Elsevier

Journal of Controlled Release

Volume 132, Issue 3, 18 December 2008, Pages 153-163
Journal of Controlled Release

Review
The origins and evolution of “controlled” drug delivery systems

https://doi.org/10.1016/j.jconrel.2008.08.012Get rights and content

Abstract

This paper describes the earliest days when the “controlled drug delivery” (CDD) field began, the pioneers who launched this exciting and important field, and the key people who came after them. It traces the evolution of the field from its origins in the 1960s to (a) the 1970s and 1980s, when numerous macroscopic “controlled” drug delivery (DD) devices and implants were designed for delivery as mucosal inserts (e.g., in the eye or vagina), as implants (e.g., sub-cutaneous or intra-muscular), as ingestible capsules (e.g., in the G-I tract), as topical patches (e.g., on the skin), and were approved for clinical use, to (b) the 1980s and 1990s when microscopic degradable polymer depot DD systems (DDS) were commercialized, and to (c) the currently very active and exciting nanoscopic era of targeted nano-carriers, in a sense bringing to life Ehrlich's imagined concept of the “Magic Bullet”. The nanoscopic era began with systems proposed in the 1970s, that were first used in the clinic in the 1980s, and which came of age in the 1990s, and which are presently evolving into many exciting and clinically successful products in the 2000s. Most of these have succeeded because of the emergence of three key technologies: (1) PEGylation, (2) active targeting to specific cells by ligands conjugated to the DDS, or passive targeting to solid tumors via the EPR effect.

The author has been personally involved in the origins and evolution of this field for the past 38 years (see below), and this review includes information that was provided to him by many researchers in this field about the history of various developments. Thus, this paper is based on his own personal involvements in the CDD field, along with many historical anecdotes provided by the key pioneers and researchers in the field. Because of the huge literature of scientific papers on CDD systems, this article attempts to limit examples to those that have been approved for clinical use, or are currently in clinical trials. Even so, it is impossible to know of and include all such examples and to properly credit all the key people who helped to bring the various technologies and devices to the clinic. The author apologizes in advance for all omissions.

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

References (35)

  • F. Theeuwes, T.T. Higuchi, Osmatic dispensing device for releasing beneficial agent, US Patent 3,845,770, Nov. 5,...
  • R. Langer et al.

    Polymers for the sustained release of proteins and other macromolecules

    Nature

    (1976)
  • E. Schmitt, R. Polistina, Surgical sutures, US Patent 3,297,033, Jan. 10,...
  • G. Boswell, R. Scribner, Polylactide-drug mixtures, US Patent 3,773,919, Nov. 20,...
  • T. Tice, Personal...
  • J. Kent, D. Lewis, L. Sanders, T. Tice, Microencapsulation of water soluble active polypeptides, US Patent 4,675,189,...
  • W. Gombotz, M. Healy, L. Brown, Very low temperature casting of controlled release microspheres, US Patent 5,019,400,...
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