Date of Award

Summer 2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemical Engineering - (Ph.D.)

Department

Chemical, Biological and Pharmaceutical Engineering

First Advisor

Simon, Laurent

Second Advisor

Armenante, Piero M.

Third Advisor

Bilgili, Ecevit Atalay

Fourth Advisor

Xu, Xiaoyang

Fifth Advisor

Chan, Rick

Abstract

A novel dissolving microneedle array system is developed to investigate permeation of a sumatriptan succinate formulations through the skin aided by iontophoresis. Three formulations consisting of hydrophilic, positively charged drug molecules encapsulated in a water-soluble biologically suitable polymer, polyvinylpyrrolidone (PVP), have been accepted by the U.S. Food and Drug Administration (FDA). The microneedle systems are fabricated with 600 pyramid-shaped needles, each 500 µm tall, on a 0.785-cm2 circular array. In vitro transdermal studies with minipig skin and vertical Franz diffusion cells show > 68% permeation of sumatriptan over a 24-hour period. A combination of microneedle and electrical current density ranging from 100 to 500 µA/cm2 using Ag / AgCl electrodes displays increased flux with current density. At 500 µA/cm2, a dissolving array loaded with 4.3 mg sumatriptan leads to a steady-state delivery rate of 490 µg/cm2h with negligible lag time. In theory, a 9.58-cm2 microneedle-array patch loaded with 47.30 mg of sumatriptan succinate could provide the required plasma concentration, 72 ng/ml, for nearly six hours.

In parallel, a mathematical model based on first principles is developed to predict the amount of drug delivered into the skin using software (e.g., Mathematica). A system of mass balance equations are derived to simulate the dissolution, diffusion, electromigration and transport of the active ingredient through the epidermis. The analytical approach allows for the evaluation and estimation of the effects of key parameters (i.e., loading dose, polymer concentration, needle height, needle pitch width and current density) on the release profile. The skin layer concentration increases significantly with either increased loading dose or elongated height of the microneedle. The percentage of sumatriptan permeating through skin increased favorably with increased electrical current applied to microneedle patch. An inverse correlation was observed between the pitch width (center to center distance of adjacent needles) and the cumulative amount of sumatriptan permeated into the dermis. Predicted cumulative release data from mathematical model simulations of each of the three formulations were successfully validated with in vitro permeation data administered with Franz cells and minipig skin.

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