(W1130-01-03) The Development of Extended-Release and Mucoadhesive Buccal Films of Adipic Acid by Hot-Melt Extrusion for Long-Term Relief of Xerostomia

Purpose: The main goal of this study is to develop an extended-release buccal film to stimulate salivary production in patients with xerostomia (dry mouth). Previous studies focused on the preparation of immediate release buccal films for instantaneous relief of the dry mouth condition. Three different stages of formulation development trials were performed to optimize an extended-release buccal film that adheres to the buccal mucosa for treatment and/or amelioration of xerostomia condition using hot-melt extrusion technology (HME). The films include Adipic acid (APA) which is a food acidulant known to stimulate the salivary glands to secrete more saliva in the attempt to neutralize induced mouth acidity.

Methods: Hypromellose (HPMC) was selected as a film forming polymer due to its good extrudability via HME, availability in a variety of molecular weight/viscosity grades, and its mechanical strength. Physical mixtures (20 gm batch size) of APA and different viscosity grades of HPMC were extruded in the co-rotating twin-screw extruder (Haake Minilab, ThermoFisher Scientific®). The screw speed of the extrusion process was set at 50 rpm, extrusion temperature ranged between 100 °C to 120 °C, and a rectangular shaped 2 mm film die insert was used to shape the extrudates. Drug content and the in vitro drug release profiles of all the films in simulated saliva (pH 6.8) were determined. A 1 mL sample was withdrawn at 0.5, 1, 3, 4, 6, and 8 hours, and APA was quantified using HPLC-UV system (Waters Corporation, Milford, MA, USA), and Atlantis T3 C18 column from Waters. In stage 1 formulation development trials, 30% w/w drug load and 70% w/w of HPMC (15LV, 100 LV or K 15M) were used. However, due to the high solubility of APA over 50% was released in the dissolution medium within 30 minutes. In stage 2 formulation development trials, 20% w/w of an additional extended-release polymer (Ethyl cellulose, Eudragit RSPO or Carbopol 971P) were added to the APA/HPMC compositions, but the release of APA was still too fast. In stage 3 formulation development trials, higher percentages of the hydrophobic polymer Eudragit RSPO (50%, 60% and 70% w/w) were employed. The different stages of formulation development trials are listed in Table 1.

Results: APA content for all the films was within 90%-110%. Films from stage one and two did not control the burst APA release since at least 47% to 50% was released in the first 30 minutes. Stage three films comprising Eudragit RSPO were capable of controlling the release of APA for up to 8 hours as shown in Figure 1. However, the films comprising Eudragit RSPO imparted poor mechanical strength to the films and changing the percent of HPMC K15 LV in the composition did not improve this feature. Trials performed with plasticizers (polyethylene glycol 1500, triethyl citrate and polypropylene glycol) yielded films with visually better mechanical strength with no effect on APA release. Further optimization to improve the flexibility and adhesiveness of the films to the buccal mucosa will be conducted. Future studies will focus on quantifying the mechanical strength and adhesiveness of the films upon the addition of plasticizers and additional bioadhesive agents. A texture analyzer will be used to evaluate the films’ mechanical stiffness, and bioadhesivity to porcine buccal membrane. Optimized films will be further characterized by DSC, XRD to assess the physical state of APA in the films. Further physical characterization of the films will be performed including uniformity of thickness, diameter, weight, content uniformity and surface pH.

Conclusion: HME technology was employed to develop extended-release APA buccal films for the treatment of xerostomia. Additional studies will be conducted to improve the mechanical and bioadhesive properties of the films. A D-optimal mixture design will be used to optimize the three main ingredients; the release retarding polymer, the mucoadhesive agent and the plasticizer.

References: Domb, A. J., Brama, B., & Mizrahi, B. (2015). U.S. Patent No. 9,161,909. Washington, DC: U.S. Patent and Trademark Office.
Zhang, J., Feng, X., Patil, H., Tiwari, R. V., & Repka, M. A. (2017). Coupling 3D printing with hot-melt extrusion to produce controlled-release tablets. International journal of pharmaceutics, 519(1-2), 186-197 3 Eleftheriadis, G. K., Monou, P. K., Bouropoulos, N., Boetker, J., Rantanen, J., Jacobsen, J., ... & Fatouros, D. G. (2020).
Elkanayati, R. M., Chambliss, W. G., Omari, S., Almutairi, M., Repka, M. A., & Ashour, E. A. (2022). Mucoadhesive buccal films for treatment of xerostomia prepared by coupling HME and 3D printing technologies. Journal of Drug Delivery Science and Technology, 75, 103660.

Table 1. Stages of buccal film development

Figure 1. Dissolution release profiles from third stage of development