In 1986, the Christian Dior brand first incorporated liposomes in cosmetics as part of its Capture line. Since that time, many cosmetic manufacturers followed suit by incorporating nanotechnology into their formulations. Nanoparticles are defined as particles ranging from 1 to 100 nm, although this definition may be altered to account for particles larger than 100 nm. Some researchers also call particles between 100 nm and 1 µm nanoparticles because they exhibit size-related properties that differ significantly from those observed in bulk materials. A number of nanoparticles such as metal oxide nanoparticles, polymeric nanocapsules, fullerenes, nanocrystals, solid lipid nanoparticles and nanostructured lipid carriers have been investigated for cosmetic applications.1, 2
Nanoparticles in cosmetic preparations are found to: improve the stability of various cosmetic ingredients such as unsaturated fatty acids, vitamins or antioxidants by encapsulating them; increase the efficacy and tolerance of UV filters on the skin surface; make the product more aesthetically pleasing; and enhance the penetration of certain active ingredients to the epidermis. This article reviews various forms of nanoparticles used in the cosmetics industry and discusses their properties, mechanisms of action and possible health effects.
Metal Oxide Nanoparticles
The most widely used metal oxide nanoparticles in cosmetic preparations such as lotions and sunscreens are titanium dioxide (TiO2) and zinc oxide (ZnO). They are efficient, photostable UV filters that absorb UVB and UVA radiation and re-emit it as less damaging UVA through visible fluorescence or heat.3 Formulations that utilize TiO2 or ZnO as the only active sunscreen agents provide photoprotective properties and reduced risk of irritation compared to other sunscreen ingredients; avobenzone, for example, offers protection against UVA rays but it can also be a skin irritant.4 An ideal sunscreen formulation must efficiently block UVA/UVB radiation, be non-toxic and be aesthetically appealing. Uncoated TiO2 absorbs photons of light and emits an excited electron, which can be transferred to free radicals and absorbed into dermal layers, resulting in oxidative damage.5 To stop the formation of reactive oxygen species (ROS) and prevent the agglomeration of particles, TiO2 and ZnO are generally coated with aluminum oxide, silicon dioxide or silicon oils.6
While sunscreens formulated with traditional mineral particles will have a noticeable white, chalky appearance, mineral titanium dioxide-based and zinc oxide-based nanomaterials allow for sunscreens that are less white at the skin surface due to their small size. The whiteness of TiO2 and ZnO were determined and compared with reflectance density of dried coatings on a black background of the two particulates at varying concentrations.7 The results found that a ZnO nanoparticle formulation appeared less white than TiO2 at all concentrations, even nano-sized TiO2.
Transparency can be achieved by reducing nanoparticle size; the transparency threshold is the point at which particles have been made small enough to achieve transparency. For ZnO nanoparticles, this threshold is 30 nm,8 and should be even smaller for TiO2. Further reduction of the nanoparticle size entails the risk of rendering the nanoparticles skin penetrable, with potential toxic consequence.
Many sunscreen products contain nanoparticles of ZnO and TiO2. They provide both dispersibility and attractive skin feel. To enhance their efficiency, the standard ZnO and TiO2 UV protection systems can be modified. For example, carnauba wax-loaded nanoparticles have been shown to improve the sun protection factor of TiO2 in aqueous media without the use of complex formulations.9 This could be due to the mechanism of electron trans-fer taking place from the π delocalized organic compounds, i.e., cinnamates, to the empty conductive bands of the TiO2 aggregates. This transfer may be more effective when the TiO2 crystals are encapsulated or bonded by the carnauba wax and not when these crystals are attached to the surface of the wax particles. A recently launched inorganic UV absorbera incorporated low levels (0.67%) of manganese (Mn) into TiO2 to overcome any problems with free radical generation. The manganese acts to trap any charges excited by UV light absorption within the particle, thus practically eliminating the opportunity for the charges to move to the surface and create damaging free radical species.
In relation, concerns have been raised regarding the possible systemic absorption of TiO2 and ZnO nanoparticles, which may occur as a consequence of nanoparticle contact with human skin.10–14 Ideally, nanoparticles should remain on the skin surface or in the uppermost layer of skin, the stratum corneum (SC). Penetration into deeper parts of the skin down to the living cells should be avoided. Typical experiments testing the penetration of nanoparticles into skin employ a tape stripping technique, in which SC is consecutively removed.15
The nanoparticle penetration profile is the plotted by analyzing the amount of SC and the amount of nanoparticles removed with each tape strip. The thickness of the skin strip relative to the whole thickness of the horny layer can be determined via different methods, including transepidermal water loss measurement and spectroscopic assay.16 In addition, multiphoton imaging of nanoparticle penetration is even more advantageous than tape stripping due to its noninvasive nature.17 Direct imaging of the sunscreen nanoparticles in skin in vivo could address concerns for public safety. Further, some research shows that, for mineral sunscreens, TiO2 does not seem to penetrate the epidermis,18 and ZnO has limited systemic absorption, if any.19
Polymeric nanocapsules are spherical hollow structures into which active ingredients are encapsulated, and surrounded by a polymer shell to either protect such sensitive substances from oxidizing or degrading—which typically occurs when they are exposed to oxygen, light or heat; to control their burst or release, as in the case of nutraceuticals, fragrances and vitamins; or to avoid incompatibilities between ingredients. The most widely used polymers to create nanocapsules include poly-(ε-caprolactone) (PCL), poly-L-lactide (PLA), poly-(glycolic acid) (PGA), poly-(lactide-co-glycolide) (PLGA), poly-(alkylcyanoacrylates), poly-(butylcyanoacrylates), poly- (ethylcyanoacrylates), poly-(alkylene adipate), polyvinyl acetate (PVA), cellulose acetate phthalate, cellulose acetate butyrate and poly-(ε-caprolactone)-block-poly-(ethylene glycol).
