Enhanced drug loading of in situ forming gels for oral mucositis pain control

Abstract

Localized delivery to oral mucositis ulcerations requires specialized dosage forms, (e.g. in situ forming gels) delivered to the site in relatively low volumes. However, this is challenging for drugs with low solubility such as Bupivacaine γ-Linoleate (Bup-γL). The objective of this study is to develop an in situ forming gel with enhanced loading of Bup-γL for oral mucositis pain control. Two co-solvents (PEG400 and ethanol) and eight solubilizers (Tween 80, sodium lauryl sulfate, Cremophor® RH40, Cremophor® EL, Kolliphor® HS 15, Soluplus®, PEG 3350 and PEG8000) were screened for their capability to solubilize Bup-γL. Among all tested solubilizers, sodium lauryl sulfate (SLS) showed the highest solubilizing capacity (8.83 ± 0.94 mg/mL). This was considered to be a consequence of the similarity between the structure of SLS and Bup-γL. On the addition of SLS to the in situ forming gels, the drug loading was enhanced from ~6.5 to ~10.5 mg/ml. The formulations were characterized for their gelation temperature, rheological properties, in vitro drug release and short-term storage stability. The gelation temperatures of the in situ forming gel formulations were significantly reduced with enhanced drug loading. The in vitro drug release profiles showed good fit to both the first order and the Higuchi models. Formulations with SLS demonstrated sustained drug release (time to plateau ~7 h) compared with formulations without SLS (time to plateau ~3.5 h). This study offers an effective strategy to enhance drug loading of in situ forming gels. The enhanced drug loading will reduce the dosing volume and as such is expected to reduce any unwanted numbing of the healthy mucosa.

Keywords: Bupivacaine γ-Linoleate; Enhanced drug loading; In situ forming gels; Oral mucositis; Sodium lauryl sulfate; Solubilization; Storage stability.