Thymoquinone-Loaded Polymeric Films and Hydrogels for Bacterial Disinfection and Wound Healing.

The purpose of this study was to synthesize and characterize novel biocompatible topical polymeric film and hydrogel systems that have the potential to deliver the antibacterial agent thymoquinone (TQ) directly to the skin target site to manage the local wound infection and thereby wound healing. The polyvinyl pyrrolidone (PVP) matrix-type films containing TQ were prepared by the solvent casting method. In vitro skin permeation studies on human cadaver skin produced a mean flux of 2.3 µg TQ/cm2/h. Human keratinocyte monolayers subjected to a scratch wound (an in vitro wound healing assay) showed 85% wound closure at day 6 in the TQ group (100 ng/mL TQ) as compared to 50% in the vehicle control group (p = 0.0001). In a zone-of-inhibition (ZOI) assay, TQ-containing films and hydrogels completely wiped out Staphylococcus aureus in 10 cm diameter Tryptic Soy Agar plates while 500 µg/mL gentamicin containing filters gave 10 mm of ZOI. In an ex vivo model, TQ-containing films eradicated bacterial colonization on human cadaver skin. Furthermore, in a full-thickness wound infection model in mice, TQ-containing films showed significant activity in controlling Staphylococcus aureus infection, thereby disinfecting the skin wound. In summary, TQ-containing PVP films and hydrogels developed in this study have the potential to treat and manage wound infections.

Evaluations of Quality by Design (QbD) Elements Impact for Developing Niosomes as a Promising Topical Drug Delivery Platform.

Topical corticosteroids are used to treat a variety of skin conditions such as allergic reactions, eczema, and psoriasis. Niosomes are a novel surfactant-based delivery system that may be used to deliver desoximetasone via topical product application in order to mitigate common side effects associated with traditional oral delivery routes. The aim of this research was to identify the critical material attributes (CMAs) and critical process parameters (CPPs) that impact key characteristics of drug-loaded niosomes using a systematic quality by design (QbD) approach. An organic phase injection method was developed and used to manufacture the niosomes. The CMAs were identified to be drug amount, concentrations of surfactant and cholesterol, and types of lipids. The CPPs were phase volumes, temperature, mixing parameters, and addition rate based on previous research. The quality attributes measured were entrapment efficiency, particle size distribution, PDI, and zeta potential. These were used to determine the quality target product profile (QTPP) of niosomes. The experimental data indicate that the critical impacting variables for niosomes are: surfactant and cholesterol concentrations, mixing parameters, and organic-phase addition rate. Based on the experimental results of this study methanol:diethyl ether (75:25) as the organic system, drug:surfactant:cholesterol in 1:2:1 concentration, stearic acid as the charge-inducing material, 20 mL external phase and 10 mL internal phase volume, 65 °C external phase temperature, 60 min mixing time, 650 RPM mixing speed and 1 mL/ml addition rate is the ideal combination to achieve desirable desoximetasone niosomes with optimum entrapment efficiency and particle size for topical application.

Solubility-physicochemical-thermodynamic theory of penetration enhancer mechanism of action.

The hypothesis for the investigation was that the overall mechanism of action of skin penetration enhancers is best explained by the Solubility-Physicochemical-Thermodynamic (SPT) theory. To our knowledge, this is the first report of the application of SPT theory in transdermal/topical/enhancer research. The SPT theory puts forward the concept that the mode of action of enhancers is related to solubility parameters, physicochemical interactions and thermodynamic activity. This paper discusses these concepts by using experimentally derived permeation data, various physicochemical and solubility parameters (ingredient active gap (IAG), ingredient skin gap (ISG), solubility of active in the formulation (SolV) and the formulation solubility in the skin (SolS)) generated by using FFE (Formulating for Efficacy™ - ACT Solutions Corp) software. These studies suggest that there is an inverse relationship between measured flux and IAG values given that there is an optimum ingredient skin gap, SolV and SolS ratio. The study demonstrated that the flux is actually proportional to a gradient of thermodynamic activity rather than the concentration and maximum skin penetration and deposition can be achieved when the drug is at its highest thermodynamic activity.

Effects of solvents and penetration enhancers on transdermal delivery of thymoquinone: permeability and skin deposition study.

Thymoquinone (TQ) is a quinone-based phytochemical that was first identified in 1963 in Nigella sativa (black cumin seed) by El-Dakhakhany. Based on the ideal characteristics of transdermal delivery, TQ is potentially an attractive candidate for transdermal drug delivery. The aim of this study was to investigate the feasibility of transdermal delivery of TQ and to assess the effect of an ethanol and propylene glycol donor solvent system along with various compositions of receptor solvents. The effects of penetration enhancers on the in vitro skin permeation and TQ skin absorption were studied using human cadaver skin in Franz diffusion cells. The permeation of saturated solutions of TQ was investigated with 5% v/v of each of the following enhancers: Azone (laurocapram), Transcutol® P (Tc), oleic acid, ethanol, Polysorbate 80 (Tween 80), and N-methyl-pyrrolidone (NMP). The results indicated that Azone, oleic acid, and Tc were able to provide adequate TQ flux and may be the agents of choice for use in a novel transdermal formulation of TQ. These penetration enhancers were also able to generate TQ reservoirs in the skin that may be useful to provide sustained release of TQ from the stratum corneum over longer periods of time.

Strat-M® synthetic membrane: Permeability comparison to human cadaver skin.

The aim of this work was to investigate the correlation of permeation behavior of transdermal formulations through a novel synthetic membrane (Strat-M® EMD Millipore, MA) and human cadaver skin. Strat-M® membranes were designed with the intent to share similar structural and chemical characteristics found in the human skin however, omitting any biological behavior due to the absence of viable cells. Both human skin and the membrane display a layered structure with a very tight top layer. Additionally, the Strat-M® membrane contains a combination of lipids in a specific ratio similar to what is found in the human stratum corneum (SC). Formulations containing nicotine and a chemical penetration enhancer (CPE) were used for evaluating drug penetration to understand how each enhancer impacts the permeability of nicotine as a model compound. The permeability measurements of human cadaver skin and Strat-M® membrane were performed with Franz diffusion cell methods accompanied by HPLC analysis. A good correlation of the permeability data was obtained through human cadaver skin and Strat-M® membrane. Thus, Strat-M® has the potential to be used as a screening tool for evaluating topical/transdermal formulations through the human cadaver skin.

Membrane properties for permeability testing: Skin versus synthetic membranes.

Synthetic membranes that are utilized in diffusion studies for topical and transdermal formulations are usually porous thin polymeric sheets for example cellulose acetate (CA) and polysulfones. In this study, the permeability of human skin was compared using two synthetic membranes: cellulose acetate and Strat-M® membrane and lipophilic and hydrophilic compounds either as saturated or formulated solutions as well as marketed dosage forms. Our data suggests that hydrophilic compounds have higher permeation in Strat-M membranes compared with lipophilic ones. High variation in permeability values, a typical property of biological membranes, was not observed with Strat-M. In addition, the permeability of Strat-M was closer to that of human skin than that of cellulose acetate (CA > Strat-M > Human skin). Our results suggest that Strat-M with little or no lot to lot variability can be applied in pilot studies of diffusion tests instead of human skin and is a better substitute than a cellulose acetate.