Influence of Permeation Enhancers on the in Vitro Skin Permeation of Ketorolac Tromethamine Through Excised Rat Skin: A Mechanistic Study

Abstract

Objective: Ketorolac tromethamine (KT) is considered as a member of Non-steroidal anti-inflammatory drugs that used as an analgesic and antipyretic agent. The main aim of this research was to investigate the effect of some herbal and chemical permeation enhancers on the in vitro skin permeability of KT.Method: Ketorolac permeability experiments through rat skin pre-treated with some of permeation enhancers, namely urea, eucalyptus oil, olive oil, and menthol, were performed in fabricated Franz diffusion cells and compared with hydrated rat skin as control. The permeability parameters evaluated include steady-state flux (Jss), permeability coefficient (Kp), and diffusion coefficient (D). The penetration enhancers permeability enhancement mechanisms were investigated by comparing changes in peak position and their intensities of asymmetric (Asy) and symmetric (Sym) C-H stretching, C=O stretching, C=O stretching (Amide I), and C-N stretching of keratin (Amide II) absorbance using fourier transform infrared spectroscopy (FT-IR), as well as by comparing mean transition temperature (Tm) and their enthalpies (ΔH) using differential scanning calorimetery (DSC). KT permeability parameters through rat skin were evaluated with and without chemical enhancers such as eucalyptus oil, olive oil, menthol, and urea.Result: The skin showed barrier for ketorolac permeability through the whole skin and that diffusion into the skin was the rate-limiting step for drug flux. Urea, eucalyptus oil, olive oil, and menthol were the most effective enhancers as they increased flux 0.02, 0.017, 0.016, and 0.012 times and diffusion coefficient 0.079, 0.194, 0.129, and 1.35 folds in comparison with hydrated skin, respectively.Conclusion: FT-IR and DSC results showed lipid fluidization, extraction, disruption of lipid structure, and irreversible denaturation of proteins in the stratum corneum layer of the skin by permeation enhancers.

Systematic Review on the Effectiveness of Essential and Carrier Oils as Skin Penetration Enhancers in Pharmaceutical Formulations

“…Conversely, olive oil is less effective than most terpenes, certain surfactants, and organic solvents. In vitro permeation studies have reported a lower enhancement activity of olive oil in the permeation of ketorolac as compared to limonene, cineole, menthol, and eucalyptus oil from solution and reservoir transdermal patches [59,74]. Moreover, the in vitro and ex vivo studies carried out by Hussain et al [25] and Maniyar and Kokare [85] found it to be less effective than turpentine oil [25] and peppermint oil [85] in the permeation of diclofenac potassium and lopinavir from a gel and liposome, respectively.…”

“…The dominant mechanism of the penetration of eucalyptus oil is the partitioning of the essential oil into the skin, as reported by Chi-Hsien [57] during the formulation of a photosensitizer microemulsion and El-Maghraby et al [58] during the mutual transdermal administration of indomethacin and benzocaine microemulsions. Eucalyptus oil was also used in the formulation of miconazole and ketorolac solutions and was found to exert its permeation enhancement activity by several mechanisms, i.e., lipid fluidization, disruption lipid structure, and irreversible keratin denaturation in SC, resulting in higher enhancement ratios [ER] of flux [ERF], diffusion [ERD], and permeability [ERP] as compared to hydrated skin [59,60]. The fluidization mechanism of eucalyptus oil was exploited in the enhancement of felodipine permeation from a niosome formulation [61].…”

“…Menthol was effective when used in the formulation of an aceclofenac microemulsion [92], as well as having a significant role in the enhancement of 18-β-glycyrrhetinic acid and boswellic acid permeation from matrix-and reservoir-type transdermal patches, respectively [93]. Menthol is more effective than vegetable oils such as linseed oil and sunflower oil [74] and has been shown to be more effective than olive oil, with greater enhancement activity for ketorolac from a solution and a reservoir-type transdermal patch [59,74].…”

“…When comparing menthol with limonene, eucalyptol, and eucalyptus, the in vitro permeation studies carried out by Prakash et al [74] and Saadatzadeh et al [59] found a lower permeation enhancement effect of menthol on ketorolac tromethamine through rat skin. In addition, an ex vivo study carried out by Khullar et al [68] found a similar permeation effect compared to clove oil during mefenamic acid emulgel formulation.…”

“…There are some controversial reports: the in vitro permeation study carried out by Pelikh et al [112] found that olive oil produced a greater increase in the permeation of hesperetin and rutin from a nanocrystal as compared to urea, whereas urea is more effective at enhancing the permeation of ketorolac tromethamine from a gel than olive oil [59]. Moreover, olive oil was more effective than liquid paraffin on the permeation of flurbiprofen from foam and gel [23], whereas Shokri and Javar [121] found it to be less effective in an ex vivo permeation study in which collagen was formulated in a solution.…”