Monoketonic Curcuminoid-Lidocaine Co-Deliver Using Thermosensitive Organogels: From Drug Synthesis to Epidermis Structural Studies

Abstract

Organogels (ORGs) are remarkable matrices due to their versatile chemical composition and straightforward preparation. This study proposes the development of ORGs as dual drug-carrier systems, considering the application of synthetic monoketonic curcuminoid (m-CUR) and lidocaine (LDC) to treat topical inflammatory lesions. The monoketone curcuminoid (m-CUR) was synthesized by using an innovative method via a NbCl₅-acid catalysis. ORGs were prepared by associating an aqueous phase composed of Pluronic F127 and LDC hydrochloride with an organic phase comprising isopropyl myristate (IPM), soy lecithin (LEC), and the synthesized m-CUR. Physicochemical characterization was performed to evaluate the influence of the organic phase on the ORGs supramolecular organization, permeation profiles, cytotoxicity, and epidermis structural characteristics. The physico-chemical properties of the ORGs were shown to be strongly dependent on the oil phase constitution. Results revealed that the incorporation of LEC and m-CUR shifted the sol-gel transition temperature, and that the addition of LDC enhanced the rheological G'/G″ ratio to higher values compared to original ORGs. Consequently, highly structured gels lead to gradual and controlled LDC permeation profiles from the ORG formulations. Porcine ear skin epidermis was treated with ORGs and evaluated by infrared spectroscopy (FTIR), where the stratum corneum lipids were shown to transition from a hexagonal to a liquid crystal phase. Quantitative optical coherence tomography (OCT) analysis revealed that LEC and m-CUR additives modify skin structuring. Data from this study pointed ORGs as promising formulations for skin-delivery.

Keywords: curcuminoids; lidocaine; organogels; poloxamer; skin structural analysis.

Figure 1

Chemical structure of (A) monoketone curcuminoids, (B) curcumin, and (C) a scheme of the ‘Claisen-Schmidt’ condensation reaction to synthesize the m-CUR.

Figure 2

PL-based organogels preparation scheme. Inserted pictures below show (A) PL407 hydrogel, (B) PL407 + IPM organogel (ORG), and (C) m-CUR-loaded PL407 + IPM ORG.

Figure 3

Representative scanning electron micrographs of the (A) PL407 hydrogel, (B) m-CUR, (C) LDC, (D) ORG, (E) ORG-LDC, (F) ORG-LEC, (G) ORG-LEC/m-CUR, (H) ORG-LEDC/LEC, and (I) ORG-LDC/LEC/m-CUR. Scale bar = 500 μm.

Figure 4

Representative sol–gel transition temperature rheograms: (A) ORG and ORG-LDC, (B) ORG-LEC and ORG-LDC/LEC, and (C) ORG-LEC/m-CUR and ORG-LDC/LEC/m-CUR; rheological frequency sweep analysis for the ORGs formulations (D) without LDC and (E) with LDC.

Figure 5

Permeation profiles of lidocaine hydrochloride (LDC) from ORG-LDC, ORG-LDC/LEC and ORG-LDC/LEC/m-CUR across the Strat-M^® membrane. Data expressed as mean ± standard deviation, n = 6/experiment.

Figure 6

Cell viability percentage determined after HaCat cells treatment with ORG formulations (n = 6/concentration) by using the Methylthiazolyldiphenyl-tetrazolium bromide (MTT) reduction test.

Figure 7

ATR-FTIR characterization of the (A) ORG, ORG-LEC, and ORG-LEC/m-CUR formulations, as well as the stratum corneum (SC) samples treated with these formulations for (B) 4 h and (C) 24 h. FTIR of a SC control sample (without ORG treatment) was also displayed.

Figure 8

Optical Coherence Tomography (OCT) scans of dermatomed pig ear skin treated with ORGs for (A) 4 h and (B) 24 h, and (C) optical attenuation coefficient. Data are presented as mean ± SD (n = 3). Statistical differences by one-away ANOVA test relative to control vs. ORG-LEC and control vs. ORG-LEC/m-CUR, where p < 0.01 (**).