(M1130-12-70) Development and Evaluation of Transdermal Delivery System of Tranylcypromine for the Treatment of Depression

Purpose: Depression is a common and serious illness that causes a persistent feeling of sadness and loss of interest affecting a person’s daily functioning. Tranylcypromine (TCM) (logP=1.34, MW=133.19 g/mol) is a monoamine oxidase (MAO) inhibitor that is used to treat depression and is available only as oral tablets. The oral administration of tranylcypromine causes the inhibition of MAO in the gastrointestinal area and has the potential to cause a life-threatening hypertensive reaction due to ingestion of tyramine-containing food, also known as the “Cheese effect”. Transdermal delivery of tranylcypromine avoids gastrointestinal absorption and hepatic effects, thereby eliminating the possibility of such interaction along with other systemic side effects. The development of a transdermal delivery system can be very beneficial to patients suffering from depression by improving the compliance, efficacy, and tolerability to the treatment regimen. Thus, we investigated the transdermal delivery of tranylcypromine through the development of a 2-day suspension-based transdermal delivery system (TDS).

Methods: The delivery TCM was determined via passive permeation and following the incorporation of different concentrations of penetration enhancers, namely isopropyl myristate (IPM) (10% v/v and 15% v/v), oleyl alcohol (10% v/v), oleic acid (10% v/v) and combination of oleic acid (5% v/v) and oleyl alcohol (5% v/v). One of these enhancers was selected to incorporate in the final adhesive blend. The saturation solubility of TCM in the adhesive and enhancer blend was determined to be very low, so a suspension-based TDS was formulated. The transdermal patches were formulated in two types of pressure-sensitive adhesives (PSAs) as the matrix, acrylate (DURO-TAK 87-2516) and polyisobutylene (PIB) (DURO-TAK 87-4908) by solvent evaporation technique incorporating drug, penetration enhancer, release liner, and backing membrane. The optimized patches were characterized for their adhesive properties, drying time, peel test, shear strength, and uniformity in drug content. In vitro permeation studies were performed on dermatomed porcine ear skin using vertical static Franz diffusion cells and the receptor samples were collected at predetermined time points for 48 hours. The samples were analyzed in a validated UPLC method.

Results: The primary screening of penetration enhancers indicated that IPM significantly enhanced the permeation of TCM as compared to passive and other penetration enhancers and thus was selected as an additive in the formulation of TDS. The TDS were optimized in acrylate and PIB PSAs which incorporated 15% w/w of TCM, 10% w/w of IPM, fluoropolymer-coated polyester film as the release liner (3M ScotchPak™ 9744), and ethylene-vinyl acetate coated (3M™ CoTran™ 9728) as the backing membrane. Acrylate-based suspension TDS delivered a higher amount of drug (712 ± 21.46 µg/cm²) with a decreased lag time of 0.13 ± 0.05 hours at the end of 48 hours as compared to passive (461.49 ± 75.55 µg/cm²) with a lag time of 0.9 ± 0.1 hours and PIB-based suspension TDS (559.25 ± 12.37 µg/cm²) with a lag time of 0.25 ± 0.09 hours. The drying time was optimized by casting the formulated matrix on the release liner and determining the percent weight loss until 60 minutes by placing it over a weighing balance. There was no significant weight loss after 40 minutes for the acrylate matrix patch and 50 minutes for the PIB-matrix patch indicating that the volatile solvents present in the respective PSAs have evaporated and thus were determined as optimized drying time. The drug content was determined as 13.12 ± 0.71 and 14.99 ± 1.35 % w/w respectively for acrylate and PIB-based TDS. The time required for the TDS to fall from the shear tester plate when subjected to a shear force (weight used = 50 g) and the average force required to peel the patch from the peel tester plate were higher for the acrylate matrix patch when compared to that of PIB, as indicated in Table 1. Lesser force was required to peel the release liner from the backing membrane for acrylate-based TDS despite it demonstrating higher tack properties (as shown in Table 1) than the PIB matrix patch.

Conclusion: The acrylate and PIB-based suspension TDS were successfully developed, and both delivered TCM successfully across the skin. Acrylate-based TDS had higher delivery, reaching the 2-days therapeutic target dose to treat depression. This establishes the feasibility of formulating a transdermal delivery system for TCM.


Table 1: Characterization results of acrylate and PIB-based suspension TDS


Figure 1: (a) Total delivery of tranylcypromine across the skin via passive permeation, acrylate pressure-sensitive adhesives (PSA) based suspension TDS, and PIB PSA based suspension TDS (b) Permeation profile of tranylcypromine among the three groups (c) Lag time between the three groups (One-way ANOVA with Tukey’s posthoc analysis: ns, no significant statistical difference; statistically significant difference, * P ≤ 0.05 or *** P ≤ 0.001 or **** P ≤ 0.0001)


Figure 2: Result of characterization of acrylate and PIB based suspension TDS: (a) Average absolute positive force (b) Average positive area (c) Average separation distance (d) Average force (e) Average force required to peel the release liner from the backing membrane (f) Average time for the patch to fall; shear strength (Unpaired t-test: ns, no significant difference; statistically significant difference, * P ≤ 0.05 or *** P ≤ 0.001)