Abstract
Nutrients provide vital functions in the body for sustained health, which have been shown to be related to the incidence, prevention and treatment of disease. However, limited bioavailability, loss of targeting specificity and the increased hepatic metabolism limit the utilization of nutrients. In this review, we highlight transdermal absorption of nutrients, which represents an opportunity to allow great use of many nutrients with promising human health benefits. Moreover, we describe how the various types of permeation enhancers are increasingly exploited for transdermal nutrient delivery. Chemical penetration enhancers, carrier systems and physical techniques for transdermal nutrient delivery are described, with a focus on combinatorial approaches. Although there are many carrier systems and physical techniques currently in development, with some tools currently in advanced clinical trials, relatively few products have achieved full translation to clinical practice. Challenges and further developments of these tools are discussed here in this review. This review will be useful to researchers interested in transdermal applications of permeation enhancers for the efficient delivery of nutrients, providing a reference for supporting the need to take more account of specific nutritional needs in specific states.
1 INTRODUCTION
Nutrients provide vital functions in the body for sustained health. Undernutrition and overnutrition bring many health problems, especially the health effects of poor nutrition almost certainly accumulate over the lifetime of the individual. Chronic diseases such as obesity, cardiovascular disease and Alzheimer’s disease have been shown to be related to nutrient intake and status.- Nutrients play an important role in changing the development of disease, can stabilize or reverse the disease when adequate and timely supplemented. There is therefore an urgent need to develop rational nutrition utilization strategies to reduce the high incidence of nutrition-related chronic diseases.
Generally, chronic diseases or other clinical conditions can affect nutritional needs, and meeting this particular need may prevent secondary and tertiary disease such as tissue regeneration that timely supplement nutrients in specific tissues without causing systemic nutritional deficiencies. In addition, the biochemical dysfunction associated with the disease may lead to a demand for non-essential nutrients, making them conditionally necessary, or to toxicity for food components at levels normally tolerated by healthy people, such as inborn metabolic errors. Furthermore, age-related declines in biological networks or periods of pregnancy may also directly affect nutritional requirements and disease susceptibility. Overall, there is a growing awareness that many factors influence nutritional requirements. Based on this, there is an interest in personalized nutritional needs, following the paradigm of precision medicine.
Transdermal drug delivery has been used effectively for the treatment of diseases but could also be beneficial for cosmeceutical and food applications. Transdermal delivery systems are highly attractive as the delivery of drugs through the skin is minimally invasive. Compared to conventional administration strategies such as oral administration or intravenous injection, transdermal delivery utilizes painless self-administration at home, outside a hospital setting. These delivery systems also can avoid first-pass metabolism and significantly increase the bioavailability of therapeutic drugs, improving drug stability and biodistribution and allowing sustained release., The application and development of transdermal delivery systems represent an opportunity to allow great use of many nutrients with promising human health benefits, supporting the need to take more account of specific nutritional needs in specific states.
However, due to the skin barrier effect, some nutrients cannot be transported through the skin at the rate prescribed for treatment. In the past few years, the development of chemical permeation enhancers, carrier systems and physical technology has specifically improved the delivery of nutrients and has shown promise in clinical applications. In this review, recent advances in tools for transdermal nutrient delivery are presented. Nutrient penetration, chemical permeation enhancers, carrier systems and improved physical techniques are discussed, highlighting combinatorial approaches. Challenges and promising areas of research are also presented. Such, given that meeting nutrient needs is essential in order to be free from malnutrition and improve treatment effectiveness.
2 TRANSDERMAL ABSORPTION OF NUTRIENTS
2.1 Reason for transdermal nutrients delivery
Nutrients not only maintain the normal operation of the body but also are widely used in the diagnosis, prevention and treatment of various diseases. In an organism, macronutrients such as carbohydrates, proteins and lipids perform various functions, where carbohydrates provide energy but also act as therapeutic entities such as hyaluronic acid, and lipids act as the basic structural elements of cell membranes. Similarly, proteins and peptides are the physical building blocks of life and can be developed as therapeutic entities such as vaccines, antigens and hormones to treat disease. However, many therapeutic nutrients, such as proteins and peptides, are degraded in the gastrointestinal tract by enzymatic activity resulting in altered three-dimensional structure or absorbed in uneven distribution, leading to poor therapeutic effects.,
Vitamins and minerals play essential roles as cofactors in metabolism, including biosynthesis and energy generation. For example, vitamins C and E are natural antioxidants but have been greatly limited in therapeutics due to their light instability and oxygen sensitivity. Polyphenols are dietary components and are commonly found in plants, with good anti-oxidant activities that are beneficial for health. However, polyphenols become unstable when exposed to strong acidic conditions in the stomach, leading to poor bioavailability. Many studies have shown that the poor bioavailability of polyphenols may be directly related to the poor outcomes of clinical trials.
