Stimuli sensitive polymers and self regulated drug delivery systems: a very partial review

Abstract

Since the early days of the Journal of Controlled Release, there has been considerable interest in materials that can release drug on an "on-demand" basis. So called "stimuli-responsive" and "intelligent" systems have been designed to deliver drug at various times or at various sites in the body, according to a stimulus that is either endogenous or externally applied. In the past three decades, research along these lines has taken numerous directions, and each new generation of investigators has discovered new physicochemical principles and chemical schemes by which the release properties of materials can be altered. No single review could possibly do justice to all of these approaches. In this article, some general observations are made, and a partial history of the field is presented. Both open loop and closed loop systems are discussed. Special emphasis is placed on stimuli-responsive hydrogels, and on systems that can respond repeatedly. It is argued that the most success at present and in the foreseeable future is with systems in which biosensing and actuation (i.e. drug delivery) are separated, with a human and/or cybernetic operator linking the two.

Keywords: Glucose sensitive; Hydrogels; Self regulated; Stimuli sensitive; pH sensitive.

Figure 1

Contrast between open and closed loop drug delivery. In open loop delivery, the system releases drug in a programmed fashion determined by the control. Delivery impinges on the physiological response, which also depends on the drug’s pharmacokinetic (PK) properties. In closed loop delivery, physiological and PK information is fed back to the controller, which alters its “commands” to the delivery system. While the controller and delivery system are represented as separate components, the control aspects may be intrinsic to the delivery device.

Figure 2

Current implentation of quasi-closed loop feedback control of insulin delivery. A small electrode senses glucose and transmits it to the controller by radio waves. The controller records glucose time series, providing it to the operator (patient or caregiver), who then instructs the pump, through commands to the controller, regarding insulin delivery program. Glucose time series can be stored or transmitted for further analysis.

Figure 3

a) Stimuli that can cause reversible swelling and collapse (shrinking) of hydrogels. b) Three forces determining hydrogel swelling, and the factors affecting them. T is temperature, pH and other concentrations refer to external aqueous medium, pKa is acidity constant of ionizable groups. Polymer elasticity: filled circles are permanent crosslinks, while crosslink in center is reversible. Polymer/solvent interaction: lattice representation of solvent and polymer is not intended to be realistic. Ion osmotic pressure: Here ionization is due to –COOH + NaCl ↔ –COO⁻ + Na⁺ + HCl reaction.

Figure 4

a) Phenylboronic acids are charged in the presence of Lewis bases such as:OH⁻, and the charge is stabilized by bidentate condensation of molecules containing cis diols (e.g. sugars) depicted as orange ovals. Charging of hydrogels containing PBA’s causes them to swell. b) Polymer chains in a hydrogel containing PBA, a chains containing a high density of pendant OH groups, such as poly(vinyl alcohol) (PVA) form crosslinks, shrinking the hydrogel. These crosslinks can be displaced by free sugar molecules, causing the hydrogel to swell. c) Glucose contains two sets of diols that can complex with PBA chains. At high pH values where the PBA units are highly charged, this can lead to formation of bisbidentate binding and crosslink formation. At high glucose concentrations, this mode is suppressed since all PBA sidechains are occupied by glucose molecules. The pH at which these mechanisms operate can be lowered by incorporating amines into the hydrogel, which serve as Lewis bases (:N-) that take over the function of:OH⁻.