(T1130-06-37) Abacavir/Lamivudine Nanobased Fluid Gel System for Paediatric Antiretroviral Therapy

Purpose: The Human Immunodeficiency Virus (HIV) infection is a life-threatening epidemic that continues to negatively impact the health and wellbeing of millions of adults and children worldwide. Though there is no cure for HIV, effective antiretroviral therapy remains the cornerstone of disease management which improves the health and longevity of affected persons. However, poor adherence is a major obstacle to successful clinical outcomes because of the complexity associated with the use of HIV medications that require at least a combination of three drugs. The use of multiple therapeutic agents is challenging especially for children, because research efforts on designing innovative drug carriers, like fixed dose combinations and long acting injectables, have been more focused on adults’ patients. This means that the paediatric population tend to miss out on such advancements and their benefits which are mainly to simplify treatment to enhance convenience, adherence and desired efficacy. This has resulted in the significant shortage of innovative age-appropriate drug formulations for the paediatric population, particularly the very young children (typically ≤ 10 kg) such as neonates and infants. This study therefore seeks to specifically design an orally delivered fixed dose nanobased fluid gel system containing two key antiretroviral drugs — abacavir and lamivudine. This fluid formulation is intended for use in very young children and older children, adolescents, adults, the elderly, or individuals who have difficulty swallowing.

Methods: Formulation preparation was achieved using a two-step strategy involving the initial nanoencapsulation of abacavir and lamivudine within a biocompatible and biodegradable co-polymeric matrix to produce nanopowders that were subsequently incorporated into a methylcellulose/gelatin/xylitol-based fluid gel system to generate the nanosuspension formulation. Structural backbone, particle surface morphology and dehydrated size, hydrodynamic particle size, polydispersity index (PDI), zeta potential (ZP), textural strength, pH, and viscosity of the final abacavir/lamivudine nanosuspension formulation were determined using Fourier transformed infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), electrophoretic light scattering (ELS), textural analysis, metered pH measurement, and viscometry respectively. In vitro measurements of abacavir/lamivudine loading capacity, encapsulation efficiency and release behaviour were performed in buffer pH 1.2 and drug levels were quantified ultraviolet spectrophotometry. In vitro cytotoxicity assay was performed to determine potential biocompatibility of the drug-loaded nanosuspension using hepatoma cells (HepG2) which are frequently utilized as a toxicity model for research purposes. Cell viability was measured at different concentrations (0.075 - 1.200 mg/ml) using the CellTiter-Glo^® assay over 24 hours. Short-term formulation stability was monitored for 28 days under controlled conditions (30°C ± 2°C and 65% ± 5% humidity) following the International Council for Harmonisation guidelines.

Results: The abacavir/lamivudine nanopowder and fluid gel carriers produced a stable colloidal fixed dose nanosuspension formulation that was odorless and exhibited an aesthetically pleasing subtle golden hue with optimal flow characteristics, making it easily pourable. FTIR analysis revealed notable spectral changes that indicated successful drug encapsulation and non-destructive interactions with the excipients added. TEM and SEM analyses confirmed that the nanoparticles were spherical in nature and unhydrated particle sizes were 64 ± 34 nm and 77 ± 32 nm for abacavir and lamivudine respectively. The hydrodynamic particle sizes followed a similar trend (lamivudine = 164 ± 26 nm; abacavir = 200 ± 26 nm). PDI values were less than 0.3 indicating a narrow size distribution, which is ideal for ensuring consistent drug release and stability. The zeta potential was -31.3 ± 1 mV, and -30.7 ± 0.8 mV for abacavir and lamivudine respectively suggesting good colloidal stability and reduced likelihood of aggregation. Gel strength of 0.042 ± 0.002 N; pH value of 4.100 ± 0.030 and medium viscosity of 177.300 ± 0.570 mPa.s were obtained. Drug encapsulation efficiency ranged from 27 to 42% and loading capacity was between 83 and 84% for the two drugs while in vitro release studies showed complete drug (i.e., lamivudine and abacavir) liberation within 15 minutes. The nanosuspension supported and maintained cell growth with cell viability values higher than 80% for all concentrations tested which showed that the formulation is safe to use and non-toxic. Furthermore, the nanosuspension was environmentally stable as it retained its colour and showed minimal variations in stability indicators compared to values recorded at the starting point.

Conclusion: A physicochemically stable, easy to administer fixed dose nanosuspension formulation containing abacavir and lamivudine for the management of HIV in the paediatric population was developed. This serves as a potentially viable alternative to current treatment choices and provides more options for older/adult patients who prefer oral liquid dosage forms or those who are having trouble swallowing.

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Acknowledgements: This work was funded by the Faculty of Health and College of Pharmacy, Research Establishment grant, Dalhousie University, Canada (Grant ID: R34000).