These nutrients have the greatest compliance by oral administration, but they may be limited by serious problems such as increased hepatic metabolism and loss of targeting specificity, resulting in a high degree of adverse reactions and toxicity. Furthermore, the structural characteristics of nutrients and their limited bioavailability may cause significant obstacles to their distribution. One possible administration method is transdermal administration, which goes beyond the shortcomings of current therapies (Figure ).
Reason for transdermal nutrient delivery.
2.2 Nutrients passively penetrate through the skin
Skin is an important organ of the human body, consisting of the epidermis, dermis and hypodermis/subcutaneous layers. Based on the different developmental stages and morphological characteristics of cells, the epidermis layer can be divided into stratum corneum, stratum granulosum, stratum spinosum and stratum basale from the outermost to innermost layer. The stratum corneum acts as a barrier to limit penetration of most substances into the skin unless they are low molecular weight lipophilic compounds (Figure ). This barrier is formed by around 15–25 layers of dead keratinocytes/corneocytes that are filled with keratin bundles and other proteins, with the dead keratinocytes embedded in a lipidic matrix that resembles a “brick and mortar” structure. Lipids are found between corneocytes and include ceramides, free fatty acids and cholesterol; these lipids contribute significantly to the barrier function., The dermis layer is a hydrophilic layer that lies just below the epidermis layer. The hypodermis/subcutaneous tissue is the deepest layer of the skin and is high in fat. Blood vessels, nerves, lymph vessels and skin appendageals are present in the dermis and hypodermis layers. There are several transdermal delivery pathways available for nutrient transportation: (i) the intercellular pathway, which is suitable for the transmission of lipophilic nutrients; the intracellular (transcellular) pathway, which facilitates the permeation of hydrophilic nutrients that diffuse through the corneocytes to ultimately enter the systemic circulation and (iii) the transappendageal pathway., The skin appendageals include hair follicles and pilosebaceous follicles (sebaceous and sweat glands). The hair follicles are an attractive option for nutrient penetration, especially for high molecular weight (>500 Da) nutrients, although these follicles occupy a relatively low proportion (0.1%) of the entire skin surface.
Schematic structure of the skin layers and nutrients permeation pathways through the skin barrier.
Many nutrients with a molecular weight of less than 500 Da have good transdermal absorption effects and can effectively penetrate the skin. These low molecular weight (<500 Da) lipophilic nutrients primarily cross the lipid layers of stratum corneum via free volume diffusion., Fatty acids show varying abilities to penetrate the lipid bilayers of skin and break the intercellular lipid matrix of the stratum corneum, depending on their structures and physicochemical properties. Compared to unsaturated fatty acids, saturated fatty acids have higher melting points, thus limiting their solubility in skin lipids. Linoleic acid, a polyunsaturated essential fatty acid, has two cis-unsaturated double bonds at C9 and C12 locations and can passively penetrate the skin by causing lipid disorganization in the stratum corneum and inducing the redistribution of endogenous fatty acids., In a different mechanism from that of linoleic acid, oleic acid disrupts the stratum corneum barrier by incorporating itself into the lipid lamellae and increasing the disordering of the alkyl chain. Different fatty acids can together exert synergetic effects to enhance skin penetration, thus natural oils with plentiful unsaturated fatty acids typically exhibit a higher degree of disturbance in skin lipids and may act as natural penetration enhancers., Terpenes are naturally occurring hydrocarbons and important components of plant essential oils. The reducing effect of cyclic terpenes on the skin barrier function is greater than that of linear terpenes, with reversible action on skin barrier function. Monocyclic and bicyclic terpenoids show different effects on the skin barrier function, where monocyclic terpenoids increase the fluidity of lecithin phospholipids and bicyclic terpenoids increase the polarity of lipids. The permeation capacity of low molecular weight hydrophilic nutrients is generally poor given the minimal pore network in stratum corneum, but low molecular weight hydrophilic nutrients like water or glucose primary can diffuse into the skin through pores.
High molecular weight (>500 Da) nutrients will also penetrate through the stratum corneum, but their transdermal penetration effects are much slower because they diffuse with a relatively slow lateral flow of skin lipids. High MW nutrients passively penetrate the skin by the appendageal pathway. Polysaccharides, which have great potential value in the cosmetic industry due to their good absorption, moisturizing and nourishing effects on skin, are high molecular weight nutrients. Polysaccharides can penetrate the skin, but the formation of a thin film on the skin surface can dramatically reduce the penetration rate of polysaccharides and even block penetration. Protein peptides with different molecular weights have different penetrating effects, and larger molecular weight proteins are less able to penetrate, and these molecules can only stay on the skin surface. However, some cell-penetrating peptides can modify growth factor to facilitate their permeation into the skin without requiring chemical or physical modification.