The core of a nanocapsule is often filled with oil, which can dissolve lipophilic active ingredients including: α-tocopherol and α-tocopherol acetate, triglycerides rich in linoleic and/or linolenic acid(s), pentaerythritol tetra(2-ethylhexanoate), clofibrate, tocopherol linoleate, fish oil, hazelnut oil, bisabolol, farnesol, farnesyl acetate, ethyl linoleate and ethylhexyl para-methoxycinnamate.20 These nanocapsules are considered to be more robust and stable compared with liposomal formulations, as polymeric nanocapsules are held together by strong covalent bonds.
Nanocapsules can be functionalized or modified to achieve desirable properties and meet specific aims. In some cosmetic products such as perfumes, long-lasting fragrance is desired, so to prevent fragrance from being diluted or washed off, it can be encapsulated into nanocapsules, the surface of which are modified to have a high cationic charge density. Since the skin surface has a net negative charge under normal physiological conditions, the cationic nanocapsules have a strong affinity to skin, which improves the adhesion of fragrance on skin.21
Another nanocapsule modification is a response to environmental changes and release of the payload accordingly. Hu and Liu incorporated a hydrogel into a facial mask designed to respond to temperature.22 When the temperature increased, the hydrogel shrunk and released the encapsulated nutrients.23 The researchers also designed smart fabrics with antibacterial properties that responded to external stimuli by turning from semi-transparent to opaque.
Nanocapsules have also been intensively investigated as sunscreen vehicles. Polymeric nanocapsules can form a protective film on the skin surface and retard penetration of the active sunscreens into the viable tissue. Polyvinyl alcohol 10,000 Mw (PVA), for instance, was substituted with various fatty acids to generate different lipophilicity24 and the sunscreen filter benzophenone-3 (oxybenzone) was encapsulated in a series of PVA-acid nanocapsules. The ability of the PVA-fatty acid nanocapsules to prevent the transport of benzophenone-3 across porcine ear skin in vitro was then tested. Results showed the highest degree of transport occurred when the sunscreen was applied in a solution without the nanocapsules.
In addition, PVA-fatty acid nanocapsules significantly decreased the percutaneous absorption of benzophenone-3. This result was promising, as the sunscreen should remain on the skin surface to protect the skin from UV radiation. Furthermore, nanocapsules with a higher degree of substitution prevented absorption more efficiently. In addition to benzophenone-3, nanocapsules have been used to encapsulate octyl methoxycinnamate (OMC)25, 26 and octyl salicylate. It was reported that OMC-loaded cellulose acetate phthalate nanocapsules delivered less OMC into the SC than a conventional nanoemulsion.25
Generally, polymeric nanoparticles are unable to cross intact SC. Wu and Guy et al. determined the disposition and penetration of polystyrene or poly(methyl methacrylate) nanoparticles (< 100 nm) and an associated lipophilic model active component on and within porcine skin following topical application.27 The polymers were covalently bound with the fluroescent probes fluorescein methacrylate and Nile Red, which served as a model active. Under confocal laser scanning microscopy, the two fluorophores differentiated the fate of the polymeric vehicle on and within the skin from that of the active. The results demonstrated the polymeric nanoparticles did not penetrate beyond the superficial SC; interestingly, they also showed some affinity for hair follicles and released the active into the skin. This lack of penetration of the polymeric nanoparticles across intact SC is perhaps not surprising since even if the intercellular channels in the SC are ~ 100 nm wide, it seems unlikely for a ~ 50 nm nanoparticle to traverse the SC transcellularly because the intercorneocyte space is not empty but rather filled with multiple lipid bilayers. The rigidity and ability to form a film of polymeric nanoparticles further undermines the possibility of their permeation across the SC.27
Fullerene is a carbon allotrope. Spherical fullerenes are known as “buckyballs” and consist of 60 carbon atoms (C60). In the past few years, fullerene (C60) and its derivates have been used as active compounds in the preparation of skin rejuvenation formulations. They are incorporated for their wide range of biological activities, including potent ROS scavenging and potential antioxidant functions.28 Free radicals, such as superoxide anion, hydroxyl radicals and lipoperoxide, are produced in abundance following exposure to UV radiation. Due to their high reactivity, free radicals attack and destroy nearby living tissues, thus Burangulov et al. developed a cosmetic composition comprising fullerene clusters in a cosmetically acceptable carrier to prevent or retard free radical oxidation processes in the skin.29 Fullerenes can remove these free radicals; however, there is a notable safety concern regarding the use of fullerenes in cosmetic products as some reports show that fullerenes may cause brain damage in fish,30 kill water fleas and have bactericidal properties.31
Nanocrystals, which were invented in the 1990s, are a novel way to deliver hydrophobic drugs and cosmetic actives but have limited bioavailability due to their limited absorption as a result of dissolution velocity,32 which is increased by their increased surface area. Moreover, this approach can produce amorphous materials that possess a higher saturation solubility than crystalline materials.
