(W0930-03-16) Development of Metformin HCL Sprinkles for Pediatric Oral Administration Using Hot-Melt Extrusion

Purpose: Recently, the Centers for Disease Control and Prevention (CDC) published worrying data about the significant increase in the number of children and young people living with type 2 diabetes (1). Metformin Hydrochloride (HCL) was the first antidiabetic medication to be approved by the FDA for pediatric use in patients older than 10 years of age (2). Therefore, developing formulations that will increase the compliance of pediatrics using metformin HCL has become a necessity. The most challenging aspect in developing a pediatric formulation is taste masking the bitterness of metformin HCL. Therefore, in this research we attempted to prevent the release of metformin HCL until the drug is fully swallowed. A pH dependent polymer (Eudragit^® EPO) was used that will only solubilize in pH values under 5 (3), therefore preventing the release of the drug in saliva (pH 6.8). The aim of the study is to develop a metformin HCL sprinkle dosage form as a taste masked child friendly formulation using hot-melt extrusion technology.

Methods: The formulation was developed with two different drug loads (20% and 40%) to be compared to pure metformin HCL. The physical blends were mixed using MaxiBlend (GlobePharma) for 10 minutes. Then MiniLab II (Thermo Scientific) was used to hot-melt extrude the formulations at a temperature of 130 °C with screw speed set at 50 rpm/min. A round die was used to yield a thin filament that was then cut into sprinkles with lengths shorter than 2.5 mm. The drug content of both drug loads formulations was evaluated. Then, drug release was performed using USP dissolution apparatus 1 (ERWEKA light) for the two formulations and the pure drug. A dissolution medium of 1000 mL buffer solution with a pH of 6.8 was used and the rotation speed was set at 100 rpm/min. Samples were collected at 10, 20, 30, 40, 50, 60, and 90 seconds. The collected samples were then analyzed using High-Performance Liquid Chromatography (HPLC). The Mobile phase consisted of 60 % Acetonitrile and 40 % phosphate buffer with a pH of 5.7. The flow rate was set at 1 ml/min, the injection volume was set at 20 µL and the Atlantis^® T3 5 µm 4.6 x 250 mm Column was used. The peaks were detected at a wavelength of 233 nm.

Results: The extrusion process went smoothly with the torque values between 1.2 and 1.4 Nm. The extruded filaments were creamy white in color with brittle texture resulting in perfectly shaped sprinkles after cutting (Figure 1). The drug content was assessed for both drug load formulations and was found to be within acceptable range. Both drug loads showed minimal release in the dissolution medium (pH 6.8) compared to the pure drug (Figure 2). At 10 seconds, the pure drug released approximately 83.8% of its content into the dissolution media whereas the 20% and 40% drug load formulations released only 6.1% and 5.2%, respectively. After 90 seconds, the pure drug release increased to reach 86.7% whereas the release of the formulation in both drug loads remained minimum between 7.3 – 8.3 %.

Conclusion: The results from the performed studies indicate that the drug was entrapped into the polymeric carrier, Eudragit^® EPO, preventing its release and thus theoretically eliminating the bitter taste. The use of hot-melt extrusion and Eudragit^® EPO as a polymeric carrier has successfully masked the taste of metformin HCL sprinkle formulation. This finding has a promising potential to impact the development of pediatric formulations.

References: 1. CDC Newsroom. Centers for Disease Control and Prevention. [Online] August 24, 2021. https://www.cdc.gov/media/releases/2021/p0824-youth-diabetes.html.
2. Use of Metformin in Pediatric Patients. Buck, Marcia L. 7, July 2004, Pediatric Pharmacotherapy, Vol. 10.
3. Pharmaceutical significance of Eudragit: A review. Ch. Niranjan Patra, Richa Priya, Suryakanta Swain, Goutam Kumar Jena, Kahnu Charan Panigrahi, & Debashish Ghose. s.l.: Elsevier, 2017, Future Journal of Pharmaceutical Sciences, Vol. 3, pp. 33-45.

Figure 1: The extruded filaments after cutting them into sprinkles.

Figure 2: A comparison between the drug release % of pure Metformin HCL, 20% drug load formulation, and 40% drug load formulation in simulated saliva pH 6.8.