Miniaturization of a Simulated Gastric Fluid Dispersion Experiment On a Microfluidics System

The miniaturization of preclinical safety assessment studies using a microfluidic chip system and optical microscopy can help reduce compound requirements, time, and costs in formulation development.
Apr 02, 2013

Formulations for preclinical safety assessment studies are often prescreened by formulation scientists in vitroprior to use in animal models. By simulating the precipitation characteristics of a formulation in biorelevant media, the performance of a formulation can be predicted. The predictability depends on the sensitivity of detection and simulation of the mixing of the vehicle and biorelevant media. The authors describe the miniaturization of these types of experiments using a microfluidic chip system, combined with detection by optical microscopy. The results show the potential of microfluidics as a tool to help reduce compound requirements, time, and costs in formulation development.

Dispersion experiments are heavily used in the pharmaceutical industry to screen potential oral formulations in vitro. The studies are run to rank how several formulations will perform prior to dosing new chemical entities in vivo. The experiment intends to mimic what occurs as the formulations are dosed orally and traverse through the gastrointestinal tract (1, 2). This experiment also is used to understand the mechanism of variability upon oral dosing. As a result, compound and animal resources can be spared when failed formulations are not pursued in actual animal studies. This experiment is particularly useful in drug discovery and development by saving time and resources while still advancing drug candidates.

Microfluidic systems

Microfluidic systems are evolving as useful tools for miniaturizing a variety of standard laboratory experiments (3). Many industries are using such systems, and more recently, the pharmaceutical industry is taking note (4). There are applications for microfluidics across the pharmaceutical industry ranging from scaling down the synthesis of challenging molecules to evaluating the effects of new chemical entities on biological systems (5).

Microfluidic systems are of particular interest to the pharmaceutical sciences as tools for formulation development. Emulsion-based formulations are highly prevalent in the industry. Okushima et al. demonstrated that monodispersed double emulsions could successfully be generated with tunable control over the size and number of internal droplets produced (6). In this example, a specialized chip with hydrophobic and hydrophillic junctions was used to generate the various double emulsions.

Liposomes also have been of interest to formulation scientists for several decades (7). Jahn et al. demonstrated the successful generation of liposomes on a microfluidics device (8). The liposomes generated were monodispersed, and the size of the particles was controlled by varying the flow rate. The mixing capabilities of the chip allowed liposomes to self-assemble in the channel, which would also allow for drug encapsulation and ultimately liposomal formulation preparation.

Both of these studies used droplet-based microfluidics. The liposome-generation example used the microfluidic technique of hydrodynamic focusing, and the double-emulsion example used T-junction droplet generation (9). With respect to droplet microfluidics, the methods are complementary. In general, droplet-based microfluidic systems have the advantage of creating separated droplets that distinguish small amounts of reagents (10). T-junction droplet-generation systems are particularly flexible as several T-junctions can be placed in tandem, thereby allowing sequential reactions or mixing opportunities to occur.

This article describes the use of a T-junction droplet microfluidics system to evaluate oral formulations of select model compounds by executing a simulated gastric fluid (SGF) redispersibility experiment directly on a microfluidics chip. This article describes preliminary proof-of-concept experiments. Morever, the results show the potential to save significant amounts of compound, animal resources, time, and cost in developing formulations for new chemical entities.