Transdermal Iontophoresis; A Non-Invasive Treatment Method for Chemotherapy-Induced Nausea & Vomiting with Elevated Patient’s Compliance Deniz Özdin Msc of Pharmaceutics Istanbul University, Faculty of Pharmacy Department of Pharmaceutical Technology deniz.ozdin@gmail.com

Iontphoresis Enhanced drug delivery, involving application of low, physiologically acceptable electrical potential with constant density (≤0.5 mA/cm2), which facilitates movement of predominantly hydrophilic charged molecules as well as lipophilic ones across the biological membranes. Principle of iontophoresis is lied on ‘electrorepulsion’, i.e., charged molecules are repelled by similarly charged electrodes into the skin and toward the opposit charged electrode. electrode Anode Ag Cathode AgCl

Transdermal Iontophoresis Skin, the largest single organ of the body is attractive to formulators as an accessible means of drug input. I.V 1.Non–invasive administration 2.Non–invasive monitoring 3.Higher patient compliance 4.Fisibility of non-hospital application Oral 1.Avoidance of GI &liver first pass effects 2.Controlled and continuous drug delivery 3.Easy removal of the dosage form Transdermal Iontophoresis TDD 1.Smaller patch size 2.Shorter on-set time (reduced lag time) 3.Individualized therapy 4.Delivery of higher M.W. drugs 5.Independent of skin’s permeability 6.Safety

Parameters influence IP delivery Presence/absence of background electrolyte Types of competing ions Donor drug concentration pH of the donor phase Current density Duration of current apply

Two Principal Mechanisms of IP Electromigration and Electroosmosis Electromigration (Electrorepulsion) : Movement of the ions in the presence of the electrical current which is resullt of direct interaction between applied electric field & charged species present in the formulation Brings anodal & cathodal iontophoresis... Electromigration is the most dominant transport mechanism of iontophoresis

Anodal & Cathodal iontophoresis Cathodal IP Anodal IP

Electroosmosis & Skin Electrical Property Skin electrical properties should be most considered in iontophoresis and formulation strategies. Isoelectric point of the skin: is the pH value which membrane has no charge, i.e., the skin barrieres support a net charge of zero (pH 4.4-4.8) Thus, at physiologic pH the skin behaves as negatively charged, cation-permselective membrane follows that current passage causes a net convective solvent flow in the anode-to-cathode direction This phenomenon is referred to electroosmosis. ‘Electroosmosis’ Skin COOH COO− COO − Isoelectric point Physiologic pH (7.4)

D+ Anode Cathode Reduction: AgCl + → Ag(metalic) + Clˉ D+ D0 D0 Electrolyte Solution Ag AgCl Ag Anode Cathode D+ D0 Na+ D0 Cl− Cl− Cl− intrinsic Cl− intrinsic Cl− produced Cl− intrinsic Na+ D+ Oxidation: Ag(metalic) + Cl־ → AgCl + e Reduction: AgCl + → Ag(metalic) + Clˉ

IP System Requirements & Electrochemistry Voltage source Electrodes & related Electrolyte solutions Salt bridge IP system works like electrolytic cell Permeation study Active ingredient 25 mM Trizma HCl Skin (Pig or human) 750 µm thickness Side-by-side diffusion cells transport area 0.64 cm2 Ondansetron hydrochloride Physicochemistry: Pka: 7.4 Log p: 2.14 MW: 365.9 Da Ondansetron hydrochloride Pharmacokinetic: T50: 3-4 h Foral: 60% Mean Css: 30-40 ng mL-1 Max. Css:183-199 ng mL-1 Cl: 500 mL min-1

Background electrolyte in donor Donor pH Enough low for ondansetron solubility Enough high for maintenance of selective permeability & thus anodal electroosmosis Trizma HCl pH ≈ 5.2

Ondansetron log D value & % Ionization Log D = log P – log Handerson–Hasselbalch: pH % ionization Log D 5 99.60 - 0.1 6 96.17 0.88 6.5 88.81 1.35 7 71.63 1.75 7.4 50 2.00

