Drug Delivery Design: Industry versus Academia

By Krystal Brown

How often do you take ibuprofen? How often do you think about how it works to provide relief?

As a common over-the-counter drug, ibuprofen inhibits cyclo-oxygenase enzymes in tissues to diminish their inflammatory response. Though ibuprofen has been used for more than 50 years to ease pain and stiffness, it would be worthless without an effective delivery system. Oral drug delivery provides a convenient method of drug administration whose ease promotes patient comfort and compliance.

According to Professor David Grainger, chair of the department of pharmaceutics and pharmaceutical chemistry at the University of Utah, 86 percent of drugs on the market are taken orally, mainly relying on drug dissolution in the stomach or upper intestine and then passive absorption through cell membranes to enter the bloodstream. Using long-established methods, several chemical and physical drug benchmarks are used to predict whether a drug will be efficiently absorbed orally.

Due to their long history of use, little fundamental research is currently done on oral delivery methods; consequently, many standard measurement methods for oral drug delivery, dosing and uptake, have remained largely unchanged.

Professor Grainger stated that researchers competing for federal grants are expected to focus on new, cutting edge delivery methods. Oral delivery vehicles and drug delivery strategies are often considered low innovation, often not supported by federal monies, leaving academia without research and training mechanisms in an area of high priority with the pharma industry. 

One way around this is to develop new methodologies that improve current standard measurement capabilities.

One such standard, the partition coefficient, estimates how well a drug molecule will insert into cell membranes by measuring its equilibrium partitioning in solution between immiscible bulk phase water and octanol. Despite widespread use of this water/octanol model, its significant divergence from cell membrane properties makes the corresponding partition coefficient a purely correlative measure, often only one of several variables determining a drug’s cell entry potential. 

Dr. Grainger cited this “poor correlation between drug in vitro properties and in vivo efficacy” as a major problem for applying basic research tools to actual drug delivery design. Synthetic lipid bilayers are a superior cell membrane model to the water/octanol system and can be customized to incorporate different types and ratios of lipids, cholesterol, proteins, and ligand molecules for modeling drug uptake. 

Despite many desirable properties, the challenges associated with studying such lipid membrane interfaces have led to the continued preference of the water/octanol system in pharmaceutical industry; however, research in the Professor John Conboy group in the department of chemistry at the University of Utah aims to change that. 

Recently, Trang Nguyen of the Conboy group has demonstrated the use of deep ultraviolet–visible sum-frequency generation (UV-vis SFG) to measure the partition coefficients of several drug molecules, including ibuprofen, in lipid bilayers.

As a coherent laser technique, UV-vis SFG has an inherent surface sensitivity and utilizes the native electronic transitions of the molecule of interest. This allows the drug partitioning into lipid bilayers to be monitored without chemical modification and with low limits of detection—two major obstacles in studying these interfaces. This enables a kind of retrofit to existing drug delivery designs seeking cell membrane absorption, allowing researchers to evaluate possible drug molecules in screens with more biologically relevant information.

With this, the Conboy group has provided a new method for assaying one property long-recognized as important to oral drug delivery efficacy. Nonetheless, the pharmaceutical field is changing to offer more significant challenges to delivering new drug classes. Ten years ago, most of the top 10 drugs on the market were small molecules taken orally; however, Professor Grainger says that by 2014, eight of the top 10 drugs on the market are predicted to be proteins—biologic drugs currently incapable of effective oral delivery and thus delivered via injection.

Since many of these drug activities will still involve cell membrane penetration, the lipid bilayer model can still offer valuable information. Additionally, biologics are expensive and often suffer from stability and shelf-life issues. Their interactions with lipid membranes could offer hints for new methods to stabilize and preserve the protein-based drugs in their formulations using membranes. 

Researchers in the Conboy group have already used UV-vis SFG to quantify protein-ligand interactions in model bilayers. This is an example of how fundamental research methods may continue to have relevance to the developing pharmaceutical industry.