Chiral 4-O-acylterpineol as transdermal permeation enhancers: insights of the enhancement mechanisms of a transdermal enantioselective delivery system for flurbiprofen.
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ABSTRACT:
SUBMITTER: Chu T
PROVIDER: S-EPMC7269032 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Overlook of chiral consideration in transdermal drug delivery increases administrated dose and risk of side effects, decreasing therapeutical effects. To improve the transdermal delivery efficiency of eutomer, this work focused on investigating the law and mechanism of enantioselective enhancing effects of chiral permeation enhancers on drug enantiomers. Chiral nonsteroidal anti-inflammatory drugs and terpene permeation enhancers were selected as model drug and enhancers. The results indicated that the L-isomer of permeation enhancers increased the skin absorption of S-enantiomer of drug and D-isomer improve the permeation of R-enantiomer, in which the enhancement effect (ER) of L-menthol on S-enantiomer (ER = 3.23) was higher than that on R-enantiomer (ER = 1.49). According to the pharmacokinetics results, L-menthol tended to enhance the permeation of S-enantiomer better than R-enantiomer (2.56 fold), and showed excellent in vitro/in vivo correlations. The mechanism study showed that L-isomer of permeation enhancers improved the permeation of S-enantiomer by increasing the retention, but the D-isomer by improving partition for better permeation. Enantioselective mechanism indicated that the weaker chiral H-bond interaction between drug-chiral enhancers was caused by the enantiomeric conformation. Additionally, stronger chiral enhancers-skin interaction between L-isomer and S-conformation of ceramide produced better enhancing effects. In conclusion, enantioselective interaction of chiral drug-chiral enhancers and chiral enhancers-chiral skin played a critical role in transdermal drug delivery, rational utilization of which contributed to improving the uptake of eutomer and inhibiting distomers to decrease a half of dose and side effects, increasing transdermal therapeutical efficiency.
| S-EPMC10616145 | biostudies-literature
Project description:Hydroquinone (HQ) is an anti-hyperpigmentation agent with poor physicochemical stability. HQ formulations are currently elaborated by compounding in local pharmacies. Variability in the characteristics of HQ topical formulations can lead to remarkable differences in terms of their stability, efficacy, and toxicity. Four different semisolid O/W formulations with 5% HQ were prepared using: i) Beeler´s base plus antioxidants (F1), ii) Beeler´s base and dimethyl isosorbide (DMI) as solubiliser (F2), iii) olive oil and DMI (F3), and iv) Nourivan®, a skin-moisturising and antioxidant base, along with DMI (F4). Amongst the four formulations, F3 showed the greatest physicochemical stability with less tendency to coalescence but with marked chromatic aberrations. An inverse correlation was established by multivariate analysis between the mean droplet size in volume and the steady-state flux, which explains why F3, with the smallest droplet size and the most hydrophobic excipients, exhibited the highest permeation across both types of membranes with enhancement ratios of 2.26 and 5.67-fold across Strat-M® and mouse skin, respectively, compared to F1. It is crucial to understand how the HQ is formulated, bearing in mind that the use of different excipients can tune the transdermal delivery of HQ significantly.
| S-EPMC6523612 | biostudies-literature
Project description:Transdermal drug delivery is an attractive non-invasive method offering numerous advantages over the conventional routes of administration. The main obstacle to drug transport is, however, the powerful skin barrier that needs to be modulated, for example, by transdermal permeation enhancers. Unfortunately, there are still only a few enhancers showing optimum properties including low toxicity and reversibility of enhancing effects. For this reason, we investigated a series of new N-alkylmorpholines with various side chains as potential enhancers in an in vitro permeation study, using three model permeants (theophylline, indomethacin, diclofenac). Moreover, electrical impedance, transepidermal water loss, cellular toxicity and infrared spectroscopy measurements were applied to assess the effect of enhancers on skin integrity, reversibility, toxicity and enhancers' mode of action, respectively. Our results showed a bell-shaped relationship between the enhancing activity and the hydrocarbon chain length of the N-alkylmorpholines, with the most efficient derivatives having 10-14 carbons for both transdermal and dermal delivery. These structures were even more potent than the unsaturated oleyl derivative. The best results were obtained for indomethacin, where particularly the C10-14 derivatives showed significantly stronger effects than the traditional enhancer Azone. Further experiments revealed reversibility in the enhancing effect, acceptable toxicity and a mode of action based predominantly on interactions with stratum corneum lipids.