2.3 Application of nutrients as carriers
Macronutrients, such as polysaccharides, proteins and lipids, are generally recognized as safe status, show great potential in drug delivery and are widely applied as carriers to encapsulate targets due to their unique structural and functional properties. Proteins are amphiphilic which allow targets to bind or conjugate though non-covalent or covalent. Polysaccharides have a variety of biological activities and functional groups, including hydrophilic groups that enable polysaccharides to adhere to the surface of biological tissues and prolong the circulation time of targets in the body. At present, hyaluronic acid, chitosan, starch and pullulan have been used as polysaccharide carriers. The lipids as the main material of lipid carriers can be non-polar, liquid or solid polar lipids depending on the properties of the targets. Medium- and long-chain lipids can be selected to encapsulate targets such as vitamins. The targets with large molecular dimensions, in contrast, require the construction of micelles with long-chain fatty acids.
Furthermore, nutrient carriers not only deliver targets but also have synergistic therapeutic effects. Lee et al. reported that cyclized recombinant proteins have increased permeability in both cancer cells and synthetic liposomes, as well as resistance to enzymatic degradation in cancer cells, and attributed these to structural constraints imposed on proteins in the presence of short functional peptides. Hyaluronic acid, an important component of the human extracellular matrix, has a strong hydrophilic effect due to the ability of hydroxyl groups to form hydrogen bonds with water molecules and bind them to the chain. Due to its unique structural and functional properties, hyaluronic acid is often used as a carrier to promote the transdermal absorption of targets, as well as in the treatment of osteoarthritis, wound healing and extracellular matrix regeneration depending on the molecular weight to improve therapeutic effectiveness.
3 CHEMICAL PERMEATION ENHANCERS
Chemical permeation enhancers are pharmacologically inactive compounds that can partition into the stratum corneum, interacting with either the intercellular lipids or the corneocytes and temporarily reducing the permeability barrier function to facilitate diffusion without causing significant damage to skin. Chemical permeation enhancers interact with the stratum corneum in at least four ways: (i) alteration of stratum corneum lipid structure, (ii) disruption of lipid/protein organization, (iii) improved partitioning of compounds in the stratum corneum and (iv) localized separation of lipid domains to create hydrophilic pores., Examples of chemical permeation enhancers in transdermal nutrient delivery are shown in Figure .
Examples of chemical permeation enhancers in transdermal nutrient delivery.
3.1 Azone
Azone, the first molecule specifically designed as a skin penetration enhancer, reduces the diffusion resistance of molecules through the stratum corneum by the intercellular pathway. Azone includes a polar headgroup (within a seven-membered ring) linked to the C12 chain and it can increase the permeation of hydrophilic and hydrophobic peptides by interacting directly with stratum corneum lipids. Azone is relatively safe, as 10% azone applied via a patch caused no irritation on rabbit skin. Azone can be combined with other permeation enhancers for an improved transdermal penetration effect. For example, azone has been combined with ethanol and oleic acid to produce efficient permeation enhancers.
3.2 Alcohols
Alcohols include short-chain alcohols, fatty alcohols and polyalcohols. Polyalcohols such as propylene glycol, glycerol and polyethylene glycol are often used as chemical permeation enhancers. Alcohols can act as chemical permeation enhancers alone as well as in combination with other enhancers., This allows them to be used synergistically to increase the solubility of nutrients. Propylene glycols are well known as effective penetration enhancers and mainly enhance nutrient permeation flux by increasing the partition coefficient of nutrients into the stratum corneum and decreasing the polarity of the aqueous region to enter the skin lipids., Propylene glycol acts in the intracellular pathway. Transretinol penetrates the stratum corneum to enter the epidermis better in combination with propylene glycols/ethanol than by itself because the interaction between propylene glycol and skin lipids significantly promotes the penetration of transretinol. The ability of transretinol to penetrate is highly related to the penetration depth of propylene glycols. Ethanol can serve as a solvent and as a penetration enhancer. The solubility of thymoquinone is increased when ethanol is used as a cosolvent but reduced when a mixture of water with ethanol/methanol is used. The penetration of cyanocobalamin with 20% ethanol increased by 2-fold compared with the phosphate-buffered solution control but was not further enhanced at higher ethanol concentrations (up to 50%).
3.3 Fatty acids
Fatty acids are the main components in natural oils and can effectively improve the skin barrier function. Fatty acids enhance skin permeability by reversible fluidization and disorganization of skin lipids. Unsaturated fatty acids increase skin barrier permeability more effectively than saturated fatty acids, due to the structure of these molecules. Unsaturated fatty acids, such as oleic acid (monounsaturated), linoleic acid (double unsaturated bonds) and linolenic acid (triple unsaturated bonds), can promote transdermal absorption of various nutrients, with excellent permeation enhancement capabilities., For example, oleic acid significantly increased the permeability of s-methyl-L-methionine to 7.98 ± 4.43 mg/h/cm2 for higher amounts of s-methyl-L-methionine in the stratum corneum and epidermis 6 h and 12 h after application. Oleic acid can increase the fluidization and diffusivity of the skin and make a separate phase in the stratum corneum lipids, forming defects in the permeable interface to enhance the permeation of polar nutrients., However, for macromolecules such as insulin, the permeation effect of oleic acid is decreased, and other permeation enhancers must be used for delivery through the skin. Ester derivatives or chemical modifications of parent fatty acids result in fatty acid derivatives with superior penetration ability to allow movement of nutrients through the skin.
