Microneedles Assisted Iontophoretic Transdermal Delivery of Drugs

Abstract

Topical/transdermal delivery offers an attractive alternative to oral and parenteral delivery in terms of non-invasiveness, administration and termination of dose and drug stability etc. However, the excellent barrier system of skin limits the number of drugs that can be delivered in therapeutic quantities to the site of action. Various approaches such as iontophoresis (ITP), microneedles (MN), chemical permeation enhancers, phonophoresis and synthesis of lipophilic analogues have been used to increase drug permeation across skin. ITP and MN have shown promising results in enhancing the topical transdermal delivery. Further, the combination of ITP and MN (ITP+MN) has shown additive or synergistic effects on transdermal drug delivery. The effect of lipophilicity of drug on permeation across skin has been well reported. However, this effect has not been studied under the influence of ITP in microporated skin. Further, the effect of the lipophilicity of delivery vehicle on the transdermal delivery across microporated skin has not been reported. Thus, this dissertation focuses on studying the effect of lipophilicity of drug as well as the delivery vehicle on the skin permeation of drug across microporated skin under the influence of ITP. To investigate the effect of drug’s lipophilicity on its delivery across skin under the influence of ITP and MNs, we selected four model beta blocker drugs, propranolol, acebutolol, atenolol and sotalol, with similar molecular weights and pKa values but varied lipophilicity. The skin permeation of these drugs was studied under the influence of MNs, ITP and their combination across dermatomed human skin. Both ITP and MNs enhanced the skin permeation of hydrophilic as well as lipophilic drugs when used alone. However the combination strategy showed synergistic enhancement for the delivery of hydrophilic drugs. This was attributed to the creation of aqueous channels by MNs that improved the delivery for hydrophilic drugs more than lipophilic drugs. To investigate the effect of lipophilicity/polarity of the delivery vehicle on drug permeation across human skin, we formulated a nanoemulsion using fatty acids of varied lipophilicity, Caproic acid (C6), Caprylic acid (C8), Capric acid (C10) and Lauric acid (C12), for the delivery of a hydrophilic peptide molecule, Proline-Lysine-Valine (KPV). The polarity of the lipids had a significant influence on the delivery of KPV. A parabolic relationship was observed between hydrocarbon chain length and skin permeation rate. Both normal and microporated skin showed similar relationship with the hydrocarbon chain length, indicating that there is no influence of MN on this behavior. Further, the skin retention data of KPv indicated that the deposition of KPV enhanced with the lipophilicity of the fatty acid chain length.