| S-EPMC8778526 | biostudies-literature
Project description:BackgroundEthosomes have been widely used in Transdermal Drug Delivery System (TDDS) as they increase the permeation of drug across the skin.MethodsFlurbiprofen loaded vesicular ethosomes were formulated, optimized and characterized for particle size, entrapment efficiency, poly dispersive index (PDI), microscopy using Atomic force microscopy (AFM), Scanning electron microscope (SEM) and Transmission electron microscopy (TEM) and Interaction of drug and excipients were studied using Fourier transform infra-red (FTIR) spectroscopy, Differential scanning colorimetry (DSC), Thermo gravimetric analysis (TGA). Further, ethosomal formulations of flurbiprofen were evaluated for stability study of three months and in vitro drug permeation study was carried out using albino rat skin. In addition, skin irritation test was evaluated by Draize test and in vivo study of prepared formulation was examined through paw edema assay by inducing carrageenan and cold plate method.ResultsAmongst all formulations, EF5 formulation exhibited ideal surface morphology, with maximum entrapment efficiency (95%) with optimal excipient concentration i.e. 200 mg phospholipid and 35% ethanol. The ideal vesicle size was achieved as 162.2 ± 2 nm, with zeta potential - 48.14 ± 1.4 mV with the PDI of 0.341. In-vitro permeation study shows a release of 82.56 ± 2.11 g/cm2 in 24 h and transdermal flux was found as 226.1 μg/cm2/h. Cold plate test indicates that the formulation EF5 showed a marked analgesic activity and Carrageenan induced paw edema test indicates that the formulation EF5 inhibits the increase in paw edema. Ethosomal suspension at 4 °C showed maximum stability.ConclusionsThe overall study concluded that this ethosomal approach offers a new delivery system for sustained and targeted delivery for flurbiprofen.
| S-EPMC6554971 | biostudies-literature
Project description:BACKGROUND:In recent years, nanoparticles (NPs) including nanostructured lipid carries (NLC) and solid lipid nanoparticles (SLN) captured an increasing amount of attention in the field of transdermal drug delivery system. However, the mechanisms of penetration enhancement and transdermal transport properties of NPs are not fully understood. Therefore, this work applied different platforms to evaluate the interactions between skin and NPs loading triptolide (TPL, TPL-NLC and TPL-SLN). Besides, NPs labeled with fluorescence probe were tracked after administration to investigate the dynamic penetration process in skin and skin cells. In addition, ELISA assay was applied to verify the in vitro anti-inflammatory effect of TPL-NPs. RESULTS:Compared with the control group, TPL-NPs could disorder skin structure, increase keratin enthalpy and reduce the SC infrared absorption peak area. Besides, the work found that NPs labeled with fluorescence probe accumulated in hair follicles and distributed throughout the skin after 1 h of administration and were taken into HaCaT cells cytoplasm by transcytosis. Additionally, TPL-NLC could effectively inhibit the expression of IL-4, IL-6, IL-8, IFN-?, and MCP-1 in HaCaT cells, while TPL-SLN and TPL solution can only inhibit the expression of IL-6. CONCLUSIONS:TPL-NLC and TPL-SLN could penetrate into skin in a time-dependent manner and the penetration is done by changing the structure, thermodynamic properties and components of the SC. Furthermore, the significant anti-inflammatory effect of TPL-NPs indicated that nanoparticles containing NLC and SLN could serve as safe prospective agents for transdermal drug delivery system.
| S-EPMC6138933 | biostudies-literature
Project description:BackgroundZidovudine (AZT) has been the most widely used drug for antiretroviral therapy. In order to improve the therapy with this drug, different alternatives have been proposed, such as the transdermal administration. The use of permeation enhancers is necessary to favor the passage of this drug through the skin, due to its physicochemical properties and to the natural permeation barrier imposed by the skin.ObjectivesTo evaluate the effect of two permeation enhancers, sonophoresis and microneedles, on the permeability of AZT through the skin.MethodsPermeation studies with an AZT solution were performed using pigskin clamped in Franz-type cells. Sonophoresis was applied under different conditions (i.e., amplitude, duty cycle and application time), selected according to an experimental design, where the response variables were the increase in temperature of the skin surface and the increase in transepidermal water loss. ATR-FTIR was also used to demonstrate the effect of enhancers on membrane components.ResultsThe permeability of AZT through intact skin was very poor, with a very long lag time. Pretreatment of the skin with sonophoresis increased AZT transport significantly, reducing the lag time. The maximum flux (27.52 µgcm-2 h-1) and the highest total amount permeated (about 624 µg/cm2) were obtained when applying sonophoresis in continuous mode, with an amplitude of 20%, and an application time of 2 min. Sonophoresis appears to have an impact on stratum corneum proteins. The use of microneedles further increased the flux (30.41 µgcm-2 h-1) and the total amount permeated (about 916 µg/cm2), relative to sonophoresis.ConclusionThe results are encouraging in terms of promoting AZT transport through the skin using sonophoresis or microneedles as permeation enhancers.