3.4 Terpenes
Terpenes are natural chemical permeation enhancers and safe adjuvants with low irritability and good reversibility. Terpenes promote transdermal action mainly by loosening intermolecular hydrogen bonds in ceramides and improving the partition coefficients of compounds for the extraction of stratum corneum lipids. In addition, the effects of terpenes on the skin barrier function are short-lived and reversible. ATR-FTIR and molecular simulation studies demonstrate that the oxygen-containing terpenes promote permeability by forming hydrogen bonds with ceramides and then disturbing the stratum corneum lipid organization. Terpenes can interact with keratin through van der Waals forces and hydrophobic interaction., Although terpenes can promote penetration of some compounds, terpenes alone are unable to promote transdermal absorption of macromolecules such as IFNα. Therefore, modification strategies have been tested to make new permeation enhancers. For example, conjugating the amino acid derivative DDAK with terpenes significantly improved delivery of nutrients through and into the skin, with low toxicity, rapid reversibility and without irritation.
The enhanced nutrient penetration by terpenes involves physiological processes in addition to physical–chemical interactions with the stratum corneum lipids, such as interactions between menthol and TRPM8 channels. Menthol reduces calcium-dependent cadherin-regulated cell–cell cohesion by interacting with TRPM8 channels to increase transdermal penetration. Terpenes serve as permeation enhancers in the invasome that increases fluidity or flexibility with the phospholipid bilayers. Invasomes have the same structural components as liposomes except with terpenes in their structure. Oils can also work as permeation enhancers and can work with many nutrients such as terpenes and vitamins to promote the entry of macromolecules through the skin.
3.5 Surfactants
Surfactants can improve nutrient penetration into the skin by interacting with the skin lipid lamellar structure. Of the permeability enhancers, surfactants offer the least irritation but also have the smallest penetration effect likely due to their lower critical micelle concentration. Surfactants are often added to formulations to improve nutrient solubility. Non-ionic surfactants cause a slight decrease in the peak intensity at q ~ 0.1 Å−1, indicating low degree disruption on the stratum corneum structure, while anionic surfactants cause a new peak to appear at q ~ 0.2 Å−1, suggesting that anionic surfactants blend into skin lipids to form new lamellar structures. One surfactant, Tween-80, can slightly increase the permeation of nutrients in the skin and improve the thermodynamic activity of nutrients. Compared with ionic surfactants, non-ionic surfactants typically exhibit only a slight enhancement of skin permeability, which may be because non-ionic surfactants induce less skin structural disorder than ionic surfactants. However, ionic surfactants can cause skin irritation and damage, so there is less interest in the use of these materials.,
4 CARRIER SYSTEMS
4.1 Liposomes
Liposomes are phospholipid-based spherical vesicle structures and can encapsulate lipophilic, hydrophilic and amphiphilic nutrients due to their bilayer structures (Figure ). The skin penetration mechanism used by liposomes is unclear, but there are several possibilities: (i) liposomes remain on the surface of the skin and then break, allowing nutrients to diffuse freely into the skin; (ii) liposomes can fuse with skin lipids, leading to early release of nutrients from the liposomes before reaching deeper skin layers and (iii) intact liposomes permeate and enter the skin (Figure )., Liposome occlusion may improve skin hydration and allow penetration by disruption of skin lipid structures for the penetration of nutrients into different skin layers. Liposomes have been used to deliver various nutrients, such as vitamins. Liposomes can significantly enhance the stability of vitamin D3 and increase retention of vitamin D3 in the skin compared with administration of vitamin D3 solution. Vitamin D3 liposomes can restore the structure of photoaging skin and stimulate the skin to produce new collagen fibres, which can significantly improve skin appearance. However, the mechanisms remain unclear, and calcipotriol penetrates the skin better than the lipid component of the liposomes.
FIGURE 4
Schematic structure of the different types of carrier systems.
FIGURE 5
Approaches to overcoming skin barrier to transdermal nutrient delivery include lipid and/or surfactant based-carriers (liposome, ethosome, SLN, NLC, ME, nanoemulsion), dendrimer, MN, ultrasound device, iontophoresis device and jet injector.
The smaller vesicle size of liposomes will promote permeation behaviour. The deposition of nutrients into the deep skin layers can be affected by lipid composition, thermodynamic properties, particle size and surface charge in liposome formulations. Liposomes with a mean volume diameter of 40 nm significantly promote antibody production compared with albumin solution and liposomes with a mean volume diameter of 130 nm, with greater penetration and accumulation of the 40 nm elastic liposomes compared with the 130 nm. Thus, nano-liposomes loaded with nutrients are expected to improve permeation and stability for delivery. Although liposomes have been widely used, they have some disadvantages, such as toxicity and lower stability at different pH. For this reason, researchers have looked for other carrier systems, as described in Table .
