F. Cunha 1,2, A. Barnes 1, W. Schlindwein 1 and R. Linford 3 Iontophoretic Materials 1. Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, Leicester, LE1 9BH - UK 2. Laboratório de Materiais Poliméricos (Lapol) – Universidade Federal do Rio Grande do Sul (UFRGS) Porto Alegre – Brazil. 3. Research Office, De Montfort University, LE1 9BH - UK 206 th Meeting of the Electrochemical Society (ECS) 2004 Fall Meeting of the Electrochemical Society of Japan (ECSJ) Oct 3-8, 2004 Honolulu - Hawaii

Outline Transdermal Drug Delivery Drugs Drug Reservoirs Recent developments Interpenetrating Polymer Networks

Transdermal Drug Delivery Iontophoretic Delivery

Drug Reservoirs skin compatibility a relatively high drug content which does not significantly evaporate or leak over time reasonable ionic conductivity so that the ionic drug will travel under an electrochemical field gradient dimensional stability so that this part of the device does not deform over time flexibility so that maximum contact with the skin is maintained.

Polymer Drug Reservoirs Poly(ethylene oxide) - PEOPoly(vinyl pirrolidone) – PVPPoly(vinyl alcohol) – PVA Hydroxyethyl methacrylate - HEMA Chitosan

Drug Reservoirs We have synthesised a novel polymer containing two interpenetrating polymer networks (IPN’s)

Castor Oil 4,4’-Methylenebis(phenyl isocyanate) MDI prepolymer Synthesis of First Polymer Step 1

PEG 1500 First polymer (polyurethane) Pre polymer Synthesis of First Polymer Step 2

Methyl methacrylate Crosslinker (EGDMA) Second polymer (poly(methyl methacrylate)) Synthesis of Second Polymer

Interpenetrating Polymer Network 1.The polyurethane provides good adhesion 2.The poly(methyl methacrylate) provides good tear resistance 3.The poly(ethylene glycol) provides enhanced ionic conductivity 4.This membrane can be made in a one-pot synthesis! Polyurethane PMMA

Drug Penetration Through Skin Ideal molecular properties - Low molar mass (<600 DA, high diffusion coefficient) - Adequate solubility in oil and water (high concentration gradient) - Lipophilic molecules - A balanced partition coefficient - Low melting point -Good example : NICOTINE C 10 H 14 N 2

Drugs Glucose (a-D-Glucose) Lidocaine hydrochloride Fentanyl Sufentanil Scopolamine

TDD Market The total market for TDD products in the US, major European markets, and Japan was approximately $2.5 billion in 2001

Lidocaine Hydrochloride 2-Diethylamino-N-(2,6-dimethylphenyl)acetamide Lidocaine HCl MW = 270.8

PDRE Polymer Drug Reservoir Electrolyte Swelling Lidocaine HCl in PG/PEG Drug Reservoir Optimisation PDREPDRE One –pot synthesis Lidocaine HCl in PG/PEG One –pot synthesis Lidocaine HCl

Solvents (PG/PEG400) 100/025/7550/5075/250/100 Drug Solubility (g.g -1 ) Swelling (%) Drug (w/w %) Conductivity (S.cm -1 ) DDR (mg.ml -1.h -1 ) 5.7x x x x x PU/PMMA IPNs – Lidocaine HCl

Drug delivery by Iontophoresis Constant current mA

a.c. Impedance

Drug delivery by Iontophoresis IPN/PEG 400/Lidocaine:HCl

IPNs based on castor oil (natural product) can be used as ionic drug reservoir for iontophoretic drug delivery; The membranes are mechanically stable and can form gels containing lidocaine hydrochloride in propylene glycol, poly(ethylene glycol) and their mixtures; Drug delivery by Iontophoresis from PU IPNs

Higher values of drug delivery in mg/ml were obtained for IPN/PG/Lidocaine:HCl gels, at constant current of 2.0 mA, when compared to IPN/PEG400/Lidocaine:HCl gels; Drug delivery by Iontophoresis from PU IPNs

(PG) Propylene Glycol (E1) 2- pyrrolidinone (E2) 1-Dodecyl-2-Pyrrolidinone Skin Penetration Enhancers

Drug delivery by Iontophoresis from PU IPNs The role of Skin Penetration Enhancers at 2.0 mA

Drug delivery by Iontophoresis from PU IPNs The role of Skin Penetration Enhancers at 2.0 mA

Drug delivery by Iontophoresis from PU IPNs IPN- E2

The cumulative concentration of lidocaine:HCl transported through cellophane membranes from IPN/E2 gels increases linearly with the applied current. There is, however, a passive diffusion of ~ 10 mg/ml at zero current; Drug delivery by Iontophoresis from PU IPNs

Comparing the three enhancers PG, E1 and E2, propylene glycol is the solvent with the higher drug delivery rate. There is a correlation between solvent polarity and drug release through the cellophane membrane; Drug delivery by Iontophoresis from PU IPNs

The mixtures of PG and 1-Dodecyl-2-Pyrrolidinone show a synergic effect between both solvents. There is an enhancement of the drug delivered through the cellophane when 10, 20 or 50% of 1-Dodecyl-2-Pyrrolidinone is added to PG. Drug delivery by Iontophoresis from PU IPNs

Integrated Iontophoretic System Components that could use polymer electrolytes are shaded in yellow Sensor Anode Cathode Drug reservoir ion reservoir Battery Skin Patient tissue bloodstream

Summary Polymer electrolytes can be made using ionic drugs; such films display properties which may be useful in iontophoretic devices These films are stable at physiological temperatures Pilot experiments using a synthetic membrane in place of skin show that therapeutic levels can be delivered directly from a polymer electrolyte by iontophoresis

Acknowledgements Brazilian Research Agency C A P E S