1. Transdermal Drug Delivery – Assessment of in vitro skin permeation Shashank Jain

2. Introduction Transdermal and topical drug delivery Advantage-  Site specific application  First pass metabolism  Avoid GI side-effects  Controlled drug delivery  Non-invasive Limitation-  Dose  Large molecules  Skin irritation and metabolism  Rate limiting stratum corneum 2

3. Skin structure 3

4. Pathways for drug permeation Stratum corneum Epidermis Dermis Blood supply 4

5. Approaches Physical:  Microneedle  Iontophoresis  Electrophoresis Chemical:  Ethanol  PEG Colloidal:  Liposome  Ethosomes  Microemulsion 5

6. Iontophoresis 6

7. Ethosome Mechanism of skin delivery via ethosome vesicles* 7

8. Assessment of in-vitro permeation Fick’s law of diffusion 8

9. A] Side-Bi-Side In-vitro experiment setup 9

10. In-vitro experiment setup (contd.) B] Vertical Franz 10

11. In-vitro experiment setup (contd.) C] Flow Through Cells: 11

12. In-vitro permeation study procedure Step 1. Skin selection Human skin Animal skin Human skin equivalent Step 2. Isolating skin section Step 3. Experimental setup Mounting skin section Temperature Air bubble Step 4. Sampling Step 5. Drug deposition study Step 6. Data analysis Permeation flux Cumulative drug permeation Drug deposition 12

13. A typical permeation profile Cumulative drug permeated/area Time 13

14. References: Naik, A., Kalia, Y.N., Guy, R.H., 2000. Transdermal drug delivery: overcoming the skin’s barrier function. Pharmaceutical Science & Technology Today 3, 318-326 Verma, P., Pathak, K., 2010. Therapeutic and cosmeceutical potential of ethosomes: An overview. J Adv Pharm Technol Res 1, 274-282 http://www.permegear.com/primer.pdf Bolzinger, M.-A., Briancon, S.p., Pelletier, J., Chevalier, Y., 2012. Penetration of drugs through skin, a complex rate-controlling membrane. Current Opinion in Colloid & Interface Science 17, 156-165. 14

15. Thank You 15

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17. Document BA/BE in order of preference are (1) pharmacokinetic (PK) measurements based on measurement of an active drug and/or metabolite in blood, plasma, and/or urine; (2) pharmacodynamic (PD); (3) clinical trials; and (4) in vitro studies. The BA/BE determination based on PD (or clinical) and dermatokinetics. DPK encompasses drug concentration measurements with respect to time, based on a stratum corneum concentration-time curve Topical: If two formulation produce comparable stratum corneum concentration-time curves may be BE A plot of stratum corneum drug concentration versus a time profile should be constructed to yield stratum corneum metrics of Cmax, Tmax and AUC. Transdermal delivery systems, are considered to be bioequivalent if they yield comparable bioavailability-based plasma concentration–time profiles when administered to the same individuals under similar dosage conditions. Two oral or transdermal formulations are judged BE if they produce comparable plasma concentration-time curves. 17