TABLE 1. Carrier systems for transdermal nutrient delivery.
| NUTRIENTS | CARRIER TYPE | SKIN TYPE | REF. |
|---|---|---|---|
| Hyaluronic acid | Liposomes with sponge Haliclona sp. spicules | Porcine skin in vitro, mice skin in vivo | |
| Growth factor | Liposomes | Porcine skin in vitro | |
| Polar tetrapeptide PKEK | Microemulsion | Human skin in vitro | |
| Growth factor | Microemulsion | Rat skin in vivo | |
| Carvacrol | Microemulsion | Piglet skin in vitro | |
| Silibinin and epigallocatechin-3-gallate | Dendrimers | Rat skin in vitro | |
| Vitamin E and caffeine | Transfersomes, ethosomes and transethosomes | Pig skin in vitro | |
| 3-O-cetyl ascorbic acid and tocopherol acetate | Phospholipid nanoparticles | Pig skin in vitro | |
| α-tocopherol | Nanoemulsion | Rat skin in vitro | |
| Vitamin D3 | Nanostructured lipid carriers | Rat skin in vitro | |
| Progesterone, α-tocopherol and lycopene | Microemulsions | Porcine skin in vitro | |
| Vitamin K1 | Nanoemulsions | Porcine skin in vitro |
4.2 Ethosomes
Ethosomes are lipid-based vesicular nanocarrier systems containing a very high percentage of ethanol and can change the regular and close arrangement of stratum corneum lipids. Compared with liposomes, ethosomes have better biocompatibility and higher permeability, and they have been explored for the delivery of molecules to deeper skin layers given their advantages. These systems can entrap a wide range of nutrients, including hydrophilic, lipophilic, and high molecular weight entities. Thymosin β-4, a macromolecular protein with good physicochemical properties, can be effectively administered by transdermal absorption using ethosomes. Compared with the free thymosin β-4 group, thymosin β-4 in an ethosomal gel exhibited a superior therapeutic effect, with cumulative amounts within 5 h 1.67 times higher and wound healing time half of that without ethosomes. Therefore, ethosomes are quite promising for the transdermal administration of macromolecular protein nutrients.
4.3 Dendrimers
Dendrimers are three-dimensional nanoparticles and synthetic macromolecules with definite composition and structure. Dendrimers are widely used as transdermal carriers for nutrients such as proteins and peptides and are radially symmetric. A central atom covalently combines with other atoms to form the inner core structure of dendrimers, and the highly branched external composition forms the dendrimer structure. These branches promote the formation of cavities and nutrients can be incorporated into these cavities. Several factors influence nutrient delivery and skin penetration including size, molecular weight, surface charge and hydrophobicity. Pretreatment of skin with dendrimers alters the skin barrier due to interactions of the dendrimers with the negatively charged phosphate head groups of skin phospholipids, enhancing the permeation of silibinin and epigallocatechin-3-gallate compared to that achieved with passive diffusion. Dendrimers can also be used as vehicles for bioconjugates with prodrugs or as hosts for encapsulated or adsorbed drugs. Bioconjugates of folate, biotin, riboflavin, cholic acid and phosphorylcholine have been synthesized and tested with dendrimers, and increased cellular uptake of the drug has been reported with dermatological application.
4.4 Lipid nanoparticles
Lipid nanoparticles include solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) that differ in their lipophilic matrix structure. SLNs are mainly composed of solid lipids, while NLCs are composed of solid and liquid lipids. Compared with SLNs, NLCs increases formulation stability. Similar to liposomes, SLNs and NLCs use occlusion to enhance skin penetration. The lipid nanoparticles attach to the skin surface and accumulate, fuse and deform under capillary force, and form a membrane on the skin surface that can reduce moisture loss and increase the hydration of the skin for improved permeation., Nanoparticles with fuorescence probes can accumulate in hair follicles and distribute over a skin section after 1 h. They are then phagocytosed and taken into cells by the endosomal-lysosomal route. Nanoparticles can disturb keratin structure to ultimately reduce the stratum corneum barrier function. Additionally, nanoparticles containing triptolide can effectively suppress the expression of skin reaction factors (IL-4, IL-6, IL-8, MCP-1 and IFN-γ in HaCaT cells).
Lipid nanocarriers can also improve the stability and encapsulation efficiency of nutrients. Lipid nanocarriers significantly protect all-trans-retinoic acids from photodegradation and are non-toxic to fibroblast cells. Hydrogel-based NLC can delay the release of carotenoids, suggesting this material should be an efficient carrier for slow release. Hydrogel-based NLCs containing carotenoids for the treatment of skin inflammation also slightly inhibit the expression of inflammatory cytokines in both in vitro and in vivo tests, with a superior in vivo anti-inflammatory effect. Nanoparticles based on polysaccharides, such as chitosan, β-cyclodextrin, carboxymethylcellulose and propylstarch, have good biodegradability, biocompatibility, adhesion and enhanced mucosal permeability and interact with the skin to promote transdermal nutrient diffusion by fluidizing the epidermal lipid and protein domains.
