(W1030-05-26) Transdermal Lamivudine Deep Eutectic Systems for the Long-Term Management of Pediatric Hepatitis B Virus and HIV Infections

Purpose: Infections caused by hepatitis B virus (HBV) as well as human immunodeficiency virus (HIV) affect approximately 400,000 children and they require lifelong management. Lamivudine (logP: -0.9, MW: 229.26 g/mol) is a nucleoside antiviral drug approved for the treatment of HBV and HIV infections in the pediatric population due to its excellent safety and efficacy. Existing marketed formulations of lamivudine (LAM) include once or twice-a-day tablets and oral solution which are administered alone or in combination with other antiviral agents. Several studies have demonstrated the compliance issues associated with oral antiviral drugs in the pediatric population. A transdermal delivery route offers several advantages over the traditional oral route such as high patient compliance, effective drug utilization, and mitigation of drug-related side effects. Ideal properties of a drug molecule for transdermal delivery include log P between 1-3, molecular weight below 500 Da, neutral charge, and a melting point less than 250 °C. LAM, due to its hydrophilic nature, has poor transdermal permeation. We hypothesize that the transformation of LAM into deep eutectic systems using pharmaceutically acceptable lipophilic counterions with inherent permeation-enhancing capability will improve the physicochemical properties as well as transdermal permeation of LAM.

Methods: Lipophilic anionic counterions such as oleic acid, linoleic acid, capric acid, geranic acid, and docusic acid were interacted with LAM in 1:1 and 1:2 molar ratios (drug:counterion) to yield deep eutectic systems (DESs). Briefly, the components (lamivudine + counterions) were weighed and added to an adequate quantity of methanol, stirred for 3 h at room temperature, filtered through a 0.22 µ nylon filter, followed by solvent evaporation using a rotary evaporator. The resultant DESs were characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), nuclear magnetic resonance (NMR), and Fourier transform infrared (FT-IR) spectroscopy. The in vitro permeation (IVPT) studies were carried out using the Franz diffusion apparatus to evaluate the ability of various LAM formulations (100 µL) to augment LAM transport across the dermatomed porcine ear skin. Briefly, each LAM DES was dissolved in propylene glycol (PG) to obtain a concentration equivalent to 10 mg/ml of LAM. A solution of pure LAM in PG and DES gold standard, choline geranic acid (CAGE), was prepared to obtain a LAM concentration of 10 mg/ml. The electrical resistance of pig ear skin samples was evaluated to ensure the barrier integrity of the skin. Samples (300 µL) were collected from the receptor compartment at 0, 0.5, 1, 2, 4, 6, 8, 22, and 24 hours, followed by replacement with fresh receptor compartment media. The samples were analyzed for lamivudine concentration using a validated RP-HPLC method. Ordinary one-way ANOVA was performed to understand the statistical difference among treatment groups.

Results: The FT-IR and ¹H NMR analyses of the developed LAM DESs revealed the presence of ionic as well as hydrogen bond interactions between LAM and various anionic counterions during DES formation. All DESs exhibited distinct thermal stability profile compared to pure LAM. The DSC and PXRD data confirmed varying degrees of amorphization in the developed LAM DESs indicating the impact of the counterion used for the DES preparation. Particularly, the PXRD data of LAM-Doc and LAM-Ole (1:1 and 1:2 molar ratios of LAM and the counterion) exhibited the absence of characteristics peaks corresponding to LAM, indicating the formation of DES with full amorphization, whereas the remaining LAM DESs showed the absence and/or shifting of LAM characteristics peaks demonstrating the formation of DESs with partial amorphization. Further, IVPT studies showed that all the DESs of LAM yielded higher transdermal delivery of LAM as compared to the LAM solution in the PG control group (1.26 ± 0.07 µg/cm²). LAM-Ole (1:2) DES showed the highest transdermal delivery of LAM (141.64 ± 9.81 µg/cm²) which was significantly higher (p < 0.0001) than the LAM solution in CAGE (39.73 ± 10.10 µg/cm²), the current gold standard of transdermal DES. LAM-Ole (1:1) DES also showed greater transdermal permeation of LAM (55.96 ± 18.97 µg/cm²) compared to LAM in CAGE but the difference was not statistically significant. Overall, the LAM DES containing LAM to counterion ratio of 1:2 showed greater transdermal delivery of LAM compared to their 1:1 DES counterparts indicating the importance of the ratio of drug to counterion ratio in the DES on the transdermal drug delivery

Conclusion: LAM DESs based on the bulky counterions with permeation-enhancing capability effectively modified the physicochemical and biopharmaceutical properties of hydrophilic LAM, thereby augmenting its transdermal permeation. The alteration in crystalline behavior and permeation enhancement of LAM was influenced by the alkyl chain length of the counterion and molar ratio of LAM to counterions in the developed LAM-DESs. Among various LAM-DESs that were developed, LAM-Ole (1:2) resulted in the highest transdermal delivery of LAM. Taken together, this study underscores a promising strategy for the transdermal delivery of LAM, offering a patient-friendly and non-invasive strategy for the long-term management of pediatric HBV and HIV infections.


The white crystalline powder of lamivudine (LAM) was transformed into viscous deep eutectic systems, LAM-Ole (1:1), LAM-Ole (1:2, LAM-Doc (1:2) and LAM-Doc (1:1), upon interaction with oleic acid or docusic acid in 1:1 or 1:2 molar ratio.


Summary of transdermal delivery of lamivudine (LAM) from various deep eutectic systems (DESs)


Comparative delivery of lamivudine (LAM) from various deep eutectic systems (DESs) and controls a) Cumulative amount delivered to the receptor in 24 hours b) Permeation profiles