This paper was written by Professor Robert Langer of MIT, who has written and published over 1300 scientific articles in the fields of Drug Delivery, Chemistry, Biotechnology, and pharmaceuticals, making him the most cited engineer in History [1]. The central purpose of this article is to outline the route in which different drugs take to navigate through the body and retain their pharmacodynamic functions. The article outlines the process in which drugs are designed and administered to the body, to give the reader an understanding of the different limitations that different methods encounter, such as “Getting past the Gut”, “Penetrating the skin”, “Entering the Lungs” and “Controlling Release” [2]. Langer’s article is laid out in a hard to read fashion, but displays brilliant insights into the drug delivery field in the areas he covers.

R. Langer

Figure 1 – Robert Langer
Source: http://news.mit.edu/sites/mit.edu.newsoffice/files/images/2016/robert-langer-mit-failure-resilience_2.jpg

In the introductory paragraph of the article, a statement is made that “pills can be coated with a shell that protects them against the stomach secretions due to the insolubility of the shell, but dissolves readily once the pill has reached a more alkaline environment in the small intestine”. Langer goes on to state that if the drug is made of proteins, by which most biotechnological agents are, that the drug also needs to be able to avoid the protein destroying enzymes called proteases. Drugs that are coated also presented the problem of limited control on their pharmacokinetics. Langer suggests coating the drugs in their own bodyguards, but proceeds to state that the drugs will then be too large to cross through the gut lining and into the bloodstream. Langer’s arguments show that his ideas were before their time, and it can be seen from a paper conducted in 2014, by Kinam Park, about “the controlled drug delivery systems, past, present and future”, that the development of new drug delivery systems requires consideration of multiple parameters, such as the drugs starting point or administration, delivery route, drug release kinetics and materials within the drug, before the drug can ultimately be used in human patients [3]. Langer’s methods were correct, and were the basis for what the field of drug delivery is now, as he was investigating the parameters involved to deliver the most optimal dose of a drug through the most effective drug delivery system specific to the target area.

Image1

Figure 2 – Overview of drug delivery systems from basic research to clinical applications

Figure 1 offers an overview of drug delivery research from an article published in 2014. This article was written 12 years after Langer’s paper, and as can be seen from the image, Drug delivery systems that Langer was focused on, are still the core parameters involved in present drug delivery systems. Langer’s ideas were focused on release kinetics and pharmacokinetics, which, as can be seen from Figure 2, are all interlinked with eachother. Langer stated that all aspects of drug delivery needed to be accounted for when developing a new drug delivery system, and this principle is still essential in the present day research being conducted in the field [3].

polymer

Figure 3 – Diffusion as a Drug Release Mechanism

Langer offers solutions to solve the issue of penetrating the gut’s intestinal wall, which were quite innovative and effective for a paper wrote in 2002, as Langer’s suggested methods such as bioadhesive polymer coatings that allow the drug to bind to the gut lining and squeeze between the cells, linking the drugs with carrier molecules in order to be taken up by the cells receptors and passed through into the bloodstream, linking drugs to targeting molecules that aim to bind with cell receptors on the intestinal cells, which pass the drug through the cells, in order to be taken up by the bloodstream. Langer identified the parameters in which may directly affect the delivery of the drug through the gut, but failed to account for the changing physiological environment of the fed gut, the physiochemical interactions between the drug and the fed gut, and the characteristics of the fed gut. There are still gaps in the knowledge related to the exact effects in which food and alcohol have in the gut environment, which Langer doesn’t account for in his assessment of “Getting Past the Gut”, but more recent studies in drug delivery systems are trying to account for by using in-silico and in-vitro testing with similar environments and parameters [5].

gastro

Figure 4 – Gastrointestinal physiology [5]

When comparing this method to more advanced drug delivery systems in recent years, a study wrote in 2015 by Ritu Goyal, about “Nanoparticles and Nanofibers for topical drug delivery” detailing the use of iontophoresis as a method for drug delivery through the skin, which uses physical enhancers such as ultrasound to temporarily disorder the skins Stratum Corneum, which is the principal barrier to drug diffusion, to increase the ability to administer the drug by up to 5000 times. Although effective, this drug delivery system has been said to be invasive and cause damage to the skins barrier properties in the long term, while causing numerous side effects [4].

Langer suggests that the lungs are an excellent route to pass drugs through to reach the bloodstream, and goes into details about the difficulties in designing inhaler devices that can administer sufficient amounts of aerosol particles that can penetrate the lung deeply, while making the statement, that lung administered drugs only deliver less than 10% of their contents. In recent years, formulation strategies to sustain drug release in the lungs has been focused on, with advancements coming in the ability to enhance the drug residence time in the lungs, protect the drug against degradation, and release the drug in a controlled manner at a therapeutically optimal rate [6]. Langer’s Suggestions that the lowering of the density of the particles present in the drugs while increasing their size and porosity proved to be another ahead of its time proposal, as new drugs such as microparticles and nanomedicines are being designed to be administered through the lungs due to their aerodynamic properties [6].


Finally, the development of drug delivery systems that have the ability of controlling release may be the most important aspect of this paper that Langer introduces to the field of drug delivery. Langer goes into detail about the control of the therapeutic level of the drug in the body without the need for frequent administration, and offers a solution of gold capped microchips that can be dissolved by electrical charges to release the drug inside the microchip at the desired times. Langer’s innovative mind set is one of his strongest qualities, as he had the ability to look ahead and propose ideas that are still being researched and developed in modern times.

Langer’s main points to take from this articles were the aspirations of developing drugs that could be administered at any time, at the correct dosage, anywhere in the body with specificity and efficacy. Through Langer’s research and suggestions, modern drug delivery systems have been developed and based off technologies and idea’s that Langer proposed, which is why Robert Langer is known as possibly the most successful chemical engineer in the drug delivery field.

References

[1] – Langer Labs. (06/01/17). Professor Robert Langer. Available: http://web.mit.edu/langerlab/langer.html. Last accessed 09/03/17.

[2] – Robert Langer. (2003). Where a pill won’t reach. Scientific American. n/a (n/a), 50-57.

[3] – Kinam Park. (2014). Controlled drug delivery systems – Past, Present and Future. Journal of Controlled Release. 190 (n/a), 3-8.

[4] – Ritu Goyal. (2015). Nanoparticles and Nanofibers for Topical drug delivery. Journal of Controlled Release. 2040 (n/a), 77-92.

[5] – F.J.O Varum. (2013). Food, Physiology and Drug Delivery. International Journal of Pharmaceuticals. n/a (n/a), n/a.

[6] – Cristina Loira-Pastoriza. (2014). Delivery strategies for sustained drug release in the lungs. Advanced Drug Delivery Reviews. 75 (n/a), 81-91.

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