ReviewThe origins and evolution of “controlled” drug delivery systems
Section snippets
The origins of “controlled” drug delivery
In the mid-1960s Judah Folkman, MD, at Harvard was circulating rabbit blood inside a Silastic® (silicone rubber) arterio-venous shunt and discovered that if he exposed the tubing to anaesthetic gases on the outside, the rabbits would fall asleep. [1] He proposed that short, sealed segments of such tubing containing a drug could be implanted, and if the silicone didn't change in dimensions or composition, the implant would become a constant rate drug delivery device. [2] (Fig. 1) He also showed
The “MACRO era” of zero-order “controlled” drug delivery devices
The first CDD devices that Alza designed were macroscopic in scale. One was an ophthalmic insert called the Ocusert® that released the anti-glaucoma drug, pilocarpine, at a constant rate in the eye, and another was called the Progestesert®, an intrauterine device (IUD) that released the contraceptive steroid, progesterone, at a constant rate in the uterine cavity. (Fig. 3) Each used poly(ethylene-co-vinyl acetate) or polyEVA as the rate-controlling membrane (RCM) in a constant rate, reservoir
The “MICRO era” of sustained release, biodegradable microparticle and phase-separated depot delivery systems
Biodegradable polymers of poly(hydroxy acids) were developed for sutures in the 1960s and 1970s; that technology was adopted by drug delivery researchers in the 1970s and reached the clinic in the 1980s. Thus, the field of controlled DD evolved from the macroscopic, zero order PK devices in the 1970s and 1980s, to “sustained release” macro/microscopic biodegradable depot systems that first reached the clinic in the mid to late 1980s. Most of the drugs being released were potent molecules, like
The “NANO era” of targeted or site-controlled drug delivery systems
In the mid to late 1970s the concept of polymer-drug conjugates or “nano-therapeutics”, independently arose at various places around the world. Three key technologies were the major factors that stimulated the immense activity and clinical success of nano-therapeutics from the late 1980s to the present. (Fig. 9) The first was the concept of “PEGylation”, which refers to polyethylene glycol-conjugated drugs or drug carriers. The second is the concept of “active targeting” of the drug conjugate
“Surface-controlled” drug delivery systems
Surface release of drugs from thin, drug-containing films or release of drugs from coated oral tablets were among the earliest surface-controlled DDS, which is another form of controlled drug delivery. These DDS have been clinically successful since the 1960s. These examples could also be categorized into one of, or a combination of, the macroscopic, microscopic and nanoscopic categories.
Sustained release of the anti-coagulant, heparin from polymer surfaces was one of the first successful drug
The future of “controlled” drug delivery
There are many challenges and much excitement to come in the future of controlled DDS. As our knowledge of biology (especially cell biology and DNA) increases, so will our ability to design nano-scale DDS that are serum stable and efficiently taken up by specific cells, then escape the endosome and target specific sites and pathways within the cells. With this increased ability to control the efficiency and specificity of the delivery process, along with increased ability to design potent
Acknowledgments
Much of the information in this article has been the author's personal knowledge, gained over the past 40+ years, and in addition, the author has solicited personal information from the many individuals involved in the history and evolution of the controlled drug delivery field, and Jindra Kopecek, Tom Tice and Howie Rosen have been especially helpful. It is worth noting one more time that this article is about the early history and evolution of clinical applications of controlled drug delivery
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