Date of Award

2024

Document Type

Dissertation

Degree Name

Doctor of Pharmaceutical Sciences - Pharmaceutics

Department

Pharmaceutical Sciences

First Advisor

Kenza Benzeroual

Committee Chair and Members

Kenza Benzeroual, Chair

Grazia Stagni

Almas Babar

Chinmay Shukla

David Taft

Keywords

Dermis, Disposition, Ex-vivo, Pharmacokinetics, Skin conditioning, Topical formulation

Abstract

It is well known that the composition/excipients of a topical dermatological drug product (TDDP) affect the permeation of an active pharmaceutical ingredient (API) through the skin. While it is generally accepted that the vehicle mostly modulates the release of the API from the product, little is known whether the vehicle might also influence the kinetics of the API within the skin itself. In one attempt to answer this question, we developed an ex-vivo model using pig ear and a retrodialysis/microdialysis technique to deliver the API directly into dermis and measure the API dermal pharmacokinetics (dPK). We compared the dPK of a model API, Diphenhydramine (DPH), between the untreated skin (control) and the skin conditioned with common components of topical drug products (TDP) such as: jojoba oil, ethanol, glycerin, and petrolatum USP.

Fresh, full thickness pig ear were cut in 5x15 cm rectangles. In each trial, two pieces of skin were placed on a cellulose membrane atop of (37 ℃, pH 7.4) bath with the inner ear facing up. Eight microdialysis probes (1.7 cm dialysis window) were inserted in pair in each piece of skin. Then an adhesive chamber was placed on top of three pairs of probes and the cavity filled with 3 mL of vehicle, whereas the fourth pair served as control. In each trial, two vehicles were tested, three replicates each. Ethanol and jojoba oil were studied in 3 trials while petrolatum USP and glycerin were studied in another 3 trials. The application sites of the vehicles were randomized from one trial to another. Each microdialysis probe was perfused with a solution of DPH (10 µg/mL) in normal saline (NS) for 6 hours (retrodialysis or delivery phase) then the solution was switched to plain NS and sampling continued for an additional 12.5 hours (“disappearance” or microdialysis phase). Flow rate was 0.5 µL/min and samples were taken at 2, 3, 4, 6 time points over the first 6 hours and every 2 hours for the remainder of the experiment. The experiment was run for a total of 18.5 hours. Dialysate samples were analyzed with a validated HPLC assay. Probe depth and the corresponding total skin thickness for each probe were measured before and after the experiment with ultrasound. The “elimination rate constant” (z) was calculated from LN-transformed data collected from the terminal phase. Here, the elimination would be most correctly termed as disappearance since there is no blood circulation in an ex-vivo model. Dermis clearance (CL) was calculated as:

𝐶𝑙𝐷𝑒𝑟𝑚𝑖𝑠 = 𝐷𝑜𝑠𝑒2−6 / 𝐴𝑈𝐶2−6

Where Dose is the dose delivered by retrodialysis during the 2-6 hr period and AUC is the corresponding area under the curve. Finally, apparent volume of distribution (Vd) was calculated as Vd = CL/z. One-way ANOVA was performed on the LN-transformed parameters; elimination half-life (HL), Vd, and CL. The P-value set for this analysis was 0.05.

Dermal pharmacokinetics parameters of DPH when treating the skin with jojoba oil or ethanol and petrolatum USP or glycerin were calculated. It was observed that HL of DPH was significantly decreased when skin was conditioned with petrolatum USP, ethanol, and jojoba oil compared to unconditioned skin. However, conditioning the skin with glycerin did not have any significant effect on the dermal HL of DPH compared to unconditioned skin. This study has shown that dermal formulation excipients may influence API’s disposition through the modulation of skin micro-structure.

Download

Available for download on Wednesday, June 25, 2025

Share

COinS