| S-EPMC8602535 | biostudies-literature
Project description:Chemical penetration enhancers (CPEs) are present in a large number of transdermal, dermatological, and cosmetic products to aid dermal absorption of curatives and aesthetics. This wide spectrum of use is based on only a handful of molecules, the majority of which belong to three to four typical chemical functionalities, sporadically introduced as CPEs in the last 50 years. Using >100 CPEs representing several chemical functionalities, we report on the fundamental mechanisms that determine the barrier disruption potential of CPEs and skin safety in their presence. Fourier transform infrared spectroscopy studies revealed that regardless of their chemical make-up, CPEs perturb the skin barrier via extraction or fluidization of lipid bilayers. Irritation response of CPEs, on the other hand, correlated with the denaturation of stratum corneum proteins, making it feasible to use protein conformation changes to map CPE safety in vitro. Most interestingly, the understanding of underlying molecular forces responsible for CPE safety and potency reveals inherent constraints that limit CPE performance. Reengineering this knowledge back into molecular structure, we designed >300 potential CPEs. These molecules were screened in silico and subsequently tested in vitro for molecular delivery. These molecules significantly broaden the repertoire of CPEs that can aid the design of optimized transdermal, dermatological, and cosmetic formulations in the future.
| S-EPMC555729 | biostudies-literature
Project description:Buccal mucosa has recently received much attention as a potential route for systemic delivery of drugs, including biologics and vaccines. The aim of this work was to gain insight into the mechanism of fatty acids as buccal permeation enhancers, by studying the effect of a series of medium and long chain fatty acids on the permeation of a model high molecular weight and hydrophilic molecule, fluorescein isothiocyanate labelled dextran (FD-4, m.w. 4 kDa) across porcine esophageal epithelium. A parabolic relationship between fatty acid lipophilicity and enhancement was obtained, regardless of the presence and number of double bonds. The relationship, which resembles the well-known relationship between permeability and lipophilicity of transdermal delivery, presents a maximum value in correspondence of C10 (logP approx. 4). This is probably the ideal lipophilicity for the fatty acid to interact with the lipid domains of the mucosa. When the same analysis was performed on skin data, the same trend was observed, although the maximum value was reached for C12 (logP approx. 5), in agreement with the higher lipophilicity of the skin. The results obtained in the present work represent a significant advancement in the understanding of the mechanisms of action of fatty acids as buccal penetration enhancers.
| S-EPMC6321376 | biostudies-other
Project description:Ethosomes are widely used to promote transdermal permeation of both lipophilic and hydrophilic drugs, but the mechanism of interaction between the ethosomes and the skin remains unclear. In this work, it was exploded with several technologies and facilities. Firstly, physical techniques such as attenuated total reflectance fourier-transform infrared and laser confocal Raman were used and the results indicated that the phospholipids configuration of stratum corneum changes from steady state to unstable state with the treatment of ethosomes. Differential scanning calorimetry reflected the thermodynamics change in stratum corneum after treatment with ethosomes. The results revealed that the skin of Bama mini-pigs, which is similar to human skin, treated by ethosomes had a relatively low Tm and enthalpy. Scanning electron microscopy and transmission electron microscopy showed that the microstructure and ultrastructure of stratum corneum was not damaged by ethosomes treatment. Furthermore, confocal laser scanning microscopy revealed that lipid labeled ethosomes could penetrate the skin via stratum corneum mainly through intercellular route, while during the process of penetration, phospholipids were retained in the upper epidermis. Cell experiments confirmed that ethosomes were distributed mainly on the cell membrane. Further study showed that only the drug-loaded ethosomes increased the amount of permeated drug. The current study, for the first time, elucidated the mechanistic behavior of ethosomes in transdermal application from molecular configuration, thermodynamic properties, ultrastructure, fluorescent labeling and cellular study. It is anticipated that the approaches and results described in the present study will benefit for better design of drug-loaded ethosomes.
| S-EPMC6733291 | biostudies-literature
Project description:Chemical penetration enhancers are often used to enhance transdermal drug delivery. However, the fundamental mechanisms that govern the interactions between penetration enhancers and skin are not fully understood. Therefore, the goal of this work was to identify naturally fluorescent penetration enhancers (FPEs) in order to utilize well-established fluorescence techniques to directly study the behavior of FPEs within skin. In this study, 12 fluorescent molecules with amphiphilic characteristics were evaluated as skin penetration enhancers. Eight of the molecules exhibited significant activity as skin penetration enhancers, determined using skin current enhancement ratios. In addition, to illustrate the novel, direct, and non-invasive visualization of the behavior of FPEs within skin, three case studies involving the use of two-photon fluorescence microscopy (TPM) are presented, including visualizing glycerol-mitigated and ultrasound-enhanced FPE skin penetration. Previous TPM studies have indirectly visualized the effect of penetration enhancers on the skin by using a fluorescent dye to probe the transdermal pathways of the enhancer. These effects can now be directly visualized and investigated using FPEs. Finally, future studies are proposed for generating FPE design principles. The combination of FPEs with fluorescence techniques represents a useful novel approach for obtaining physical insights on the behavior of penetration enhancers within the skin.
| S-EPMC3294199 | biostudies-literature