(W1130-03-19) A Novel Plant-Based Orally Disintegrating Films Platform Using Hydroxypropyl β-Cyclodextrin for Pharmaceutical Product Development of Poorly Soluble Drugs

Purpose: An orally disintegrating film (ODF) is desired for pediatric and geriatric applications, improving compliance, convenient to use in absence of water as well as helpful for patients complaining of dysphagia. In addition, they can serve as an effective life cycle management strategy for a pharmaceutical drug product. In this study, we developed a novel plant-based excipient platform to investigate the solubility and release of melatonin (a poorly soluble BCS class II drug) in an ODF dosage form.  The goal was to develop an ODFs platform with consistent drug content, robust mechanical properties, and rapid disintegration, offering a patient-friendly plant-based drug delivery system.

Methods: A phase solubility study was conducted using melatonin (BOC Sciences, USA) and hydroxypropyl β-cyclodextrin (KLEPTOSE^® HPB, Roquette) as a function of increasing molar concentrations, following the method described by Higuchi and Connors [1]. The saturation solubility of melatonin in 300 mM HPβCD solution was evaluated at 25 °C and 40 °C using high-performance liquid chromatography at 282 nm wavelength (HPLC, Vanquish Core, Thermo Scientific™, MA, USA). Oral films were prepared by solvent casting, using hydroxypropyl pea starch (LYCOAT^® RS 720, Roquette), which exhibits excellent film-forming properties, as the polymer matrix, and sorbitol (NEOSORB^® P 60W, Roquette) as the plasticizer. The formulations were cast on polyethylene terephthalate (PET) sheets and dried at 25 °C/40% relative humidity for 24 hours. Two film types were prepared: Melatonin control (containing LYCOAT^® RS 720 and NEOSORB^® P 60W) and HPβCD–melatonin complex films (containing KLEPTOSE^® HPB, LYCOAT^® RS 720 and NEOSORB^® P 60W). From here on, they are referred to as M-Control and M-Complex films, respectively. The film dimensions were standardized to 11/16 × 1 5/16 inches. Physical characterization included measurement of film weight and thickness using a precision balance (Mettler Toledo) and a digital micrometer (Mitutoyo), respectively. Thermal behavior and crystallinity were analyzed by differential scanning calorimetry (DSC; Q2000, TA Instruments), X-ray diffraction (XRD; Rigaku Ultima IV), and polarized light microscopy (PLM; Olympus BX53) at 40x magnification. Mechanical properties—tensile strength, Young’s modulus, and elongation at break—were evaluated using a C texture analyzer (TA.XTplus, Stable Micro Systems, UK) equipped with miniature tensile grips, operated at a crosshead speed of 10 mm/min. Drug content was quantified from three individual films per formulation using HPLC method (described above). Disintegration testing was performed by immersing the films in 2 mL of simulated saliva (pH 6.8, Pickering Laboratories, USA) at 37 °C under mild agitation (25 RPM), and the amount of drug released in saliva at 30 seconds was quantified by HPLC.

Results: The solubility of neat crystalline melatonin at 25 °C is 1.4 mg/ml, and its solubility increased ~25-fold in 300 mM HPβCD at 25 °C and ~43-fold at 40 °C (Figure 1). DSC showed a melting peak (~117 °C) for crystalline melatonin, a broadened peak for M-Control films and an absence of any crystalline peaks in M-Complex films (indicating amorphization of melatonin in the presence of HPβCD). XRD showed crystalline peaks in M-Control films and an amorphous halo pattern in M-Complex. PLM confirmed birefringence in M-Control films, while no birefringence was observed M-Complex (Figure 2). Another visual observation was that M-Complex were transparent, whereas M-Control films appeared translucent. In addition, both films were smooth and flexible (Figure 1). M-Complex had higher weight (121.9 ± 7.3 mg) and thickness (128 ± 3.8 µm) compared to M-Control films (90.8 ± 4.9 mg; 117.2 ± 5.4 µm). Both had comparable tensile strength (~6 MPa). Young’s modulus was slightly higher in M-Complex films (8.0 MPa/%) vs. M-Control films (6.8 MPa/%), while elongation was 1.2% and 1.5%, respectively. A uniform drug content was obtained for M-Control and M-Complex films. The amount of melatonin loaded to per film for M-Complex increased with on complexation temperature. The drug content for M-Complex films was 1.9 (± 0.1) mg and 3.2 (± 0.1) mg for complex made at 25C and 40C, respectively. All films disintegrated within 30 seconds. M-Complex films released 94% of the drug in 30 seconds versus only 17% from the control (Figure 3).

Conclusion: A plant-based excipients platform composed of KLEPTOSE^® HPB, LYCOAT^® RS 720 and NEOSORB^® P 60W was successfully used to manufacture orally disintegrating films. Incorporating HPβCD–melatonin complexes into ODFs significantly enhanced melatonin’s solubility, induced amorphization, and higher drug release. The films exhibited good organoleptic characteristics with respect to mechanical integrity as well as quick disintegration (less than 30 seconds). This ODF platform presents a viable strategy for pediatric/geriatric delivery, neuropsychiatric indications, as well as an important life cycle management tool for drug products.

References: [1] Higuchi, T., & Connors, K. A. (1965). Phase-solubility techniques. In C. N. Reilley (Ed.), Advances in Analytical Chemistry and Instrumentation (Vol. 4, pp. 117–212). New York: Interscience.


Figure 1. Phase solubility profile of melatonin with hydroxypropyl β-cyclodextrin (HPβCD) and visual appearance of oral films.


Figure 2. Solid-state characterization of melatonin oral films by DSC, XRD, and PLM.


Figure 3. Mechanical properties and drug release profiles of melatonin oral films.