(W1130-12-72) In Vitro Evaluation of an Extended Released Methylphenidate Hydrochloride Product Sprinkled on Food Vehicles

Purpose: Sprinkle administration of capsule content with soft food is a common practice to improve swallowability [1, 2]. However, taking the medications with food vehicles prior to oral administration may alter the potency and stability of the drug product, also possibly increase side-effects [3-5]. Methylphenidate hydrochloride (MPH) sprinkle formulation is used for the treatment of attention-deficit hyperactivity disorder in children who prefer their medications to be sprinkled on a small amount of food vehicles prior to administration. The objective of this study is to develop in vitro analytical and characterization methods for an extended release (ER) MPH drug product sprinkled onto different amount of food vehicles, and to assess the integrity and in vitro dissolution of enteric-coated granules exposed to food vehicles.

Methods: An electronic pH meter (Mettler-Toledo, OH, USA) was used to measure food vehicle pH. A Discovery Hybrid Rheometer (TA Instruments Inc. DE, USA) was used to measure the viscosity of food vehicles. The MPH ER drug product (JORNAY PM, 40 mg) was purchased from WEP Clinical. The MPH ER capsule was opened, and drug contents were sprinkled onto 15 mL or 15 g of food vehicles for 2 hours before dispersing the granules on a glass slide to measure granule diameter, length, and width using a static auto imaging system (Morphologi 4-ID, Malvern, UK). The surface features, internal structure, and elemental analysis of drug product were examined using a scanning electron microscope coupled with energy-dispersive X-ray spectroscopy (SEM/EDX, TESCAN Mira3, PA, USA). An Ultra Performance Liquid Chromatography (UPLC) method was developed and validated using Acquity UPLC (Waters, MA, USA) for the analysis of drug content and drug dissolution. For dissolution study, the weight of six capsules were individually weighed and recorded. Capsules were opened and mixed with apple juice (15 mL) or applesauce (5 or 15 g) and kept at room temperature for 2 hours before conducting the dissolution studies. The food-drug mixtures were placed into baskets (40 mesh) and operated as per USP 1 apparatus method at 75 rpm, 37 ̊C. Dissolution testing was conducted at 3 stages: Stage 1 (0-2 hours) in 700 mL of pH 1.2 hydrochloric acid (HCl); Stage 2 (2-6 hours) in 900 mL of pH 6.0 phosphate buffer; and Stage 3 (6-24 hours) in 910 mL of pH 7.2 phosphate buffer. Samples were withdrawn at 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, 22, and 24 hours.

Results: Mean pH of applesauce and apple juice were 3.61 ± 0.02 and 3.63 ± 0.01, respectively. The pH values of tested food vehicles were less than pH 7.0, which is the dissolution and ionization threshold of enteric methacrylic acid copolymer. Apple juice exhibited low viscosity (0.001±0.00 Pa.s), while applesauce showed higher viscosity (0.643±0.136 Pa.s). Mean particle size of MPH ER granules before sprinkle administration was 861±47 µm. The particle size of granules exhibited minimal change (p >0.05) after being sprinkled on applesauce (815±70 µm) and apple juice (825±74 µm) for 2 hours. The circularity, aspect ratio, and convexity of the particles were greater than 0.9, and the elongation ratio is near 0, which mean that particles remain round and smooth in shape after being sprinkled. SEM/EDX images confirmed that MPH ER granules were fully covered by the enteric coating layers. The structure of the enteric coating was not affected by acidic food vehicles (i.e., applesauce and apple juice). However, the in vitro dissolution of drug-food mixtures revealed that drug dissolution rate in stage 3 differed when different food vehicles were used for sprinkle.  For sprinkle administration with apple juice (15 mL) and applesauce (15 g), less than 0.5% drug dissolution was observed during stage 1 (pH 1.2) and stage 2 (pH 6.0). After transition to stage 3 media (pH 7.2), approximately 100% drug dissolution was achieved in 24 hours. However, the dissolution time of 50% of the label content for drug-apple juice mixture and drug-applesauce mixture was 14 and 16 hours, respectively. The similarity factor for these profiles (apple juice 15 mL vs. apple sauce 15 g) was 46. When the amount of apple sauce used for sprinkle changed from 15 g to 5 g, the dissolution rate at stage 3 was increased and the similarity factor (apple sauce 5 g vs. apple juice 15 mL) was 76.

Conclusion: The in vitro analytical and characterization methods for an MPH ER drug product were successfully developed.  The characterization results (e.g., analysis of granule morphology) showed that the integrity of the MPH ER drug product remained unaltered after being sprinkled on applesauce and apple juice for 2 hours. However, dissolution studies revealed that a higher amount of food incorporated in the dissolution baskets resulted in slower drug release. Further studies would be needed to properly assess the impact of the soft food volume used in the dissolution studies on in vitro drug performance.

References: 1. Liu, F., et al., Patient-centered pharmaceutical design to improve acceptability of medicines: similarities and differences in pediatric and geriatric populations. Drugs, 2014. 74(16): p. 1871-1889.
2. Lee, H.S., et al., Sprinkle formulations-A review of commercially available products. Asian J Pharm Sci, 2020. 15(3): p. 292-310.
3. Martir, J., et al., Impact of Food and Drink Administration Vehicles on Pediatric Formulation Performance Part 2: Dissolution of Montelukast Sodium and Mesalamine Formulations. AAPS PharmSciTech, 2020. 21(7): p. 287.
4. Pavloff, N., et al., The effect of food and liquid pH on the integrity of enteric-coated beads from cysteamine bitartrate delayed-release capsules. Drug design, development and therapy, 2018. 12: p. 2795.
5. Wells, K.A. and W.G. Losin, In vitro stability, potency, and dissolution of duloxetine enteric-coated pellets after exposure to applesauce, apple juice, and chocolate pudding. Clinical therapeutics, 2008. 30(7): p. 1300-1308.

Acknowledgments: This project was supported in part by the appointment of Kai-Wei Wu and Md Sohel Rana to the Research Participation Program at the CDER/OPQ/OTR of the U.S. FDA, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the FDA.
Disclaimer: This abstract reflects the views of the authors and should not be construed to represent the FDA’s views or policies.