The use of naloxone (NAL) for opioid overdose treatment is limited mostly to parenteral (intravenous, intramuscular, and subcutaneous) or intranasal route due to significant first-pass metabolism associated with oral delivery. Injectables are painful and frequent administrations by the existing routes for patient stabilization due to the short half-life of NAL are needed. Alternative delivery systems would be beneficial if they provide a balance between sustained release properties and a comparable rapid release as is achievable with the available parenteral forms. Thus, the goal of our study is to design a clinically viable polymeric microneedle (MN) patch for NAL. MNs of varying geometric dimensions were fabricated. In vitro skin permeation data for the best-performing patch was mathematically modeled and predictions on geometric parameters for a MN patch of comparable pharmacokinetic properties to parenteral and intranasal NAL as seen in the market were determined. From these evaluations, the need to devise ways to improve flux and amount of drug released from a patch per time was identified. We explored the influence of iontophoretically driving ionized drug content in MN patches on cumulative permeation of NAL from the best-performing MN patch. To optimize the iontophoresis parameters, the influence of citrate phosphate buffer strength on drug release profile was evaluated. Also, the impact of combining iontophoresis and higher drug loading was evaluated. A reduced lag time of about 5-15 min was observed with fabricated polymeric MN patches. From the polymeric MN patch P1 loaded with 50 mg/mL of NAL, a significant drug flux of 15.09 ± 7.68 ��g/cm2/h was observed in the first 1 h (p.Increasing MN length and density (P2 and P3) made a significant difference in the amount permeated and flux (pin-vitrorelease from the best-performing patch (P3) revealed the significance of needle base diameter and needle count in improving systemic pharmacokinetics of NAL from the MN patches. With this approach, an optimized design of the patch that can reproduce the clinical pharmacokinetics of NAL obtained with commercial devices was predicted. Investigation on the influence of iontophoresis in improving flux from the P3 patch shows about a 2-fold (p

Hydrogel membranes with different charge properties, positively charged 2-(N, N-Dimethylamino)ethyl methacrylate-co-butyl acrylate (DMEMA-co-BuA), neutral 2-hydroxyethyl methacrylate-co-butyl acrylate (HEMA-co-BuA), and negatively charged acrylic acid-co-butyl acrylate (AA-BuA) were designed and synthesized for investigation of the transport mechanism of iontophoresis. The hydrogels were characterized by determination of the equilibrium hydration and dimensional change. To study the different crucial factors influencing iontophoretic transport, three model compounds, positively charged phenylpropanolamine (PPA), zwitterionic phenylalanine (Phe), and negatively charged 3-phenylpropionic acid (3-PPA) were selected. These compounds have similar structure and molecular weight but different charge properties. Three transport conditions, passive diffusion, anodal and cathodal iontophoretic transport, were used in this dissertation. A novel parameter, E v , was developed to quantitatively evaluate the enhancement of transport due to the electro-osmotic flux. E v values were obtained by comparing the enhancement/hindrance factor (E-value) through charged membrane to that through neutral membrane with comparable hydration. The model compounds, hydrogel membranes, and transport conditions used in this study made the iontophoretic transport a complicated system with twenty-seven possible different combinations. The E v values can be used to determine the electro-osmotic effect under various iontophoretic conditions with different permeants. The results showed that E v values of permeants with similar structure and molecular weight are robust to permeant charge. Passive diffusion and anodal/cathodal iontophoretic transport of PPA through HEMA-co-BuA and AA-co-BuA of different compositions were conducted. Linear relationships were established between the reciprocal of hydration and the logarithm of flux, E-value, and E v value. It is found that iontophoretic transport of drug through hydrogels is governed by free volume theory. To explore the pH effect on iontophoretic transport through hydrogel, the transport behaviors of Phe through HEMA-co-BuA under three transport conditions in the pH range of 1.5 to 11.2 were investigated. A mathematical model was developed to describe the effect of pH on iontophoretic transport. This model has successfully predicted the total permeability of Phe at various pH values. The distribution and charge of species depended on pH and thus affected iontophoretic transport. The passive, anodal and cathodal transport behaviors of 3-PPA through negatively charged human skin were in agreement with those through the negatively charged hydrogel membrane AA-co-BuA (60:40). It was shown that the negatively charged hydrogel membrane could be used as a model membrane to study transport behavior through human skin.