Contributors : Dr. Partha Roy, Assistant Professor, Department of Pharmaceutical Technology, Adamas University

Small Drugs: The concept of small drugs originated from Richard Feynman revolutionary lecture stating “There’s Plenty of Room at the Bottom” in American Physical Society annual meeting held in California Institute of Technology on December 1959.The journey since the birth of the concept to modern day small drugs or nano-scale medicines is a fascinating one. Nowadays nanomedicines have penetrated into almost all segment of marketed therapeutics with their clinical application increasing at an explosive rate day by day. Nanomedicines today represent nano pharmaceuticals, nanoimaging agents and theragnostic with a size range of 1 to 100 nm. These small variants enjoy the spotlight of healthcare sector because of their plethora of advantages like enhanced effectiveness, site-directed drug delivery, controlled drug release, lesser side-effects, reduced dosing frequency, high patient compliance and ease of personification compared to existing marketed drugs. The newest charisma of nanomedicines is their theragnostic application where they function simultaneously in therapy and diagnostic.

Global Market Share: Due the immense opportunities of such tiny therapeutics their global market share is expected to touch 350 billion USD by 2025 with a steep CAGR of over 11%.

Virus: They are obligate intracellular parasites which associate with host cells through varying receptor-ligand interactions. Viruses are a constant global threat to the health-care sector and socioeconomic growth because of their fast spread and high morbidity/ mortality rate as they can adapt to diverse conditions by genetic mutation. Added complexities include drug resistance development, different replication stages in divergent sub-cellular compartments and diverse viral replication dynamics.

COVID-19 Pandemic: Presently the world is in a shut-down mode due to World Health Organization declared pandemic crisis caused by COVID-19 virus. COVID-19 is spherical or pleomorphic enveloped single strand RNA viruses decorated with spiky projections which provide a crown-like appearance leading to its other name “CORONA”. The viral diameter ranges from 60 nm to 140 nm and has four sub types of which the beta-type is the main culprit behind severe acute respiratory syndrome claiming millions of human lives throughout the world. In the absence of any specific anti-viral drug or vaccine the global death toll due to the virus outbreak shows steep rise while its impact on global economy is just the opposite. The two cornerstones of COVID-19 treatment are therefore supportive and symptomatic while the most important requisite is isolation to sabotage mass spread. Therefore there is a huge drive in healthcare research for search of new drugs, new drug delivery systems, drug repurposing and newer diagnostic agents to control the pandemic.

 In order to mitigate these unique challenges presented by viral infections, the best available clinical solution can be the small drugs.

Small Drugs with big buzz Why?

1. Small drugs due to their unique nano-scale size undergo speedy entry in sub-cellular chambers, obstruct viral attachment to host cell, enhance drug bioavailability and evade drug resistance.
2. These small drugs can be engineered so that they can deliver appropriate bioactive concentration to the targeted site for eg. a specific sub-cellular region depending on the viral replication stage and mode of action of the drug.
3. The surface-to-volume ratio of these small drugs is quite immense which allows facile loading of antiviral drug cocktail.
4. Additionally the drug dose required to influence biological activity when formulated as nanomedicine is extremely low.
5. The overlapping of the features described in b, c and d helps in overcoming drug resistance and minimizes the chances of side effects in unwanted tissues and organs.
6. During intravenous administration these small drugs can be surface modified with hydrophilic polymers such as polyethylene glycol (PEG). The surface decoration with PEG prevents opsonization of the nanomedicines which enhances their circulation in blood stream, delays reticulo-endothelial system uptake and finally leads to bioavailability enhancements.
7. The release of the antiviral bioactive from such small drugs can be controlled and sustained for a longer period than conventional antiviral drugs. This further contributes to its clinical attractiveness as it reduces the dosing frequency and ensures better compliance from the patients.
8. Sometimes these smartly designed small drugs can be used in combination with classical antiviral drugs to ameliorate the solubility and stability of the conventional therapeutics and assist in programmed drug release. This also has a great impact in diminishing dosing frequency and intensify patient acceptance.
9. New technological advancements have further enriched the development of these small drugs. Nanomedicines today are designed to provide therapy and diagnostic simultaneously. This theragnostic capacity can be a useful strategic ploy against COVID-19 infection where there is an urgent need of both therapeutic and diagnostic agent to control the pandemic.

The array of unique properties presented by small drugs makes them the best possible weapons in our therapeutic arsenal to fight the COVID-19 pandemic. But one area associated to such drugs that is relatively unexplored is its impact on acute/ chronic/ long-term toxicity which needs to be investigated extensively if these small drugs are to be established as COVID-19 therapeutics.

References

1. http://www.phy.pku.edu.cn/~qhcao/resources/class/QM/Feynman’s-Talk.pdf
2. https://www.grandviewresearch.com/press-release/global-nanomedicine-market
3. Singh et.al, Therapeutic Advances in Infectious Disease. 2017, Vol. 4(4) 105 –131.
4. Nikaeen et.al, Nanomedicine (Lond.) (Epub ahead of print). 2020. doi.org/10.2217/nnm-2020-0117.
5. Szunerits et.al, Molecules. 2015, Aug 3;20(8):14051-1481.