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J. Biomater. Sci. Polymer Edn, Vol. 19, No. 6, pp. 755–767 (2008)  Koninklijke Brill NV, Leiden, 2008.
Also available online – http://www.brill.nl/jbs

Smart polymers for responsive drug-delivery systems

TAMAR TRAITEL, RIKI GOLDBART and JOSEPH KOST ∗
Department of Chemical Engineering, Ben-Gurion University of the Negev, P.O. Box 653,

Beer Sheva 84105, Israel

Received 29 March 2007; accepted 12 July 2007

Abstract—The rapid advancement of biomedical research has led to many creative applications for biocompatible polymers. As modern medicine discerns more mechanisms, both of physiology and of pathophysiology, the approach to healing is to mimic, or if possible, to recreate the physiology of healthy functioning. Thus, the area of smart polymers for responsive drug delivery has evolved. The developments fall under two categories: externally regulated or pulsatile systems (also known as ‘open-loop’ systems) and self-regulated systems (also known as ‘closed-loop’). The externally controlled devices apply external triggers for pulsatile delivery such as: ultrasonic, magnetic, electric, light and chemical or biochemical agents. The self-regulated systems, on the other hand, are defined as systems where the controlled variable is detected, and as a result, the system output is adjusted accordingly. The release rate is controlled by feedback information, without any external intervention. The self-regulated systems utilize several approaches for the rate control mechanisms such as thermal, pH-sensitive polymers, enzyme–substrate reactions, pH-sensitive drug solubility, competitive binding, antibody interactions and metal-concentration-dependent hydrolysis.

Key words: Responsive drug-delivery system; intelligent drug-delivery systems; smart polymers; externally regulated; pulsatile; self-regulation; ‘open-loop’; ‘closed-loop’.

INTRODUCTION

The rapid advancement of biomedical research has led to many creative applications for biocompatible polymers. As modern medicine discerns more mechanisms, both of physiology and of pathophysiology, the approach to healing is to mimic, or if possible, to recreate the physiology of healthy functioning. Smart polymeric drug-delivery systems have the ability to respond to environmental changes and consequently, alter their properties reversibly enabling an efficient and safe drug delivery.

The developments fall under two categories: externally regulated or pulsatile systems (also known as ‘open-loop’ systems) and self-regulated systems (also

∗To whom correspondence should be addressed. E-mail: kost@bgu.ac.il

Review

756 T. Traitel et al.
known as ‘closed-loop’). The following chapter outlines the fundamentals of this

research area.

DEVELOPMENT OF CONTROLLED DRUG DELIVERY SYSTEMS

Control of drug concentration levels over time

While newer and more powerful drugs continue to be developed, increasing attention is being given to the methods of administering these active substances. In conventional drug delivery, the drug concentration in the blood rises when the drug is taken, then peaks and declines. Maintaining drug in the desired therapeutic range with just a single dose, or targeting the drug to a specific area (lowering the systemic drug levels), are goals that have been successfully attained with commercially available controlled release devices [1, 2]. However, there are many clinical situations where the approach of a constant drug delivery rate is insufficient, such as the delivery of insulin for patients with diabetes mellitus, anti-arrhythmics for patients with heart rhythm disorders, gastric acid inhibitors for ulcer control and nitrates for patients with angina pectoris. The onset of infection of medical device or biomaterial surfaces is an additional clinical situation where responsive delivery system of anti-inflammatory drugs can be useful. Furthermore, studies in the field of chronopharmacology indicate that the onset of certain diseases exhibit strong circadian temporal dependence. Therefore, time-dependent release of drugs, such as β-blockers, birth control, general hormone replacement, immunization and cancer chemotherapy, is required.

Treatment of all these clinical scenarios could be optimized through the use of responsive (‘smart’) delivery systems [3 – 9], which are, in essence, man-made imitations of healthy functioning.