Mucoadhesive in situ forming gel for oral mucositis pain control

Abstract

The current first line therapy for oral mucositis pain control is unsatisfactory as it results in only a short duration of modest pain relief. Developing mucoadhesive in situ forming formulations to prolong pain relief is challenging due to their complex physicochemical properties and the unique requirements for oral mucosa application. The objective of this study is to develop a mucoadhesive in situ forming gel to deliver a novel drug molecule, Bupivacaine γ-linoleate (Bup-γL), for prolonged and more potent oral mucositis pain control. The formulation is sprayable at room temperature, and forms a mucoadhesive gel on contact with the oral mucosa. The pain would be managed by forming an adhesive protective layer from irritating agents (such as bacteria, food, etc.), and also by anesthetizing the nerve cells with Bup-γL. Pluronic® F127 and F68 were used to achieve in situ forming properties. Either Carbopol® or Noveon® was included as a mucoadhesion enhancer. Formulation preparation methods were extensively investigated. The physicochemical properties of the gels were characterized, including gelation behavior, ex vivo mucoadhesion, rheological properties, in vitro drug release and sprayability. The polymer mixing sequence was determined to have a profound impact on the preparation time of blank formulations. A final drug content in a range of 6.21-6.51 mg/mL was obtained using the optimized method. The gelation temperature was significantly reduced by the addition of hydrophobic Bup-γL. Both Carbopol® and Noveon® significantly improved mucoadhesion without compromising the other main properties of the system (such as gelation temperature and drug content). Drug release from the formulation showed pH sensitive responses where lower pH favored faster drug release due to the ionization of Bup-γL. This study offers a promising strategy to achieve prolonged oral mucositis pain control. Moreover, a promising platform for the mucoadhesive in situ gels that allows high loading of hydrophobic drugs has been developed.

Keywords: Bupivacaine; In situ forming; In vitro release; Mucoadhesion; Oral mucositis; Pluronic; Rheology.