Responsive Drug Delivery System Presenter: Bo He 12/10/03

Outline Traditional drug dosing & introduction to responsive drug delivery systems Commercially available sensors & drug delivery systems Responsive drug delivery systems under development Challenge & perspective A commercially available responsive drug delivery system – insulin pumps

Traditional Drug Dosing Medicine or injections Each person responds uniquely Noticeable symptoms are not sufficient to support timely and accurate dosing Examples- diabetes, cardiovascular disease, acute pain Controlled release – frequent exposure, side effects, tolerance Drug absorption, distribution, and metabolism can vary widely among individuals, even within the same family. It’s hard to predict when the heart stroke will happen. Unpredictable absorption of injected insulin can give you unpredictable blood sugar level.

Responsive Drug Delivery Systems Combination of Biosensors & controlled release system Revolutionized medicine by enabling individualized therapy Sense continuously to manage unpredictable condition Immediate respond with appropriate countermeasure Give the patients more flexibility and less disruption of the daily life

Example: Insulin Pumps An insulin reservoir (like a regular syringe) A small battery operated pump A computer chip for control Infusion set- a thin plastic tube to deliver insulin to the body Pump therapy A basal rate & bolus insulin Combination with Glucose sensors Reservoir and pump are incorporated in a plastic case about the size of a beeper.

The Importance of Control Programmed release controlled by microchips More flexibility & less pain Reduced the risk of side effects More than 200,000 people in the US wear insulin pumps Predictable blood sugars Flexible meal intake, go sports, no multiple shots every day.

Ideal Responsive Drug Delivery Disadvantages of available systems Not automatic, the user has to decide the dose The results are not always reliable Sensors and controlled drug delivery systems are not combined Ideal systems Sense minute amounts of marker molecules Immediate response In vivo detection and delivery Small, biocompatible, accurate and reproducible Biomolecule acting In vivo detection and delivery provides immediate response with minimal disruption to the patient’s daily life.

Type of Drug Delivery Commercially available Responsive Noninvasive reverse iontophoresis devices Implantable fusion pumps Duros implant technology controlled release Responsive Closed loop Smart polymers

Biosensors, e.g. Glucowatch Biographer: non-invasive, watch-like device that measures glucose AutoSensor: a plastic part that snaps into the Biographer and sticks to the skin. Noninvasive & automatic reading every 10 mins up to 13h

Comparison of Glucose Readings

How does Glucowatch work? Based on reverse iontophoresis A low electric current pulls glucose through the skin. Glucose is accumulated in two gel collection discs in the AutoSensor. Another electrode in the AutoSensor measures the glucose.

Enzymatic pathway Glucose oxidase catalyze oxidization of glucose in hydrogel Hydrogen peroxide reacts on the platinum electrode, providing electrons Current is proportional to glucose

Controlled-release device Affecting factors Compositions of osmotic agent Thickness of semipermeable membrane Surface area

Responsive drug delivery systems Smart polymer Antigen-antibody interaction Closed loop systems Sensing and delivery combo system

Antigen-antibody interaction smart polymers A semi-interpenetrating polyacrylamide (PAAm) hydrogel Antigen—rabbit immunoglobulin G( rabbit IgG) Antibody—goat anti-rabbit IgG (GAR IgG) Takashi Miyata et al., Nature, vol 399 ,766

Antigen-antibody interaction smart polymers Effect of free antigen concentration on the hydrogen swelling ration Antigen recognition by antigen-antibody semi-IPN hydrogel

Antigen-antibody interaction smart polymers Reversible swelling changes Antigen-responsive permeation (a model protein drug haemoglobin through a membrane fabricated from hydrogel )

Schematic of Self Regulating Responsive Therapeutic System

Challenge Commercially available systems Systems under development Expensive yet not always reliable Not automatically responsive Not completely in vivo Systems under development Short lifetime and hard to reproduce Slow response time Biocompatibility (coating) Coating Passive drug release at physiological glucose levels

References Sapna K. Deo; et al. Analytical Chem. 2003, 206A-213A. www.minimed.com www.glucowatch.com R. T. Kurnik et al. Electrochem. Soc. 1998, 145, 4119-4125 Miyata, T. et al. Nature 1999, 399, 766–769. Zhang, K.; Wu, X. Y. J. Controlled Release 2002, 80, 169–178. Tanihara, M. et al. J. Pharm. Sci. 1999, 88, 510–514. www.chiprx.com www.acs.ohio-state.edu/unit/research/archive/muscles.htm Metzger, M. et al. Diabetes Care 2002, 25, 1185–1191.

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