(M0930-01-06) Formulation and Characterization of Ionic Liquid-Containing (IL) Melatonin Orally Dissolving Films (ODFs) for Buccal Drug Delivery

Purpose: Insomnia affects 30% of adults worldwide and leads to reduced physical functioning, productivity, and mental health. There are several over-the-counter products currently available to manage insomnia, but many of these have burdensome anticholinergic effects such as constipation, urinary retention, dry eyes and mouth, and cognitive impairment. As such, these medications ae not preferred in pediatric or elderly patients. However, melatonin, an endogenous hormone which regulates the sleep-wake cycle, is an over-the-counter sleep supplement that does not cause anticholinergic effects and is generally well-tolerated by a larger variety of patients. Orally dissolving films (ODFs) are thin, polymer-based films which can be loaded with drug for buccal or sublingual drug delivery. Compared to traditional oral drug delivery, ODFs avoid first-pass effect, have a faster onset of action, do not require water for administration, and can be used in patients unable to swallow oral tablets. Ionic liquids have been studied to enhance dissolution and permeation of drugs in a variety of platforms and could be utilized in ODFs to enhance their effects. Incorporation of ionic liquids may be especially beneficial with the formulation of melatonin ODFs as melatonin is a lipophilic molecule. Because of the necessity for rapid relief of insomnia symptoms, an ODF for buccal or sublingual melatonin drug delivery would be beneficial.

Methods: A formulation of 2.5 mg melatonin ODFs containing several polymers, including HPMC K4M, Kollidon K90, and polymeric solubilizer SoluPlus, plasticizer PEG 2000, and the ionic liquid DABCO was formulated using solvent-casting method and characterized for several physical properties. A control film without ionic liquid was also characterized for weight and thickness variation, tensile strength, percent elongation, folding endurance, drug release, and ex vivo permeability using pork buccal mucosa.

Results: After characterization, no statistical differences were found between the films' weight and thickness variations, tensile strength, percent elongation, and folding endurance. Film weight and thickness of the IL-containing film were uniform (average 24.5 mg ± 1 and 0.052mm ± 0.0009, respectively), indicating drug content uniformity. Tensile strength indicated high film strength (average 11.08 MPa ± 0.68), while film flexibility was lower as indicated by lower folding endurance and percent elongation (average 179 folds and 6.25%, respectively). However, drug release studies showed that the ionic liquid significantly reduced dissolution time (p-value 0.01), and indicate an extended-release profile of the film, with the IL-containing film drug having about 90% dissolved after one hour, and ex vivo permeability studies also indicated that the ionic liquid enhanced permeation of the film significantly with roughly 43% of the drug permeated in one hour, as compared to 32.3% permeated in the control film (p-value < 0.0001).

Conclusion: Insomnia is a common condition with detrimental effects on patients. Melatonin, an endogenous hormone, is a safe and effective over-the-counter supplement to aid in treating insomnia. A IL-containing melatonin film was successfully formulated and characterized, and exhibited an extended-release profile. An extended-release formulation would be especially beneficial in helping patients maintain sleep throughout the night. Melatonin would be a good candidate for IL-containing oral dissolving film delivery to increase patient compliance, safety, and health outcomes.

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Figure 1. The percent drug released of one ODF over one hour.

Figure 2. The ex vivo permeability of a film using pork buccal mucosa over one hour

Figure 3. The comparison between the blank film (melatonin without ionic liquid) and a 2% DABCO loaded melatonin film on ex vivo permeability.