(W0930-01-03) Physically- and Chemically-Enhanced Transdermal Delivery of Linagliptin

Purpose: Type-2 diabetes, the most common type of diabetes, is characterized by insulin resistance and high blood sugar. Linagliptin (logP: 2.85, MW: 472.5 g/mol) is a competitive, reversible dipeptidyl-peptidase-4 (DPP-4) inhibitor used to treat type-2 diabetes. DPP-4 inhibition increases the concentration of incretin, thereby stimulating the release of insulin in a glucose-dependent manner. Existing marketed formulations of linagliptin include tablets given twice a day. However, linagliptin has low oral bioavailability (30%) and is associated with several side effects. A transdermal delivery route offers several advantages over the traditional oral route such as high bioavailability, lower first-pass metabolism, and mitigation of certain side effects. Thus, we investigated the effect of chemical enhancers and anodal iontophoresis (ITP) on the transdermal delivery of linagliptin.

Methods: In vitro permeation (IVPT) studies were performed using vertical Franz diffusion cells across dermatomed porcine ear skin. Skin electrical resistance was evaluated to ensure barrier integrity of the skin. Receptor samples were collected for up to 24 hours and analyzed using a validated RP-HPLC method. The donor vehicle was propylene glycol (PG) for chemical enhancers and phosphate-buffered saline (1X PBS, pH 7.4) for ITP. The saturation solubility of linagliptin was determined in 1X PBS, PG, and chemical enhancers in PG (10% v/v). IVPT studies were performed using 90% saturated solutions across all treatment groups. Isopropyl myristate (IPM), oleic acid, and oleyl alcohol were screened as chemical enhancers. Since linagliptin is predominantly present as a positively charged species at the pH of donor solution, anodal ITP was carried out. The current density was maintained at 0.5 mA/cm² for 4 hours followed by passive delivery for up to 24 hours. Based on the permeation profiles, lag times were calculated for all groups. Ordinary one-way ANOVA and unpaired t-test were performed to understand the statistical difference among treatment groups.

Results: Among the chemical enhancers, oleyl alcohol (87.37 ± 11.99 µg/cm²) and oleic acid (34.33 ± 4.68 µg/cm²) delivered a therapeutic dose of linagliptin to the receptor while there was no passive permeation detected. ITP (53.05 ± 0.79 µg/cm²) showed significant enhancement in the delivery of linagliptin to the receptor (p < 0.0001) as compared to passive permeation in PBS (2.35 ± 0.79 µg/cm²). Lag time calculations showed that ITP was able to deliver linagliptin with the least lag time of 1 h, as compared to oleic acid with 3.5 h, oleyl alcohol with 4.4 h, IPM with 15 h, and passive permeation (in PBS) with 15.8 h. However, oleyl alcohol delivered a significantly higher amount of linagliptin to the receptor (p < 0.01) as compared to ITP.

Conclusion: Chemical enhancers were able to significantly enhance permeation and deliver a therapeutic dose of linagliptin to the receptor. Oleyl alcohol delivered the highest amount of linagliptin across all groups. Anodal ITP significantly enhanced permeation, delivered a therapeutic dose, and demonstrated the least lag time across all groups.


Figure 1: Comparison of the average amount of linagliptin delivered to the receptor (a) Passive permeation (in propylene glycol (PG)) versus the use of chemical enhancers – isopropyl myristate (IPM), oleic acid, and oleyl alcohol; (b) Passive permeation (in phosphate-buffered saline (PBS)) versus anodal iontophoresis (ITP); (c) Chemical enhancers versus anodal ITP.


Table 1: Lag time and receptor delivery of linagliptin via passive permeation (in propylene glycol (PG) and phosphate buffer (PBS)), use of chemical enhancers – isopropyl myristate (IPM), oleic acid, oleyl alcohol, and anodal iontophoresis (ITP).