Small Molecule Drug Delivery

Nauman, D. A., Bertozzi, C. R. (2001). Kinetic parameters for small-molecule drug delivery by covalent cell surface targeting. Biochim. Biophys. Acta, 1568,147-154. 

Most small molecule drugs are formulated for oral delivery while large molecule biopharmaceuticals are injected via parenteral means intravenous, intramuscular, subcutaneous, and infusion. 

The molecular weight or size of an optimal delivery system in vivo is imposed by the physiology of circulation and excretion. The lower limit of the molecular weight is about 30 kDa because the microtubular cells in the kidney readily excrete hydrophilic molecules whose molecular weight is 30 kDa or less.23 In fact, this is the major route of elimination for many small-molecule drugs after they are transformed into more hydrophilic metabolites. Therefore, a drug delivery system should have a combined molecular weight of 30 kDa to avoid such a quick renal clearance. 

One of the key pieces to development of a successful drug product is the ability to deliver the drug to the site of action with minimal discomfort or inconvenience to the patient. For small molecule therapeutics, there is a wide range of options available for drug administration. Delivery via injection (IV, IM, and SC), oral, nasal, ocular, transmucosal (buccal, vaginal, and rectal), and transdermal routes is possible with small molecule drugs. However, the size of proteins and the complexity of their structures severely limit the routes of administration available to proteins. 

While injection has served as the primary means of delivering macromolecules produced by biotechnology, many non-invasive routes have been explored as alternatives. Oral delivery remains the most common method of delivery for most small molecule drugs. However, oral delivery most often does not work for macromolecules because proteins are digested before they have an opportunity to reach the bloodstream. Commercially successful oral delivery of peptides and proteins has not been achievable with the exception of DDAVP (9 amino acids) and cyclosporin (11 amino acids), two digestion resistant small peptides. 

R., Whittle, B., Poly(ethylene glycol) conjugation of protein and small molecule drugs, in Drug Delivery Systems in Cancer Therapy (D.M. Brown, Ed.), Humana Press, Totowa,... 

Although there is much to be optimistic about the future of protein pharmaceuticals, there are still many unique problems with their development, production, and delivery. Among the more obvious problems with protein drugs is the fact that they are much more delicate than small-molecule drugs. Proteins such as hormones, antibodies, and enzymes cannot normally be compounded or pressed into dry pills or emulsified or concentrated into tinctures. This type of conventional pharmaceutical manufacturing and formulation would destroy the activity of most protein pharmaceuticals. Similarly most peptide hormones, antibodies, and enzymes cannot be stored indefinitely at room temperatures in nonsterile containers instead they must be kept in a cool, dark, aqueous, sterile environment for no more than a few weeks. These limitations to protein preparation and formulation have created a significant challenge to pharmaceutical chemists. Potential solutions to these problems are discussed in Chapter 4 of this book. 

Maria de los Angeles Cortes Castillo, Technology and Health Service Delivery, Pan American Health Organization, Washington, DC, Regulation of Small-Molecule Drugs versus Biologicals versus Biotech Products... 

Wong BS, Yoong SL, lagusiak A, Panczyk T, Ho HK, Ang WH, Pastorin G. Carbon nanotubes for delivery of small molecule drugs. Adv Drug DeUv Rev 2013 65 1964-2015. 

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