(T1130-06-33) Midazolam Buccal Films: Development and Characterization for Palliative Care

Purpose: Midazolam is one of the four essential drugs to promote quality end-of-life care. It has rapid onset and short duration of action to minimize risk of adverse effects [1]. In palliative care, midazolam is commonly prescribed to treat a myriad of symptoms, including anxiety, dyspnea, restlessness and seizures, as well as to induce palliative sedation [2]. In Singapore, midazolam is administered parenterally to patients on palliative care. However, this is associated with complications and compromises patient comfort and quality of life. Mucoadhesive buccal films (MBFs) are an alternative dosage form for drug delivery. Administration is painless, and drugs are absorbed through buccal capillaries into systematic circulation without undergoing hepatic first-pass effect. It is feasible to extemporaneously produce medicated films in pharmacy settings using the solvent-casting method [3]. The aim of this study is to develop and characterize midazolam MBFs prepared using the unit-dose solvent casting method [4], as well as to seek practicing pharmacists’ feedback on the preparation process and products.

Methods: Single-layered MBFs - Polymer solutions were prepared by dissolving a blend of chitosan, polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) at different concentrations in 0.3%v/v lactic acid solution, with glycerol as the plasticizer. Midazolam was added to 0.3%v/v lactic acid solution to form the drug solution, which was subsequently added to the polymer solutions in the ratio of 1:1 to form casting solutions. Thereafter, the casting solutions were pipetted into silicone wells and oven-dried to form MBFs. Double-layered MBFs - Mucoadhesive layer was first prepared by casting a solution containing Carbopol 971P and glycerol into silicone wells before oven-drying. Solutions for drug layers were prepared by dissolving HMPC, citric acid, β-cyclodextrin, midazolam and glycerol in water, and then casted over the mucoadhesive layer and oven-dried. The MBFs were characterized for appearance, thickness, folding endurance, disintegration time, moisture content and surface pH. In vitro release profiles and stability were further examined for formulations with more favorable physical attributes. Three pharmacy staff from a hospice took part in a hands-on session to prepare single-layered midazolam MBFs. Thereafter, their feedback on the preparation process and products was gathered in an online survey.

Results: Formulations of the MBFs are summarized in Tables 1A and 1B. All MBFs were round and transparent, with diameter of 2.3 cm. Central thickness of single-layered MBFs ranged between 118 and 152 μm—one-third that of double-layered MBFs. Average folding resistance of single-layered MBFs was at least 92 folds, compared to 39.6 to 75.6 folds with double-layered MBFs. Moisture content of single-layered MBFs was up to 18.96% and was lower than that of double-layered MBFs, while pH of the surfaces intended to be in contact with the buccal mucosa were similar among all films. Disintegration study conducted using USP IV apparatus found single-layered MBFs to disintegrate within an average of 4.78 minutes, while an average of minimum 52.48 minutes were required for double-layered MBFs to disintegrate. Owing to their more desirable physical characteristics, in vitro release profiles of the two single-layered MBF formulations were examined using a set-up modified from USP II apparatus, and analyzed using ultraviolet-visible (UV-vis) spectroscopy. At least 90% of midazolam dose was found to have been released within 25 minutes in S1 (Figure 1). For both single-layered MBFs, analysis using UV-vis spectroscopy detected less than 5% change in midazolam content after 1 months’ storage in an airtight and light-protected container at 25°C. All 3 pharmacy participants agreed that the steps and equipment involved to produce the MBFs were simple, and had confidence in compounding MBFs independently. Drying time was a concern raised by 2 participants. In addition, 2 participants disagreed with or were neutral about the size, texture and thickness of the MBFs being suitable for their patients, and had reservations about acceptance of the MBFs by patients or caregivers.

Conclusion: In this study, the formulations and compounding process for midazolam MBFs have been developed. The two single-layered MBF formulations exhibited desirable physical properties. In particular, for the single-layered MBF formulation S1, in vitro studies using UV-vis spectroscopy showed the release of >90% of midazolam dose within 25 minutes. Both single-layered MBFs were stable for at least 1 month when stored in cool airtight conditions away from light. In addition, feedback from pharmacy participants suggested feasibility of extemporaneous compounding of midazolam MBFs by pharmacy staff. However, physical appearance of the films and patient acceptability were identified as potential challenges. Therefore, the single-layered midazolam MBFs developed in this study have the potential for extemporaneous preparation in a pharmacy setting. Further work should be undertaken to optimize the formulations, improve physical appearance of the MBFs, examine in vivo release profiles, as well as to investigate acceptance by palliative care patients and caregivers.

References: 1. Prommer E. Midazolam: an essential palliative care drug. Palliat Care Soc Pract. 2020;14:2632352419895527. doi:10.1177/2632352419895527

2. Zaporowska-Stachowiak I, Szymański K, Oduah M-T, Stachowiak-Szymczak K, Łuczak J, Sopata M. Midazolam: Safety of use in palliative care: A systematic critical review. Biomed. Pharmacother. 2019 (114): 108838. doi: 10.1016/j.biopha.2019.108838.

3. Visser JC, Woerdenbag HJ, Crediet S, Gerrits E, Lesschen MA, Hinrichs WLJ, Breitkreutz J, Frijlink HW. Orodispersible films in individualized pharmacotherapy: The development of a formulation for pharmacy preparations. Int J Pharm. 2015 Jan 15;478(1):155-163. doi: 10.1016/j.ijpharm.2014.11.013.

4. Foo WC, Khong YM, Gokhale R, Chan SY. A novel unit-dose approach for the pharmaceutical compounding of an orodispersible film. Int J Pharm. 2018 Mar 25;539(1-2):165-174. doi: 10.1016/j.ijpharm.2018.01.047.

Acknowledgements: We would like to thank the pharmacy staff from Hospice Care Association (HCA) Singapore for their insights on palliative care practice, as well as their feedback on the extemporaneous manufacturing process of midazolam buccal films. This study is funded by the National Research Foundation, Singapore, under AcRF Tier 1 (R-148-000-311-114). The authors declare no conflict of interest.


Table 1. Formulations of single-layered and double-layered MBFs


Table 2. Physical characteristics of MBFs


Figure 1. Release profiles of single-layered MBFs