Nanoemulsion: a Review on Mechanisms for the Transdermal Delivery of Hydrophobic and Hydrophilic Drugs
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Scientia Pharmaceutica Review Nanoemulsion: A Review on Mechanisms for the Transdermal Delivery of Hydrophobic and Hydrophilic Drugs Dalia S. Shaker 1 , Rania A. H. Ishak 2, Amira Ghoneim 1,* and Muaeid A. Elhuoni 3 1 Department of Pharmaceutics &Pharmaceutical Technology, Faculty of Pharmaceutical Sciences and Pharmaceutical industries, Future University in Egypt (FUE), 11835 Cairo, Egypt 2 Department of Pharmaceutics& Industrial Pharmacy, Ain Shams University, 11591 Cairo, Egypt 3 Quality Control Department, Elnajah Medical Services, Benghazi, Libya * Correspondence: [email protected]; Tel.: +(202)-2414-2927; Fax: +(202)-2618-6111 Received: 1 June 2019; Accepted: 9 July 2019; Published: 12 July 2019 Abstract: Nanoemulsions (NEs) are colloidal dispersions of two immiscible liquids, oil and water, in which one is dispersed in the other with the aid of a surfactant/co-surfactant mixture, either forming oil-in-water (o/w) or water-in-oil (w/o) nanodroplets systems, with droplets 20–200 nm in size. NEs are easy to prepare and upscale, and they show high variability in their components. They have proven to be very viable, non-invasive, and cost-effective nanocarriers for the enhanced transdermal delivery of a wide range of active compounds that tend to metabolize heavily or suffer from undesirable side effects when taken orally. In addition, the anti-microbial and anti-viral properties of NE components, leading to preservative-free formulations, make NE a very attractive approach for transdermal drug delivery. This review focuses on how NEs mechanistically deliver both lipophilic and hydrophilic drugs through skin layers to reach the blood stream, exerting the desired therapeutic effect. It highlights the mechanisms and strategies executed to effectively deliver drugs, both with o/w and w/o NE types, through the transdermal way. However, the mechanisms reported in the literature are highly diverse, to the extent that a definite mechanism is not conclusive. Keywords: nanoemulsion; transdermal; permeability; water-in-oil; oil-in-water; mechanisms 1. Introduction Nanoemulsions (NEs) are submicron sized and have gained great interest as drug carriers for improving the delivery of therapeutic agents. They are considered an advanced nanodroplet systems for systemic, controlled, and targeted drug delivery. NEs are colloidal dispersions consisting of two immiscible liquids (water and oil), in which one liquid is dispersed in the other by means of an appropriate surfactant mixture, forming a system where the size of droplets falls in the range of 20 to 200 nm, as reported by Takur et al. [1]. Nanoemulsion (NE) in particular is a very cost-effective technique, with high storage stability, as it is easily prepared and does not always require high energy or complicated procedures [2,3]. Despite the similarities between NEs and microemulsions (MEs) in terms of their physical appearance, components, and preparation techniques, NEs are kinetically stable and thermodynamically metastable, while MEs are thermodynamically stable [4]. Transdermal drug delivery is a very established route of drug administration that is known to have enhanced therapeutic efficacy, ease of administration, and an allow an immediate withdrawal of treatment if necessary [5]. This administration route bypasses the hepatic metabolism to reach systemic circulation [6], leading to an increase in drug bioavailability. Moreover, it reduces the adverse effects of some medicines, e.g., non-steroidal anti-inflammatory drugs (NSAIDs), which are usually Sci. Pharm. 2019, 87, 17; doi:10.3390/scipharm87030017 www.mdpi.com/journal/scipharm Sci. Pharm. 2019, 87, 17 2 of 34 associated with gastrointestinal tract (GIT) drug administration [7,8]. Drug delivery via skin for systemic circulation is suitable for a number of clinical conditions, such as hypertension, arthritis, diabetes, cancer, and high blood cholesterol level [9]. Because the dose is given transdermally and is diabetes, cancer, and high blood cholesterol level [9]. Because the dose is given transdermally and sustained over a long period via tailored delivery systems, particularly in the case of NE, it is of is sustainedutmost over importance a long to period improve via patient tailored compliance delivery [10]. systems, particularly in the case of NE, it is of utmost importance to improve patient compliance [10]. 