Improvement of Imiquimod Solubilization and Skin Retention via TPGS Micelles: Exploiting the Co-Solubilizing Effect of Oleic Acid

Abstract

Imiquimod (IMQ) is an immunostimulant drug approved for the topical treatment of actinic keratosis, external genital-perianal warts as well as superficial basal cell carcinoma that is used off-label for the treatment of different forms of skin cancers, including some malignant melanocytic proliferations such as lentigo maligna, atypical nevi and other in situ melanoma-related diseases. Imiquimod skin delivery has proven to be a real challenge due to its very low water-solubility and reduced skin penetration capacity. The aim of the work was to improve the drug solubility and skin retention using micelles of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble derivative of vitamin E, co-encapsulating various lipophilic compounds with the potential ability to improve imiquimod affinity for the micellar core, and thus its loading into the nanocarrier. The formulations were characterized in terms of particle size, zeta potential and stability over time and micelles performance on the skin was evaluated through the quantification of imiquimod retention in the skin layers and the visualization of a micelle-loaded fluorescent dye by two-photon microscopy. The results showed that imiquimod solubility strictly depends on the nature and concentration of the co-encapsulated compounds. The micellar formulation based on TPGS and oleic acid was identified as the most interesting in terms of both drug solubility (which was increased from few µg/mL to 1154.01 ± 112.78 µg/mL) and micellar stability (which was evaluated up to 6 months from micelles preparation). The delivery efficiency after the application of this formulation alone or incorporated in hydrogels showed to be 42- and 25-folds higher than the one of the commercial creams.

Cyclosporine-loaded micelles for ocular delivery: Investigating the penetration mechanisms

“…In the presence of linolenic acid, the solubility of cyclosporine decreased (Table 2) regardless the polymers composition. Also the concentration of linolenic acid after cyclosporine loading (Table 2) showed to be markedly reduced by cyclosporine presence; this suggests a competition between the two molecules for the interaction with the micellar core, whose size is relatively small [27]. This result differs from the previously published data on imiquimod, where fatty acids co-encapsulation was used to increase the solubility of this hydrophobic drug into TPGS micelles [27].…”

“…Also the concentration of linolenic acid after cyclosporine loading (Table 2) showed to be markedly reduced by cyclosporine presence; this suggests a competition between the two molecules for the interaction with the micellar core, whose size is relatively small [27]. This result differs from the previously published data on imiquimod, where fatty acids co-encapsulation was used to increase the solubility of this hydrophobic drug into TPGS micelles [27]. Given the results obtained, the formulations T, TL and ST loaded with cyclosporine were selected for further studies, since they guarantee a drug solubility equal or higher than 3 mg/ml and, in the case of TL, also the presence of linolenic acid that can support drug action.…”

“…Solutol® HS15 was selected considering its capacity to improve hydrophobic drugs solubility [37,38] and its promising outcomes regarding the enhancement of corneal permeability and retention [39]. Linolenic acid was also added to the micellar formulations (see table 1 for detailed composition and codification) since data previously collected in our laboratory demonstrated the capability of fatty acids to increase the encapsulation of an hydrophobic compound [27]. Additionally, linolenic acid is a precursor of prostaglandin E1, a potent anti-inflammatory agent capable of reducing the ocular inflammation [40], promoting tear production and decreasing DES symptoms [41].…”

“…Micelles diffusion occurs in the interfibrillar matrix made of negatively charged hydrated proteoglycans consisting of a protein core with glycosaminoglycan (GAG) sidechains of repeating disaccharide units (chondroitin, dermatan, keratan or heparin sulfate) [62,63]. Indeed, previous data have demonstrated the ability of TPGS micelles loaded with NR to diffuse intact through a hyaluronic acid gel [27], possibly due to the presence of the pegylated corona [64]. The inner part of the sclera is made up of thinner and more regularly arranged collagen fibers that give rise to a more compact structure [65,66].…”

“…Non-ionic amphiphilic polymers used for micelles preparation were tocopherol polyethylene glycol 1000 succinate (TPGS) and Solutol® HS15. Furthermore, the addition of alpha-linolenic acid was assessed, in the light of the interesting results reported on fatty acids for micelles preparation [25,26] and increased drug loading [27,28]. A second aim was to evaluate micelles fate in the ocular tissues (cornea and sclera) to shed light on the penetration mechanisms.…”