4.5 Microemulsions
Microemulsions are optically isotropic systems that are mixtures of an oil phase, a surfactant, a co-surfactant and an aqueous phase, with a droplet diameter typically <100 μm. MEs have many advantages, such as increasing solubility of molecules, small droplet size, thermodynamic stability, easy preparation and amplification and high molecular loading capacity., MEs are widely used in cosmetics and cosmeceuticals. The lipid bilayer structure of the stratum corneum is dissolved or disturbed by permeation enhancers such as surfactants or lipids in MEs, to overcome the skin barrier function and open pores or channels to deliver nutrients through and into the skin. The high water phase content and low surfactant content of oil/water (o/w emulsions) have higher flux than that of w/o emulsions. MEs are formed by simple component mixing and do not require the high shear conditions that are commonly used to form ordinary emulsions or macro-emulsions. The type of oil phase also affects the size of the single-phase region in the phase diagram and the overall skin penetration of molecules. The skin penetration of lycopene significantly reduces when the acyl chain length of mono-glyceride is increased from 8 to 12 carbons, but the opposite result is found when the acyl chain length is increased further from 12 to 18 carbons.
4.6 Nanoemulsiosn
Nanoemulsions are heterogeneous, thermodynamically stable, isotropic systems composed of two immiscible liquids stabilized by the interface layer of an emulsifier and coemulsifier. The droplet size [oil in water (o/w) and water in oil (w/o)] if nanoemulsions are typically 20–200 nm., Nanoemulsions as novel nanocarriers can improve the bioavailability, absorption and bio-membrane permeation of molecules, and can also provide value-added delivery systems for nutraceutical and dietary supplements. A nanoemuslion with lemon essential oil was shown to significantly improve the permeability of vitamins with a reversible effect on the skin and was especially suitable for lipid-soluble vitamins such as a-tocopherol with modestly intrinsic bioavailability. Compared to MEs, nanoemulsions have better physical stability and improved penetration effect on the skin surface. Nanoemuslions can promote the penetration of nutrients into the stratum corneum, where they can diffuse deep into the dermis via the intercellular pathway. The transdermal mechanisms of nanoemulsions can vary with carrier characteristics and the use of penetration enhancers. Droplets with smaller particle sizes have a larger dissolved interface area due to larger surface area, increasing molecular content at the target site given the closer cutaneous contact of the nanosized droplets. Additionally, the aqueous phase and chemical permeation enhancers of nanoemulsions can cause swelling of keratinocytes in the stratum corneum, disorientation of the lipid bilayer, and fluidization of stratum corneum lipids, so the mechanism is generally alteration of the stratum corneum structure., Compared to positively charged nanocarriers, negatively charged nanocarriers have improved molecular accumulation and permeation due to repulsion, so the use of negatively charged nanocarriers allows more molecules into the skin.
5 PHYSICAL TECHNIQUES
5.1 Sonophoresis
Sonophoresis is the use of ultrasound to transport molecules through or into the skin (Figure ). Lw-frequency sonophoresis (~ kHz) may induce more effective transdermal enhancement than high-frequency sonophoresis (3–16 MHz). The mechanisms of ultrasound stimulation are not completely understood, but permeability of the skin is likely enhanced by a variety of mechanisms such as cellular-level effects, acoustic cavitation, diffusion effects and shock waves. Ultrasound effectively increases the transdermal penetration of low molecular weight nutrients. For example, the skin penetration enhancement of niacinamide and retinol with sonophoresis treatment improved 402% and 292%, respectively. The application of ultrasound to increase skin permeability may improve lipid mobility by the intracellular pathway. Ultrasound treatment can overcome the size-dependent molecular skin barrier, with better transport of macromolecules than the passive transport of micromolecules. Increased skin penetration of miR-197 was achieved with ultrasound pre-treatment, resulting in significantly reduced psoriatic pathological markers and changes in the levels of key cytokines, IL-22RA1 and IL-17RA. The different physical techniques for the transdermal absorption of nutrients are described in Table .
TABLE 2. Physical techniques for transdermal nutrient delivery.
