Electroporative transdermal drug delivery : optimization and safety

Sharma, Ashish (1998) Electroporative transdermal drug delivery : optimization and safety. Masters thesis, Memorial University of Newfoundland.

[English] PDF (Migrated (PDF/A Conversion) from original format: (application/pdf)) - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. Download (13MB) [English] PDF - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. (Original Version)

Abstract

The major hurdle in transdermal drug delivery is the barrier property of stratum corneum. This barrier can be overcome by using electroporation. Electroporation involves the application of exponentially decaying high voltage pulses of short duration, which results in a transient increase in skin's permeability. This application of electroporation in transdermal drug delivery is at its early stages of development and needs to be studied in detail. -- Objectives: -- 1) To optimize the electroporative transdermal drug delivery by investigating the following: -- i) relationship between Uelectrode (voltage drop applied across the pulse delivery electrodes) and Uskin (voltage drop across skin). -- ii) effect of electrode design on Uskin. -- iii) influence of Uelectrode, pulse length (Շ), and number of pulses on the transdermal delivery of a model flourescent molecule, i.e., terazosin hydrochloride (TRZ). -- 2) To investigate safety issues related to electroporative delivery by studying the following: -- i) reversibility of skin's enhanced permeability -- ii) histological changes in the skin due to electroporation -- In-vitro experiments were performed using freshly excised skin from hairless rats, assembled in a custom-designed cells. Gene Pulser® II (Bio Rad, CA, USA) fitted with custom designed Ag/AgCI electrodes was used for generating exponentially decaying electroporation pulses. Tektronix®- 5111 storage oscilloscope (Oregon, USA) was used for measuring the voltage drop across the skin (Uskin) and the current flowing across the skin. TRZ was detected using HPLC with fluorescent detector. Results: Use of electroporation significantly increased the transdermal delivery of TRZ. For example, electroporative delivery with 20 pulses of Uelectrode = 500 V, Շ = 20ms resulted in 15 times increased transdermal delivery of TRZ, as compared to passive diffusion. A Uelectrode of 300 V (corresponding Uskin 66 V) seemed to be the minimum voltage required to make a significant enhancement compared to the control. The delivery of TRZ increased with an increase in Uelectrode, pulse length and number of pulses. However, in order to maintain skin safety while achieving a reasonable increase in the permeability of skin the upper limit for Uelectrode and pulse length seem to be 500V (Uskin 88 V)and 20 ms, respectively. At Uelectrode of 600 V and at pulse length 60 ms the damage to the skin seems to be very apparent. The Uskin values were about 1/2 to 1/5 that of Uelectrode depending on the voltage used. Electrode design and area also had profound effects on transdermal drug delivery. The pH, macroscopic, and microscopic changes associated with the skin after pulsing indicate that the use of a large electrode would minimize the damage to the skin in comparison to a small electrode. -- Conclusions: Electroporative transdermal delivery of TRZ was markedly influenced by Uelectrode, pulse length, number of pulses and electrode design. These factors can be controlled to make this technique efficient and safe.

Actions (login required)

View Item