The engineering of physical, chemical, and biological components into systems for delivering controlled amounts of a therapeutic agent over a prolonged period, thereby maintaining plasma or tissue drug levels at a constant level. Controlled drug delivery systems can take a variety of forms, such as mechanical pumps, polymer matrices or microparticulates, and externally applied transdermal patches.
The most obvious approach for controlled drug delivery involves miniaturization of the familiar infusion system. Mechanical pumps, either totally implantable or requiring percutaneous catheters, have been used to deliver insulin, anticoagulants, analgesics, and cancer chemotherapy. Drugs are maintained in a liquid reservoir prior to delivery, so only agents that are stable in solution at body temperature can be used. Because pumps deliver precisely controlled amounts of therapeutic agents, they may find additional important applications, particularly when coupled with implanted biosensors for feedback control. See also Bioelectronics.
Many disadvantages of controlled drug delivery via pumps can be avoided by using controlled-release polymers as delivery vehicles. For a specific therapeutic agent, the rate, pattern, and duration of drug release can be modified by selecting the appropriate biocompatible polymer and method of device fabrication. See also Pharmacology; Polymer.
The best example of controlled-release polymer systems are the cylindrical silicone-based subdermal implants that release contraceptive steroids at a constant rate for years following implantation and provide economical, reliable, long-term protection against unwanted pregnancy. An intrauterine device with a controlled-release poly(ethylene-covinyl acetate) coating delivers contraceptive steroids directly to the reproductive tract; local release of certain agents can reduce the overall drug dose and, therefore, reduce or eliminate side effects produced by drug toxicity in other tissues. See also Birth control.
Transdermal controlled-delivery devices are similar in design to implantable reservoir systems. A single flat polymer membrane is placed between a drug reservoir and the skin. The polymer membrane is designed to control the rate of drug permeation into the skin over a period of several hours to 1 day. Transdermal delivery systems have been produced for agents that can penetrate the skin easily, such as nitroglycerin, scopolamine, clonidine, estradiol, and nicotine.
When nondegradable polymers are used for implanted delivery systems, the polymer must be surgically removed at the end of therapy. This procedure can be eliminated by the use of biodegradable polymers, which dissolve following implantation. Biodegradable polymers, which were first developed as absorbable sutures in the 1960s, are usually employed as matrix devices. Of the polymers tested, poly(lactide-co-glycolide) has been used most frequently. Most importantly, small microspheres of biodegradable polymers can be produced as injectable or ingestible delivery systems; injectable poly(lactide-co-glycolide) microspheres that release a peptide are used for the treatment of prostate cancer in humans. The chemistry of the biodegradable polymers can be exploited in other ways to achieve controlled delivery, for example, by linking drugs to the polymer matrix through degradable covalent bonds.
