(M1230-02-12) Management of Type-2 Diabetes via Exploration of Transdermal Delivery Strategies for 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. For a moderately lipophilic drug, it is conventional to test chemical enhancement strategies for passive transdermal delivery, whereas physical enhancement techniques are predominantly used for hydrophilic drugs. In this project, we aimed to assess the potential of physical enhancement techniques to deliver moderately lipophilic drugs with limited aqueous solubility and compare it with chemical enhancer–assisted passive transdermal delivery. Hence, we screened five physical enhancement techniques- namely iontophoresis, microneedles, sonophoresis, laser, and microdermabrasion as well as three chemical enhancers – namely oleic acid, oleyl alcohol, and isopropyl myristate to assess their effect on the transdermal delivery of linagliptin (Figure 1).

Methods: In vitro permeation testing (IVPT) studies were performed using vertical Franz diffusion cells across dermatomed porcine ear skin. Transepithelial electrical resistance (TEER) was measured to ensure the 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 physical enhancement techniques. 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. Physical enhancement techniques explored included iontophoresis, microneedles, sonophoresis, microdermabrasion, and ablative laser. The effect of physical enhancement techniques on the skin was observed via TEER measurement, methylene blue staining, histological evaluation, and confocal imaging (Figure 2). Statistical difference was concluded using one-way ANOVA analysis (p < 0.05). Based on the results obtained from IVPT studies, the lag time of systemic delivery and the permeability coefficients were calculated. Further, the steady-state flux and systemic clearance rate were considered to predict the in vivo plasma concentration for all treatment groups.

Results: An increase in transdermal permeation of linagliptin was observed due to both chemical and physical enhancement techniques. Among chemical enhancers, oleyl alcohol (87.37 ± 11.99 µg/sq.cm) and oleic acid (34.33 ± 4.68 µg/sq.cm) significantly enhanced permeation. Upon treatment with physical enhancement techniques, a significant drop in the skin’s TEER measurement was observed. Histological evaluation was used to compare the structure of intact skin with treatment groups (Figure 2). Micropores were successfully generated from microneedles and laser ablation. Post-sonophoresis, the effect of cavitation was visible as tiny ‘cavities’ indicating disruption of the skin’s structure. Post-microdermabrasion, partial or full detachment of stratum corneum was visible. Confocal imaging was used to obtain orthogonal and z-stack images of skin post sonophoresis and laser treatment. The penetration depth of ablative laser was found to be approximately 250 µm. Sonophoresis (141.13 ± 34.22 µg/sq.cm) and laser ablation (555.11 ± 78.97 µg/sq.cm) significantly enhanced permeation (Figure 2) where the laser group had the highest permeation with the least lag time across all groups (Figure 3). The in vivo plasma concentration was calculated by considering the steady-state flux, systemic clearance, concentration of applied transdermal dose, and the area of permeation. The results (Figure 3) were then compared to the C_max (5.8 ng/mL) reported in the literature from clinical studies in human volunteers with type-2 diabetes consuming 5 mg/day dose of oral linagliptin tablets. The predicted in vivo plasma concentrations obtained from the IVPT studies using chemical and physical enhancement strategies were equal to or more than the C_max observed in human clinical trials. Together, this demonstrated the feasibility of transdermal delivery of linagliptin via the incorporation of explored chemical and physical enhancement techniques.

Conclusion: Various physical and chemical enhancement strategies were explored using linagliptin as a model drug to assess the feasibility of the management of type-2 diabetes via the transdermal delivery route.

References: 1. Graefe-Mody, U., Retlich, S. & Friedrich, C. Clinical Pharmacokinetics and Pharmacodynamics of Linagliptin. Clin Pharmacokinet 51, 411–427 (2012). https://doi.org/10.2165/11630900-000000000-00000

Figure 1: Schematic representation of exploration of transdermal delivery strategies for a model lipophilic drug - linagliptin

Figure 2: I) Methylene blue staining, II) Confocal Microscopy, III) IVPT studies, IV) Histological evaluation

Figure 3: Summary of in vitro permeation studies and calculations/predictions of lag time, steady-state flux, permeability coefficient, and steady-state plasma concentrations