| NUTRIENTS | PHYSICAL TECHNIQUES | SKIN TYPE |
|---|---|---|
| Insulin | Dissolving polymer MNs | Porcine skin in vitro, mice skin in vivo |
| Bovine serum albumin, ovalbumin and lysozyme | MNs | Porcine skin in vitro, mice skin in vivo |
| Bovine serum albumin | Dissolving MNs | Porcine skin in vitro |
| Acetyl-hexapeptide 3 | MNs | Porcine skin/human skin in vitro |
| IgG | Dissolving MNs | Rat skin in vitro |
| Ovalbumin | MNs and iontophoresis | Mice skin in vivo |
| Vitamin C | Iontophoresis | Human skin in vivo |
| Glutamic acid | Ultrasound and iontophoresis | Mini-pig skin in vitro |
| Ascorbic acid | Dissolving MNs | Porcine skin, reconstructed human full-thickness skin |
| Ascorbic acid and vitamin A | Dissolving MNs | White guinea pigs in vivo |
| Vitamin K | MNs | Porcine skin in vitro |
| Vitamin D3 | Coated MNs | Porcine skin in vitro |
5.2 Iontophoresis
Iontophoresis is a physical permeation enhancement that is performed by the application of an electrical field. Drug delivery is increased with a low current density and the repulsive forces between molecules of the same charge help push the molecules into the skin. Iontophoresis works through two main mechanisms: electroosmosis and electromigration. In electroosmosis, drug delivery occurs electrically through solvent flow. In electromigration, charged ions are attracted to the oppositely charged electrode, with charge transport related to the strength of the electric field and treatment time. Electromigration is considered the predominant transport mechanism. The transappendageal pathway is key to transdermal delivery by both electroosmosis and electromigration, which has the potential to deliver macromolecules across the skin. Iontophoresis greatly enhances the permeability of vitamin C in the skin and improves the skin texture and pore tightening. Iontophoresis can also increase the skin penetration of small peptides and peptide drugs, up to 15- and 22-fold. However, iontophoresis typically needs to be combined with other technologies to be more effective. Interferon α-2b protein (19.27 kDa) is unable to pass through intact skin, either by passive diffusion or iontophoresis treatment, but can be passively delivered by micropores in vivo in rats. Iontophoresis-assistance increases the deliver of protein through microporated skin, with more proteins delivered into systemic circulation. In particular, the penetration rate of glutamic acid increased to 240% using sonophoresis and iontophoresis simultaneously. This combined effect results from the simultaneous effects of ultrasound and iontophoresis to induce a structural change in the stratum corneum and promote a solvent flow, respectively.
5.3 Microneedle-based transdermal delivery
Microneedles (MNs) have attracted much recent interest, and are devices containing micron needle-like protrusions. These protrusions can bypass the skin barrier by creating micron-sized pores to deliver large and hydrophilic molecules into the skin. Insertion of MNs is painless, with little damage to tissue because they only penetrate the non-nervous part of the epidermis, avoiding dermal nerves or blood vessels. MNs can improve patient compliance because they may be less anxiety-inducing than conventional hypodermic needles. MNs have shown great potential for transdermal delivery of nutrients, which have gained considerable attention over the past two decades. The solid MNs are the first MN used to enhance transdermal molecule delivery, and the nutrients are passively transported through microcatheters using MNs formed in the skin as a molecular absorption channel into the skin. Solid MNs can be made of different materials, including silicon, tungsten and polylactic acid, and successfully deliver some proteins such as bovine serum albumin, ovalbumin and calcein. However, the application of solid MNs is limited due to the need for a two-step application process and the fragility and non-biocompatibility of some materials.
MNs can be easily modified, with coated, hollow, dissolving, and hydrogel versions developed over the past two decades (Figure ). Coated MNs are fabricated by coating the tips of MNs with the nutrient formulation, and the nutrients are dissolved in the tissue after the coating MNs are inserted into the skin, which is mainly used for the delivery of macromolecules. The amount of molecules delivered is limited due to the limitations of the coating surface. The hollow MNs continuously deliver nutrients into the skin through the needle bores, allowing for more nutrient loading as nutrients are packed in the interior of the MN. However, hollow MNs may cause blockage due to the open needle bores. More important to note is that these types of MNs may raise safety concerns after insertion into the skin. To overcome this situation, dissolved microneedles have been developed. Dissolving MNs are prepared by mixing the nutrients with soluble and biocompatible polymers including hyaluronic acid, pullulan, sodium alginate and carboxymethyl cellulose. The dissolving MNs are inserted into the skin, the needle dissolves in the skin, and the nutrients are released from the matrix. The dissolving MNs not only deliver nutrients effectively but also have good cellular compatibility. In addition, the dissolving MNs exhibit low skin bacterial infection, less skin injury and no infection or inflammation in the body., Hydrogel-forming MNs can absorb a large amount of interstitial fluid and swell in the skin through the molecule-containing reservoir, which is different from dissolving MNs. Then the molecule-containing reservoir dissolves and molecules diffuse into the skin through the swollen MNs conduits. Molecules are transferred through the micro-conduits by MNs into the skin or further into systemic circulation through the dermal capillary network.
FIGURE 6
Approaches to overcome skin barrier to transdermal nutrients delivery associated with microneedles (MNs). MNs are first applied to the skin (A) and then used for nutrient delivery (B).