154 mM NaCl solution (Normal Saline) Receptor solution Enough ondansetron solubility Ensuring physiological levels of ions (partecularly Cl- ) Constant ion content Physiologic pH (7.4) 96-103 mM K+ 135-145 mM Na+ Cl− 3.4-4.8 mM Ca2+ Mg2+ 0.68-0.88 mM 2.1-2.6 mM 154 mM NaCl solution (Normal Saline)

Electroosmosis Marker “paracetamol” Selecting electroosmotic marker Calculating JEO of marker (which have to be equal to total Jtot of marker) 3. Converting JEO of marker to JEO of drug Determination of Electroosmotic flux Electroosmosis Marker “paracetamol” M.W. = 151.16 Weak acidic character (pka ≈ 9.51) Hydrophilic Non-ionized in studies pH values Handerson–Hasselbalch: %99 non-ionized in pH range of 5-7.4

Ondansetron Fluxss (nmol h-1) Experimental conditions Ondansetron Fluxss (nmol h-1) Concentration (mM) Current density (mA cm-2) Total EO tx 0.5 32.23±1.4 1.21±0.3 0.01 1 61.65±9.6 2.52±0.27 0.02 5 87.49±26.1 0.29±0.02 0.03 20 118.5±38.4 0.04 50 97.15±11 0.25 17.99±2.3 0.52±0.03 30.87±6.6 1.2±0.08 29.86±3.9 1.38±0.07 47.25±12.8 0.1 7.38±1.2 0.30±0.03 13.85±2.3 0.66±0.14 12.44±2.1 2.16±0.10

The total charge is carried by drug will decrease Cationic lipophilic The total charge is carried by drug will decrease Anode Cathode D+ Na+ D0 Cl− D+ D+ D+ D0 D0 D0 Lower transport efficiency ! Cl− Na+

Pharmacokinetic of Ondansetron Evaluating System Feasibility & Therapeutic Aspect Pharmacokinetic data Available surface area for transport (is doubted) Pharmacokinetic of Ondansetron Vd = 160 L Cl = 500 mL/min t50 = 3-4 h Css(mean) = 30-40 ng/mL Css(max) = 183-199 ng/mL For maintenance of steady state: Rate of administration = Rate of elimination (Css Cl) output rate Targeting input rate (K0 = A Jss ) Targeting input rate . A 40 x 500 = 20000 ng/min = 20 µg/min 3.28 µmoL/h ÷1000 x 60 (20 . 10-6 g) / 365.9 = 5,46 . 10-8 mol = 54.66 nmol/min B 199 x 500 = 99500 ng/min = 99.5 µg/min 16.32 µmoL/h ÷1000 x 60 (99.5 . 10-6 g) ÷ 365.9 = 2.72 . 10-7 mol = 272 nmol/min

Targeting Input Rate Per unit surface area 0.16 µmoL h-1 cm-2 3.28 µmoL/h 20 cm2 patch 0.82 µmoL h-1 cm-2 16.32 µmoL/h Maximum delivery 20 mM Cdonor Water solution (absence of electrolyte) 24 h iontophoresis 0.5 mA cm-2 394.37 nmol h-1 616.20 nmol h-1 cm-2 0.616 µmol h-1 cm-2 Note: Transport area: 0.64 cm2

Safety The risk of overdose and unwanted delivery has been avoided. (Handerson–Hasselbalch) 1. The pH value of OND donor solution is about 5. It means ≈%99 of OND will be present in ionized form. Thus OND would permeate through the skin only when electrical current is applied. 2. No passive permeation will occur! Passive permeation through skin necessitates drug presence in non-ionized form. However in this formulation OND exists in ionized form (≈%99)

Feasibility of developed delivery system 0.16 < 0.616 < 0.82 µmoL h-1 cm-2 Efficiency Ondansetron transdermal IP system Pediatric application Safety Applicable patch size Reduced complications of IV route Patient convenience Reduced hospital dependency

Thank you for your time and attention... Assoc. Prof. Sevgi Güngör Istanbul University, Faculty of Pharmacy Department of Pharmaceutical Technology sgungor@istanbul.edu.tr Deniz Özdin MSc of Pharmaceutics Istanbul University, Faculty of Pharmacy Department of Pharmaceutical Technology deniz.ozdin@gmail.com