(W0930-03-20) In Vitro Evaluation of Two Morphine Sulfate Extended-Release Products Sprinkled on Soft Foods

Purpose: Some drug products can be sprinkled on soft foods prior to administration to improve compliance in patients affected by dysphagia. However, generic drug product formulations for the same drug substance could perform differently when mixed with soft foods. Currently FDA recommends in vivo pharmacokinetics studies to evaluate generic formulation differences when sprinkled on soft foods. Developing in vitro methodology to discriminate the effect of soft foods on the in vitro performance of different drug product formulations may be a useful predictor of in vivo performance. Two FDA approved enterically coated drugs formulations of morphine sulfate (MS) extended-release (ER) capsules, ER1 and ER2, were studied to test the impact of formulation differences on dissolution performance after exposure to soft food. The core of ER1 pellet, a reference listed drug (RLD), is a layered structure containing a sugar core coated by a layer of MS and the core of the ER2 pellet, a generic drug of the RLD, is a matrix formed with microcrystalline cellulose, where MS is mixed in. Both pellet formulations contain ethylcellulose, polyethylene glycol, and methacrylic acid copolymer. Both drug products were sprinkled on soft foods with different properties expected to influence dissolution performance and the products were subsequently characterized for the resulting changes in dissolution, water content, and mechanical strengths.

Methods: Four soft foods, applesauce, vanilla yogurt, carrot puree, and chocolate pudding, with different characteristics were selected to study the effectiveness of the in vitro methods in detecting product performance changes. Applesauce is the only soft food described on the product labeling approved for sprinkle administration of MS ER products while the others studied are not. The pH of the soft foods was measured with a pH meter. MS ER pellets from either ER1–10 mg, ER2–100 mg, ER2–10 mg, or ER2–100 mg was sprinkled into the soft foods for 2 h to test effectiveness of the in vitro method. Dissolution was performed with a 2-stage United States Pharmacopeia (USP) dissolution Test 1 for MS ER capsules (n=6). Water content was analyzed on a thermogravimeter (n=3). Pellet diameter, cracking force and cracking distance were analyzed on a texture analyzer (n=40 pellets). Cracking distance was normalized to 1 mm to account for the diameter difference in ER1 and ER2. Non-sprinkled pellets were used as controls for all tests. An f2 similarity test compared to the individual non-sprinkled control pellets was employed for dissolution profile comparison.

Results: The pH values of applesauce, vanilla yogurt, carrot puree, and chocolate pudding, were 3.69±0.01, 4.28±0.01, 5.05±0.01, and 6.19±0.01, respectively. For all four products, percent drug dissolved at 1 h (Table 1) increased in high pH compared to low pH soft food. For ER1-10 mg and ER-100 mg, the average percent MS dissolved was within individual specified ranges recommended by the USP (percent morphine-release ≤ 10% at 1 h, 25 – 50% at 4 h, 50 – 90% at 6 h, and ≥ 85% at 9 h) irrespective of the soft food. For ER2-10 mg and ER2-100 mg, this was within the USP specified range when sprinkled on applesauce and vanilla yogurt but outside the range at 1 h and 4 h when sprinkled on carrot puree and chocolate pudding. Compared to control pellets, ER1-100 mg resulted in an increase in mean percent dissolved at 1 h with chocolate pudding (8.3±1.0%), followed by carrot puree (6.8±0.3%); but f2 test for both groups passed with values of 68.9 and 68.6, respectively. In ER2-10 mg, the largest increase in drug dissolution occurred in chocolate pudding (26.7±4.2%), followed by carrot puree (21.0±2.3%); the f2 test for both groups failed with values of 28.7 and 31.9, respectively. The mean diameters of ER1-10 mg and ER1-100 mg control pellets are 1.20±0.1 mm, and 1.26±0.1 mm, respectively; while mean diameter of ER2-10 mg and ER2-100 mg pellets are 0.86±0.2 mm, and 0.90±0.1 mm, respectively. Sprinkle administration did not show any definitive impact on the pellet diameters. Water content of sprinkled pellets were higher compared to the individual control groups for ER1 and ER2 with the highest water content occurring after being sprinkled over high pH soft foods. Non-sprinkled pellets for each strength had lower cracking distance and higher cracking force compared to sprinkled pellets. Pellets from ER1-10 mg and ER1-100 mg formulation showed longer median normalized cracking distance compared to ER2-10 mg and ER2-100 mg when sprinkled over soft foods. These results can be useful to develop in vitro-in vivo relationship models for MS ER drug products sprinkled in soft food.

Conclusion: Higher percent MS release was observed for ER2 pellets sprinkled outside the labeling conditions compared to ER1 pellets which could be attributed to their difference in structure and excipients. The in vitro methods developed for MS ER drug products sprinkled in different types of soft food were able to detect changes in product performance after exposure to soft foods in various conditions.