Microemulsions based on TPGS and isostearic acid for imiquimod formulation and skin delivery

Abstract

Imiquimod (IMQ) is an immunostimulant drug topically used for the treatment of actinic keratosis and basal cell carcinoma. IMQ formulation and skin delivery is difficult because of its very low solubility in the most of pharmaceutical excipients and very poor skin penetration properties. The purpose of this study was to develop a microemulsion to optimise imiquimod skin delivery using D-α-tocopherol polyethylene glycol-1000 succinate (TPGS) as surfactant (so as to take advantage of its thickening properties) and isostearic acid as oil phase. This fatty acid was selected since it has demonstrated a good solubilizing power for imiquimod and it has also shown to contribute to its therapeutic activity. We have built pseudo-ternary diagrams using two different co-surfactants (Transcutol® and propylene glycol-PG) in a 1:1 ratio with TPGS and then selected microemulsions in the clear and viscous regions of the diagrams. The systems were characterized in terms of rheology and X-ray scattering; additionally, the capability to promote IMQ skin uptake was evaluated ex-vivo on a porcine skin model. All the formulations selected in the gel-microemulsion regions behaved as viscoelastic solids; X-rays scattering experiments revealed in all cases the presence of an ordered lamellar structure, but with differences in terms of interlamellar distance and flexibility between Transcutol® and PG-containing systems. A higher flexibility and a greater hydrophobic volume, possibly interconnected at some point, was associated to the use of Transcutol® and had an impact on the microemulsion capacity to solubilize IMQ as well as on the capability to enhance drug uptake into the skin. The best performing gel-like microemulsion was composed of ≈ 26% of water, ≈21% of isostearic acid, ≈26% of TPGS and ≈27% of Transcutol® and accumulated, after 6h of contact, 3.0 ± 1.1 µg/cm2 of IMQ. This value is higher than the one reported in the literature for the commercial cream (1.9 ± 0.8 µg/cm2), despite the 4-times lower concentration of the vehicle (13 mg/g for the microemulsion vs 50 mg/g for the commercial cream).

Synchrotron Scattering Methods for Nanomaterials and Soft Matter Research

“…The presence of these compounds are visible on the structure at different length scales ranging from the global morphology to inner membrane interactions. SAXS studies enabled the identification of structural features underlying the efficacity of microemulsion-based drug formulations [49] and lipid-based nanoformulatons [50]. The structure of polymeric drug delivery systems, especially the change in the inner structure upon drug encapsulation, was probed by anomalous SAXS [51].…”

Regenerative Wound Dressings for Skin Cancer

“…Additionally, it was observed that higher clearance rates lead to higher inflammatory reactions [ 31 , 32 ]. Moreover, imiquimod is characterized by an inability to permeate through the dermis layer due to its low water solubility and the interactions between the amine groups and the aninonic components of the skin [ 36 , 38 ].…”

“…Imiquimod (1-isobutyl-1H-imidazo(4,5-c)quinolin-4-amine, Figure 1), is a low molecular weight nucleoside analog of the imidazoquinoline family with immunomodulating properties and indirect anti-viral and anti-tumor effects [30][31][32][33][34][35][36]. Additionally, it acts as a potent antagonist for the toll-like receptors 7 and 8 [30,31,35,37].…”

Foray into Concepts of Design and Evaluation of Microemulsions as a Modern Approach for Topical Applications in Acne Pathology

“…microemulsion in biological fluids for oral delivery [32]. In topical therapy of dermatologic conditions, an increased solubility and bioavailability was obtained for molecules like: cyclosporine in psoriasis [33]; ceramides for skin restructuration [34]; imiquimod in actinic keratosis or basal cell carcinoma [35]; penciclovir [36], acyclovir for herpes virus simplex cutaneous infection [37]; and tenoxicam for arthritis alleviation [38].…”

“…Several discoveries with positive results can be mentioned: in ophthalmology [23], for ocular delivery of retinol [24] or sacha inchi oil for dry eye treatment [25]; intranasal delivery for zidovudine [26]; sublingual delivery of insulin [27]; application of fusidic acid in wound healing [28]; vaginal delivery for fluconazole [29]; transdermal drug delivery [30]; cosmetics [31]; self-microemulsifyied systems with in situ generation of microemulsion in biological fluids for oral delivery [32]. In topical therapy of dermatologic conditions, an increased solubility and bioavailability was obtained for molecules like: cyclosporine in psoriasis [33]; ceramides for skin restructuration [34]; imiquimod in actinic keratosis or basal cell carcinoma [35]; penciclovir [36], acyclovir for herpes virus simplex cutaneous infection [37]; and tenoxicam for arthritis alleviation [38].…”