2. Skin Permeation Pathways 2. Skin Permeation Pathways The outermost layer of the epidermis, the stratum corneum (SC), forms a hydrophobic barrier Thethat outermost impedes the layer transport of the of epidermis, exogenous thechemicals, stratum including corneum drugs (SC), [11] forms. An important a hydrophobic requirement barrier that impedesfor the transdermal transport delivery of exogenous is that the chemicals, drug carried including by a vehicle drugs is able [11 to]. reach An importantthe skin surface requirement at an for adequate rate and in sufficient amounts [12]. The SC is the hardest layer of skin due to its flattered transdermalcorneocytes delivery which is thatare surrounded the drug carried by lipid by bilayers a vehicle consisting is able of to ceramides reach the [9] skin. It is surface arranged at in an 10– adequate rate and15 in rows suffi thatcient are amounts 10 μm in [thickness,12]. The SCcomposed is the hardestof highly layerkeratinized of skin cells, due known to its as flattered corneocytes. corneocytes which areThese surrounded cells are surrounded by lipid by bilayers a continuous consisting lipid phas ofe, ceramides known as the [9 ].intercellular It is arranged lipid lamellae, in 10–15 and rows that are 10 µhavem in been thickness, said to resemble composed a “brick of highly and mortar” keratinized model [13] cells,. Finally, known diffusion as corneocytes. through the SC These is the cells are surroundedsum of by a series a continuous of segments lipid of lateral phase, diffusion known and as theintramembrane intercellular trans-bilayer lipid lamellae, transport and [14] have. been said A permeant applied to the skin has three possible routes across the epidermis, as illustrated in to resemble a “brick and mortar” model [13]. Finally, diffusion through the SC is the sum of a series of Figure 1: The transcellular route, a lipid domain associated with the proteins inside corneocytes, the segmentsintercellular of lateral route, diffusion and the and appendageal intramembrane route, through trans-bilayer hair follicles, transport via associated [14]. sebaceous glands A permeantand sweat ducts applied [15]. The to thefractional skin hasappendage three possiblearea available routes for transport across the is only epidermis, about 0.1%. as This illustrated in Figureroute1: Theusually transcellular contributes route, negligibly a lipid to the domain steady associated state drug withflux. theThis proteinspore pathway inside may corneocytes, be the intercellularimportant for route, ions and and large the polar appendageal molecules that route, struggle through to cross hair an follicles,intact SC [15]. via The associated transcellular sebaceous glands androute sweat is a sequence ducts [of15 partitioning]. The fractional and diffusion appendage into alternating area available hydrophilic for transportand lipophilic is only domains about 0.1%. of cells, respectively, in the extracellular matrix [16,17]. In the intercellular route, the permeant crosses This route usually contributes negligibly to the steady state drug flux. This pore pathway may be the hard path within the extracellular matrix, without traversing the cells. Small hydrophilic importantmolecules for ions generally and large prefer polar the transcellular molecules route that struggleover the intercellular to cross an route, intact and SC the [15 reverse]. The is transcellular true route isfor a sequence lipophilic ofmolecules. partitioning The transcellular and diffusion and into intercellular alternating routes hydrophilic constitute andthe lipophilictransepidermal domains of cells, respectively,pathway [18]. in the extracellular matrix [16,17]. In the intercellular route, the permeant crosses the hard path withinThe combined the extracellular flux of these matrix,two pathways, without lipid traversing and pore, determines the cells. the Small overall hydrophilic observed flux molecules across the skin. It is widely accepted that the trans epidermal pathway is usually the predominant generally prefer the transcellular route over the intercellular route, and the reverse is true for lipophilic pathway of skin permeation and that under sink conditions, diffusion across the SC constitutes the molecules.rate-limiting The transcellular step that determines and intercellular the overall routesflux of the constitute permeant. the transepidermal pathway [18]. Figure 1.FigurePermeation 1. Permeation pathways pathways in the in skin the (the skin stratum (the stratum corneum, corneum, SC, is illustrated).SC, is illustrated). (A) The (A) transcellular The route associatedtranscellular with route the associated proteins with inside the proteins corneocytes. inside corneocytes. (B) The intercellular (B) The intercellular route and route the and appendageal the appendageal route through (C) hair follicles with associated sebaceous glands (D) via sweat ducts. route through (C) hair follicles with associated sebaceous glands (D) via sweat ducts. The combined flux of these two pathways, lipid2 and pore, determines the overall observed flux across the skin. It is widely accepted that the trans epidermal pathway is usually the predominant pathway of