Solid-State Behavior and Solubilization of Flash Nanoprecipitated Clofazimine Particles during the Dispersion and Digestion of Milk-Based Formulations

Abstract

Clofazimine, a drug previously used to treat leprosy, has recently been identified as a potential new drug for the treatment for cryptosporidiosis: a diarrheal disease that contributes to 500 000 infant deaths a year in developing countries. Rapid dissolution and local availability of the drug in the small intestine is considered key to the treatment of the infection. However, the commercially available clofazimine formulation (Lamprene) is not well-suited to pediatric use, and therefore reformulation of clofazimine is desirable. Development of clofazimine nanoparticles through the process of flash nanoprecipitation (FNP) has been previously shown to provide fast and improved drug dissolution rates compared to clofazimine crystals and Lamprene. In this study, we investigate the effects of milk-based formulations (as possible pediatric-friendly vehicles) on the in vitro solubilization of clofazimine formulated as either lecithin- or zein/casein-stabilized nanoparticles. Milk and infant formula were used as the lipid vehicles, and time-resolved synchrotron X-ray scattering was used to monitor the presence of crystalline clofazimine in suspension during in vitro lipolysis under intestinal conditions. The study confirmed faster dissolution of clofazimine from all the FNP formulations after the digestion of infant formula was initiated, and a reduced quantity of fat was required to achieve similar levels of drug solubilization compared to the reference drug material and the commercial formulation. These attributes highlight not only the potential benefits of the FNP approach to prepare drug particles but also the fact that enhanced dissolution rates can be complemented by considering the amount of co-administered fat in lipid-based formulations to drive the solubilization of poorly soluble drugs.

A 3D-Printed Polymer–Lipid-Hybrid Tablet towards the Development of Bespoke SMEDDS Formulations

“…The drugs appear to be partly crystalline in the solid SMEDDS at room temperature, and the X-ray diffraction data at least for fenofibrate support this assertion. Our experience with these compounds is that digestion of lipid formulations favours drug solubilisation [46,47]. Here, the focus was on control of dispersion of the formulation and drug and less on its solid state upon dispersion, so the effects of digestion were not studied specifically in this study.…”

Formation of Self-Assembled Mesophases During Lipid Digestion

“…Infant formulae can contain fat sources from bovine milk, goat milk and vegetable oils depending on the brand and age of the child being provided the formula. Due to the differences in lipid composition, studies have shown that the self-assembly behavior of the lipids in various types of infant formulae exhibit different mesophases during digestion, shown in Figure 13 (Salim et al, 2019;Pham et al, 2020). The triglyceride content of emulsions attempting to mimic milk has recently been shown to be a key driver for the formation of mesophases commensurate with the milk of a particular species.…”

“…The formula composition is tightly controlled to specifications in a manner similar to pharmaceutical excipients and the fat content can be controlled. Recent studies by Salim et al (2019) showed improved solubilization of the drug clofazimine when digested with infant formula. In order to progress infant formula toward approval as a formal pharmaceutical excipient, more research is needed to understand its behavior during digestion including further studies on how the composition (lipids and other components) and overall fat content impact on structure and interaction with drug cargo.…”

Small-volume in vitro lipid digestion measurements for assessing drug dissolution in lipid-based formulations using SAXS

“…These amphiphilic digestion products can self-assemble into lyotropic liquid crystalline structures in the small intestine ( Salentinig et al, 2013 , Salentinig et al, 2015 ; Clulow et al, 2018 ; Pham et al, 2020 ), in turn these structures interact with endogenous amphiphilic molecules such as bile acids to form colloidal mixed micelles with a variety of structures ( Hjelm et al, 2000 ; Hjelm et al, 1995 ; Pabois et al, 2021 ; Rezhdo et al, 2017 ; Gustafsson et al, 1999 ; Clulow et al, 2017 ). The digestion products are also capable of solubilising poorly water-soluble drugs dispersed in the LBF ( Shrestha et al, 2014 ; Salim et al, 2019a ; Boyd et al, 2018 ; Salim et al, 2020a ) making them available for subsequent absorption ( Tan et al, 2010 ; Borné et al, 2002 ; Boyd et al, 2007 ).…”