Engineering Better Delivery
I was originally trained as a classical chemical engineer with no background in biology or physiology. When an opportunity presented itself to engage in research in drug delivery, I was fascinated by the thought that someone like me – without prior training in biological sciences – can work in the area. My early fascination with the field was quickly converted into passion. The discovery of new drugs has advanced by leaps and bounds over the last few decades, leading to the introduction of advanced therapies based on peptides, proteins, and nucleic acids. However, delivery methods commonly used by patients are still rather simplistic. In this mismatch, I saw an opportunity where engineers can make a significant contribution first by understanding some of the underlying challenges and then by developing new technologies.
Transdermal delivery has many features that one desires in an ideal drug delivery system. It is painless, controllable, provides sustained drug release if required and can be easily terminated. It also offers a potential means to deliver drugs that otherwise have to be injected using needles and syringes. From an engineering perspective, skin, being the outermost organ of the body, allows us to explore various technologies, which makes the field of TDD very appealing.
Inherently, transdermal delivery is better suited for drugs that are needed at a sustained rate. Since topically applied drugs typically diffuse across the stratum corneum and eventually are absorbed in blood circulation, diffusive time lags are typically inherent to such systems. Further, transdermal systems are inherently suited for low-molecular weight and hydrophobic drugs. However, both these limitations can be overcome using enhancement technologies. A large number of enhancement techniques have been invented over the last two decades and they have significantly broadened the range of drugs that can be delivered transdermally to include proteins, peptides and nucleic acids.
That said, the clear major challenge in transdermal drug delivery is still the skin’s low permeability. Being the outermost organ of the body, it serves as the protective layer of the body. The very design that makes it a barrier against pathogens also makes it difficult to deliver drugs across the skin. To that end, technologies must be developed to make skin more permeable – but within the constraints of biocompatibility and patient compliance.
Liquid salts
My ionic liquid project was inspired by the current limitations faced by topical formulations. In particular, skin toxicity is a major challenge in the design and use of new topical drug formulations. Many drugs must be dissolved in organic solvents that are typically toxic to the skin. In addition, many drugs, such as propranolol (the drug used in that particular study), themselves show dose-dependent skin toxicity. Formulating drugs as ionic liquids mitigates both sources of toxicity. Given their fluid nature, ionic liquids eliminate the necessity of organic solvents. In addition, counter ions used to form ionic liquids shield the drug charge, which further reduces drug-induced toxicity. This was the first study that reported the design of ionic liquids to minimize skin toxicity. Such formulations can increase the spectrum of drugs that can be safely delivered via a transdermal patch. Right now, we are continuing to explore the principles described in the study for a wider variety of drugs. In addition, we plan to advance the technology to in vivo studies and towards clinical translation.
Drug delivery is more than skin deep
We have several exciting projects ongoing in the field of drug delivery in our laboratory in addition to our work on transdermal drug delivery. We are also working on oral drug delivery and targeted drug delivery. In each area, we focus on developing novel technologies to address key hurdles. For example, we have been working on oral delivery of proteins using intestinal patches. In this project, we aimed to leverage advances in transdermal drug delivery to develop technologies for oral delivery. In that context, we developed a patch technology, inspired by transdermal patches, to orally delivery proteins. Intestinal patches consist of a mucoadhesive matrix that holds the protein therapeutic. The matrix is coated on three sides by an impermeable layer that protects the matrix. The patches are delivered to the intestine using an enterically-coated capsule. Upon exiting the capsule, patches adhere to the intestinal mucosa and create a high-concentration local drug depot, thus enhancing oral drug absorption. Using this approach, we have delivered insulin, calcitonin and exenatide in pre-clinical models.
The second example deals with targeted delivery of drugs and imaging agents to inflamed tissues, which are often found in cases of cancer, Alzheimer’s disease, and arthritis. We use monocytes for this purpose as they possess a unique ability to target and penetrate into sites of inflammation. We deliver flat polymeric particles – “Cellular Backpacks” – that attach strongly to the surface of monocytes, but do not undergo phagocytosis due to the backpack’s disk-like shape and flexibility. In two separate in vivo inflammation models, backpack-laden monocytes exhibited increased accumulation in inflamed tissues, which shows promise for a new platform for both cell-mediated therapies and targeting inflamed tissues.
Such ‘hybrid synthetic-biological methods’ represent a new direction for targeted drug delivery. Synthetic carriers provide several advantages including drug encapsulation and precise engineering, whereas biological systems, in particular circulatory cells, such as monocytes, provide unique advantages including long circulation and deep tissue penetration. Hybrid systems that combine synthetic and biological systems offer advantages of both systems while avoiding their limitations.
We are also exploring methodologies to overcome other biological barriers, for example, bacterial biofilms. Biofilm-protected microbial infections in skin are a serious health risk that remains to be adequately addressed. The lack of progress in developing effective treatment strategies is largely due to the transport barriers posed by the stratum corneum of the skin and the biofilm itself. We are using ionic liquids for simultaneous biofilm disruption and enhanced antibiotic delivery across the skin layers.
Boosting transdermal uptake
A lot of exciting research is ongoing in transdermal drug delivery. But routine use of transdermal drug delivery in the pharma industry is contingent on two things: availability of methods to deliver a broader variety of drugs and overcoming the practical hurdles of cost, ease-of-use and reliability – which are essential in any product.
The last two decades have introduced several new technologies to deliver various drugs across the skin. Issues related to clinical and commercial translation of these technologies must now be addressed. Cost is particularly an issue for device-based technologies. As are those pertaining to bioavailability and local skin irritation. However, these are not unsurmountable issues; they have been addressed for many small molecules for which commercial patches exist. Now, these issues need to be addressed for a broader variety of drugs.
Our main goal is to invent and realize novel delivery systems that address important challenges in healthcare. Over the years, biotechnology has revolutionized the drug landscape and a large number of advanced drugs such as peptides, engineered antibodies, and nucleic acids have been introduced. However, these drugs are still delivered using old technologies. We believe that the delivery methods must match or exceed the sophistication and technological advances being offered by the drugs themselves. That’s a stiff challenge, but it’s also our biggest motivation.
