Development and Optimization of Imiquimod-Loaded Nanostructured Lipid Carriers Using a Hybrid Design of Experiments Approach

Abstract

Background Imiquimod (IMQ) is an immunomodulating drug that is approved for the treatment of superficial basal cell carcinoma, actinic keratosis, external genital warts and perianal warts. However, IMQ cream (Aldara ® ) has several drawbacks including poor skin permeation, local toxicity, and compromised patient compliance as a topical pharmacological option. Methods Our research aimed to develop and optimize nanostructured lipid carriers (NLCs) containing IMQ for the first time using a hybrid design of experiments approach. The optimized formulation was then incorporated into a matrix-type topical patch as an alternative dosage form for topical application and evaluated for IMQ deposition across different skin layers in comparison to the performance of the commercial product. Additionally, our work also attempted to highlight the possibility of implementing environment-friendly practices in our IMQ-NLCs formulation development by reviewing our analytical methods and experimental designs and reducing energy and solvent consumption where possible. Results In this study, stearyl alcohol, oleic acid, Tween ® 80 (polysorbate 80), and Gelucire ® 50/13 (Stearoyl polyoxyl-32 glycerides) were selected for formulation development. The formulation was optimized using a 2 k factorial design and a central composite design. The optimized formulation achieved the average particle size, polydispersity index, and zeta potential of 75.6 nm, 0.235, and – 30.9 mV, respectively. Subsequently, a matrix-type patch containing IMQ-NLCs was developed and achieved a statistically significant improvement in IMQ deposition in the deeper skin layers. The IMQ deposition from the patch into the dermis layer and receptor chamber was 3.3 ± 0.9 µg/cm 2 and 12.3 ± 2.2 µg/cm 2 , while the commercial cream only deposited 1.0 ± 0.8 µg/cm 2 and 1.5 ± 0.5 µg/cm 2 of IMQ, respectively. Conclusion In summary, IMQ-NLC-loaded patches represent great potential as a topical treatment option for skin cancer with improved patient compliance.

Combining the potential of 3D printed buccal films and nanostructured lipid carriers for personalised cannabidiol delivery

“…High surfactant concentration was illustrated to decrease surface tension, thereby stabilising the surface during homogenisation and preventing particle agglomeration which in turn leads to the production of smaller particle size [ 60 , 61 ]. Kim et al [ 58 ] and Taha et al [ 62 ] also reported similar findings. Sonication time showed biphasic responses indicating optimal sonication time was required to produce particles of the desired size as illustrated in Fig.…”

“…The positive effect of the total lipid on the size of the nanoparticles could be due to the increase in the viscosity of the formulation that in turn reduces the effectiveness of particle-breaking (sonication) processes [ 57 ]. The increased particle size with the increase in the amount of total lipid could also be attributed to other reasons such as aggregation between lipid particles, increased chances of collision as well as inadequate surfactant amount to cover the lipid particle’s surface [ 58 ]. The finding agrees with the work of Kim et al where NLCs of imiquimod with higher lipid concentration resulted in larger particle size.…”

Enhanced Skin Permeation of 5-Fluorouracil through Drug-in-Adhesive Topical Patches

“…Moreover, the 5-FU content found in the SC was much higher from the cream formulation (62.78 ± 18.9 µg/cm 2 ) compared to the Patch-CONT (24.47 ± 13.6 µg/cm 2 ), Patch-TRAN (11.33 ± 3.1 µg/cm 2 ) and Patch-OA (28.34 ± 12.5 µg/cm 2 ). This may indicate that the 5-FU from the commercial formulation was not effectively partitioned out from the SC and penetration into the deeper tissues as a target site where more invasive NMSC grows [ 34 , 35 ]. Whilst the patch formulations did not show a statistically significant difference in epidermis and dermis deposition, Patch-TRAN (76.39 ± 27.7 µg/cm 2 ) and Patch-OA (82.56 ± 8.2 µg/cm 2 ) demonstrated much deeper penetration, as indicated in the 5-FU recovery from the receptor chamber than Efudix ® cream (34.63 ± 8.3 µg/cm 2 ).…”

Imiquimod Solubility in Different Solvents: An Interpretative Approach

“…The first step was to review the IMQ solubility data reported in the literature for the solvents considered ( Table 1 ) [ 4 , 6 , 7 , 8 , 9 ]. Table S1 reports the solubility values for all the other solvents cited in the literature [ 4 , 6 , 7 , 8 , 9 , 10 , 11 ].…”