One significant limitation to transdermal delivery of therapeutic proteins is protein instability under adverse conditions. For example, insulin may undergo hydrolysis or suffer protein degradation when delivered through transdermal mechanisms. Surfactants such as dextrin can be added to the MNs to stabilize the structure of therapeutic proteins. MNs can improve the structural integrity of therapeutic proteins for better activity of therapeutic proteins. Insulin/poly-L-glutamic acid coatings are immediately dissociated and the insulin is released rapidly when coated MNs are inserted into the skin of diabetic rats skin, inducing the hypoglycaemic effect. The pharmacodynamic and pharmacokinetic characteristics of coated MNs are comparable to those of insulin administrated by intravenous injection. Drug delivery through MNs has been demonstrated using different polymer-antibody conjugates for the treatment of skin-related diseases. Peptides coupled with copper can effectively inhibit the REDOX activity of copper, and after introduction by MNs, the non-toxic copper can enter systemic circulation, suggesting this may be a potentially useful tool for mineral delivery.
MNs have also been used in combination with other transdermal delivery methods. For example, ultrasonic-assisted MNs use ultrasound stimulation to vibrate the needles, and the continuous electric field generates electrostatic force to improve nutrient penetration. Zheng et al. developed a wearable iontophoresis-driven MN patch with the strategy of press-poke, ion-driven delivery and immune response. Also, this patch could effectively deliver ovalbumin macromolecules, then induce an effective immune response, even stronger than traditional injection. Qi et al. devised the electro-responsive based on thiolated silk fibroin-assisted MNs to deliver insulin which could effectively control blood glucose before and after feeding. Overall, a combinatorial technique for transdermal drug administration is an effective method with high bioavailability for delivering different kinds of nutrients.
6 CHALLENGES AND PERSPECTIVES
Although the transdermal absorption of nutrients has made some progress in the treatment of diseases, cosmetic applications and nutritional supplements, there are still some problems to be solved. At present, the main challenges to greater application of transdermal delivery strategies are insufficient safety, a lack of clinical trials, the high industrialization cost and a lack of quality control standard system. Transdermal delivery of nutrients still faces many drawbacks associated with technique, for example, the carrier or physical technique can effectively deliver nutrients to the body, but the method cannot directly determine the in vivo stability of the nutrient matrix. Also, the underlying mechanisms of transdermal delivery remain incompletely understood due to the complex interactions of enhancers, nutrients, and skin, as well as chemical-specific variation. Furthermore, transdermal delivery of nutrients is safe in the short term, but long-term safety has yet to be evaluated. For example, nanocarriers do not trigger inflammation on the skin and can retain insulin structural integrity after release. However, there has been no research to address whether long-term use of nanoparticles is harmful to the skin. The repeated application of polymer MNs could potentially lead to the distribution and deposition of polymer throughout the body, hepatic accumulation, and/or a build-up of polymer in the dermal tissue, so this issue must be addressed. The application of pro-drugs is another chemical technique that can facilitate transdermal delivery of nutrients. Pro-drugs are covalently attached to the inert pro-moiety to overcome the skin barrier. A peptide coupled with copper can be transported into systemic circulation in a non-toxic form by inhibiting the REDOX activity of copper. However, it is unclear whether repeated application and internal release of the copper peptide could result in copper poisoning. Although students have been done in animal models, the degree of enhancement may differ between animal and human skin, so formulations may need to be adjusted for clinical testing. In addition, the industrialization cost is high and it is difficult to carry out large-scale production. The inconsistencies in vivo and in vitro also seriously hinder the process of industrial production. In many countries, the quality control standard system for transdermal delivery of nutrients has not been established, which is also an important reason for hindering the industrialization process. Therefore, further research is needed to fully understand their transdermal mechanisms and evaluate the possible safety impact for better exploitation of their inherent properties. Even though the efficacy of many tools has been demonstrated in vitro and in vivo, as well as in clinical studies, more studies are required before the large-scale integration of this technique into practical application. Investigation of potential industrial-scale applications and their effect on the stability and functionality of the encapsulated nutrients should be further carried out.
7 CONCLUSION
Nutrients not only maintain the normal operation of the body but also are widely used in the diagnosis, prevention and treatment of various diseases. In this review, we surveyed transdermal delivery of nutrients. The transdermal delivery can increase the bioavailability and targeting specificity of nutrients, maintenance of stability and sustained nutrients release. Due to their unique structural and functional properties, nutrients are widely applied as carriers and have synergistic therapeutic effects with carriers. Compared to passive penetration of the skin, the application of chemical enhancers, carrier systems and physical techniques show great potential to overcome the skin barrier and enhance penetration of nutrients. Highly efficient and safe enhancers or combinations of enhancers have been demonstrated. Carrier systems, especially physical technique-assisted ones, display great potential for the treatment of skin diseases with significant versatility in the loading of hydrophilic/hydrophobicity molecules, controlled/sustained release and enhanced skin penetration capability. However, current the application of transdermal nutrient delivery strategies is limited by insufficient safety, a lack of clinical trials, the high industrialization cost and a lack of quality control standard system. Further experiments are needed to assess any potential short- and long-term side effects associated with carrier systems or physical techniques. Long-term efficacy and safety must also be evaluated in clinical research. As additional systems are developed, emphasis should be placed on those that can be translated into clinical applications and potential industrial-scale applications, which can provide significant economic and patient benefits.
