, Byran Gowramma, Kaviarasan Lakshmanan, Veera Venkata S. Reddy Karri, and Arun Radhakrishnan. "Oral modified drug release solid dosage form with special reference to design; an overview." Current Drug Research Reviews Formerly: Current Drug Abuse Reviews 12, no. 1 (2020): 16-25.