The origins and evolution of "controlled" drug delivery systems.

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.