Formulation, optimisation and evaluation of benidipine loaded lipid vesicles dissolving microneedles for transdermal delivery / Khater Ahmed Saeed Al-Japairai

Faculty of Chemical and Process Engineering Technology

Thesis (Doctor of Philosophy) -- Universiti Malaysia Pahang – 2024

Includes bibliographical references

Benidipine (BEN) is a drug used for the treatment of hypertension. However, this drug suffers from extremely low oral bioavailability (only 20-30%) due to its poor aqueous solubility and extensive first-pass metabolism, thus limiting its efficacy for achieving optimal therapeutic levels. This study introduces a novel approach to address this significant drawback by developing BEN-loaded-lipid vesicles, namely transfersome, ethosome, and transethosome, which are then integrated into hyaluronic acid-based dissolving microneedles for transdermal application. In particular, the hypothesis proposes that this novel delivery system can effectively transport BEN through the skin by utilising the lipid vesicle’s ability to disrupt the stratum corneum and improve skin permeability, combined with hyaluronic acid-based dissolving microneedles that create microchannels, allowing for deeper skin penetration and ultimately leading to enhanced BEN bioavailability while bypassing the first-pass metabolism. In this study, the lipid vesicles were prepared using a thin-layer rotary evaporation method to produce unilamellar lipid vesicles and optimised by applying the Box-Behnken design. The results indicate that the optimised BEN-loaded transfersome (BEN-TF), ethosome (BEN-E), and transethosome (BEN-TE) showed vesicles sizes of 124.9 ± 1.49, 149.4 ± 3.81, and 168.3 ± 1.73 nm, with entrapment efficiencies (EE%) of 98.12 ± 0.18, 88.57 ± 0.38, and 96.42 ± 0.36%, and transdermal fluxes of 9.74 ± 0.53, 19.12 ± 0.19, and 20.21 ± 0.35 μg/cm2 /hr, respectively. It was found that DSC, ATR-FTIR, and XRD studies confirmed the amorphous state of BEN in the optimised formulations, while FESEM and HRTEM revealed a smooth, spherical morphology with nanosized, and uniform vesicular structures. CLSM clearly presented the depth of lipid vesicles’ permeation into the skin layers. The optimised lipid vesicles remained stable when stored at 4 °C for 3 months. Furthermore, the dissolving microneedles (DMNs) were prepared using 40% of hyaluronic acid and integrated with optimised BEN-TF, BEN-E, and BEN-TE formulations to provide further improvements in transdermal delivery. The resulting lipid-vesicles-loaded DMNs, including BEN-TF-DMNs, BEN-E-DMNs, and BEN-TEDMNs, exhibited sufficient mechanical strength, effective insertion into rat skin, and rapid dissolution. In the ex-vivo studies, the permeation coefficient of BEN was significantly improved using lipid-vesicle-loaded DMNs, compared with either optimised lipid vesicles alone or BEN-DMNs alone. In the in-vivo studies, the lipid vesicle-loaded DMNs improved the relative bioavailability of BEN by about 1.35, 1.58, and 1.86 times for BEN-TF-DMNs, BEN-E-DMNs, and BEN-TE-DMNs, respectively, compared to the oral-marketed BEN tablet. In comparison to BEN-DMNs, the relative bioavailability was enhanced by 2.49, 2.95, and 3.45 times for BEN-TF-DMNs, BEN-EDMNs, and BEN-TE-DMNs, respectively. This clearly indicates that BEN-TE-DMNs were superior to other lipid-vesicle-loaded DMNs. In conclusion, lipid vesicles combined with dissolving microneedles have shown high potential as carriers for transdermal delivery of benidipine. Further studies can be conducted to explore alternative polymers for DMN preparation, increase drug loading in the DMN arrays, validate formulations in diverse animal species, and evaluate patient satisfaction with the developed transdermal delivery system.