(W1130-12-69) Novel Electrospun Nanofiber Buccal Films for Treating Opioid Use Disorder

Purpose: Opioid use disorder (OUD) affects millions worldwide and contributes to a significant socioeconomic burden. Though much progress has been made for OUD treatment with the development of methadone, buprenorphine, naltrexone, and their injectables, a substantial portion of the OUD population could benefit from advanced additional pharmacologic treatments¹. Medication treatment advancements for OUD are greatly needed. Levo-alpha-acetylmethadol (LAAM) offers numerous behavioral and clinical advantages for use in selected patients who are not sufficiently managed with methadone and buprenorphine^{2, 3}. Among the currently FDA-approved OUD drugs, LAAM has a higher systemic circulation half-life, reducing dosing frequency (3 times per week) and improving patient compliance⁴. Although approved for OUD treatment, LAAM was withdrawn from the market. The return of LAAM to the market can significantly improve OUD treatment. We have formulated novel electrospun nanofiber films for the buccal transmucosal delivery of LAAM.

Purpose: To develop and characterize electrospun nanofiber films for the buccal transmucosal delivery of LAAM drug.

Methods: All polymer-drug formulations were prepared and loaded into a 10mL syringe with a 22G needle for electrospinning using a FLUIDNATEK® LE-50 electrospinning Machine. The electrospinning process was conducted with 15 kV, flowrate 1000 μL/h, temperature 25-30 ⁰C, and Humidity 20-30%. Fiber morphology was measured using Hitachi SEM SU-70. The drug release study was conducted in 100 mL of PBS, pH=6.8 at 37°C under constant stirring (100 RPM) using USP apparatus 1. The release media was collected at different times (5,10,15, 20, 25, 30,40, 50, and 60 minutes) and replaced with the same fresh media. Quantification of drug levels in the release media was analyzed with HPLC-UV (Shimadzu Prominence LC system equipped with a Pursuit 5 C18 column) at 216 nm wavelength. The mucoadhesive strength was measured with Bose Electroforce 3200. The ex vivo transmucosal drug diffusion was measured with Frans diffusion cells (surface area). Briefly, ~500 μm porcine buccal mucosa as the mucosal barrier (contact surface area of 0.95 cm²) and the sink condition were maintained during samples withdrawn at various time points. All samples were then analyzed via HPLC, and the apparent permeability coefficients (P_app) were measured.

Results: Buccal films were prepared using the. We have formulated fibers using FDA-approved GRAS polymers such as polyvinylpyrrolidone (PVP) and propylene glycol (PG). These electrospun nanofiber buccal films were further optimized and characterized to identify the most promising buccal films that exhibit strong mucoadhesive strength ( >0.2 Newton), smooth nanofiber morphology, and rapid drug release ( >80% drug release within 30 mins). Figure 1 indicated that the representative nanofiber buccal films showed smooth morphology with fiber diameters ranging from 0.2 to 0.3 µm. In vitro drug release study was performed using USP apparatus 1. The buccal film formulations depicted fast drug release, with 80% of drugs released within 5 minutes. The fast release is attributed to the rapid dissolution behavior of the submicron-sized water-soluble polymer nanofibers composed of PVP (Table 1). PVP-EC and PVP-EC-PG buccal film formulations showed mucoadhesive strength similar to the Niquitin (0.27 Newton) and rapid transmucosal drug diffusion across the bovine buccal mucosa, indicating it would be suitable for buccal administration. Table 2 shows that adding propylene glycol as a penetration enhancer may increase the P<sub>app by up to 2-folds. Consequently, the developed buccal film formulations have the potential to promote drug absorption into the mucosal blood vessels following the buccal administration.

Conclusion: Mucoadhesive electrospun nanofiber film formulations can be achieved in submicron diameter and showed a fast release profile, suitable for buccal administration.

References: [1] JAFFE JH: Can LAAM, like Lazarus, come back from the dead? Addiction 2007, 102:1342-3.
[2] Johnson RE, Chutuape MA, Strain EC, Walsh SL, Stitzer ML, Bigelow GE: A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med 2000, 343:1290-7.
[3] Marsch LA, Stephens MAC, Mudric T, Strain EC, Bigelow GE, Johnson RE: Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence. Experimental and Clinical Psychopharmacology 2005, 13:293-302.
[4] Anglin MD, Conner BT, Annon J, Longshore D: Levo-alpha-acetylmethadol (LAAM) versus methadone maintenance: 1-year treatment retention, outcomes and status. Addiction 2007, 102:1432-42.

Acknowledgments: This work was supported by an NIH/NIDA HEAL initiative grant (1UG3DA048768). Hadi is supported by the Fulbright DIKTI Scholarship.

Figure 1. SEM image of LAAM nanofiber films



Figure 2. The release profile of LAAM nanofiber films



Table 1. In vitro and ex vivo characterization of the LAAM nanofiber films