1. 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

2. 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

3. 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

4. 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

5. 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

6. Anodal & Cathodal iontophoresis
Cathodal IP
Anodal IP

7. 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 )
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)

8. 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

9. 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: Da
Ondansetron hydrochloride
Pharmacokinetic:
T50: 3-4 h
Foral: 60%
Mean Css: ng mL-1
Max. Css: ng mL-1
Cl: 500 mL min-1

11. 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

12. 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

13. 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) mM K+ mM
Na+
Cl− mM
Ca2+
Mg2+ mM mM
154 mM NaCl solution (Normal Saline)

14. 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. =
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

15. 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

16. 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+

17. 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) = ng/mL Css(max) = 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 = ng/min = 20 µg/min
3.28 µmoL/h
÷1000
x 60
( g) / = 5, mol = nmol/min B
199 x 500 = ng/min = 99.5 µg/min
16.32
µmoL/h
÷1000
x 60
( g) ÷ = mol = 272 nmol/min

18. 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
nmol h-1
nmol h-1 cm-2
0.616 µmol h-1 cm-2
Note: Transport area: 0.64 cm2

19. 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)

20. Feasibility of developed delivery system
0.16 < < 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

21. Thank you for your time and attention...
Assoc. Prof. Sevgi Güngör
Istanbul University, Faculty of Pharmacy Department of Pharmaceutical Technology
Deniz Özdin
MSc of Pharmaceutics
Istanbul University, Faculty of Pharmacy Department of Pharmaceutical Technology