Several hundred to tens of thousands of atoms aggregate to form a “cluster” with a typical size of about 10—600 nm, thus they must be stabilized to prevent the formation of larger aggregates. The two major processes used to produce nanocrystals are ball milling33 and high pressure homogenization,34 either in water or non-aqueous waterreduced media. Combinations of other technologies such as spray-drying and lyophilization with high pressure homogenization can produce nanocrystals with improved properties, e.g., faster production, smaller size and improved physical stability.35 Nanocrystals currently are produced via high pressure homogenization for dermal as well as oral and intravenous routes.36
Nanocrystals can increase the penetration of a poorly soluble cosmetic active into the skin because the increased saturation solubility of actives in the water phase leads to an increased concentration gradient between formulation and skin, thus promoting passive penetration. Actives penetrating from the water phase into the skin are rapidly replaced by the active molecule dissolving from the nanocrystals in the formulation.32
The process to incorporate nanocrystals into cosmetic products is straightforward. Nanocrystals are first dispersed in water, then the nanosuspension is admixed with a cosmetic product. Examples of cosmetics formulated with nano-sized crystals include creams containing rutin and hesperidin. Rutin is a poorly water-soluble plant antioxidant, thus rutin glucoside, a water-soluble rutin derivative, is typically used as an alternative. As described by one patent, after rutin was formulated as crystals and incorporated into creams, the rutin nanocrystal formulations were compared with creams containing rutin glucoside. Results showed the rutin nanocrystal formulas possessed 500x more active material and bioactivity than the rutin glucoside cream, based on the measured SPF.37
Solid Lipid Nanoparticles and Nanostructured Lipid Carriers
Lipid nanoparticles are comprised of Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs), depending on their lipid matrix organization.38, 39 SLNs are sub-micrometer in size with a lipid matrix that is solid at body temperature, and their matrices are perfect crystal lattices. The lipids employed include triglycerides, partial glycerides, fatty acids, steroids and wax. Different emulsifiers have been used to stabilize SLN dispersions, including poloxamer 188, polysorbate 80, lecithin, polyglycerol methylglucose distearate, sodium cocoamphoacetate and saccharose fatty acid esters.38
In contrast, NLCs are produced by mixing solid lipids with liquid lipids. Their matrices have a distorted structure, resulting in more space to load actives.40 NLCs also do not expulse actives during storage like SLNs due to their perfect crystal lattice matrix. The high loading capacity and improved stability of NLCs make them superior to SLNs in cosmetic applications.
Many different techniques can be used to produce lipid nanoparticles, including high pressure homogenization, emulsification-solvent evaporation, emulsification-solvent diffusion, solvent injection and phase inversion. Among them, high pressure homogenization is widely used in industry. It has many advantages over the other methods; it is easy to scale-up, it requires no organic solvents, and it has a short production time. Lipid nanoparticles can be produced by either the hot or cold high pressure homogenization technique.41
Similar to polymeric nanocapsules, the incorporation of chemically labile active ingredients such as coenzyme Q10, retinol and tocopherol into SLNs and NLCs offers protection against decomposition.42–47 It has also been found that the release of actives from SLNs and NLCs can be manipulated to achieve either a burst release or sustained delivery over a prolonged period of time.48 The formulation of topical products containing SLNs and NLCs is identical. Products can be obtained with SLNs and NLCs in three ways: by admixing SLNs/NLCs to existing products, by adding viscosity enhancers to the aqueous phase of SLNs/NLCs to obtain a gel, and by direct production of a final product containing only nanoparticles in a one-step process.
After topical application, SLNs and NLCs can form an occlusive adhesive film on the skin surface, which prevents skin dehydration.49, 50 For example, in one study, an SLN formulation containing tocopherol acetate was found to be twice as occlusive as an emulsion with identical lipid content.50 Approximately 4% of lipid nanoparticles with a diameter of ~ 200 nm should theoretically form a monolayer film when 4 mg of formulation is applied per area.51 The occlusive feature of SLNs makes them attractive to use in sunscreens52 because the lipid film formed at the skin surface retards the penetration of molecular sunscreens, thus enhancing the UV-resistant capacity and reducing potential toxicity relative to conventional formulations.
The first two commercial products containing NLCs were a cream and a serumb launched in 2005. The concentrations of coenzyme Q10 were 0.5% in the cream and 0.1% in the serum. An in vivo test showed that incorporation of coenzyme Q10 into the NLC suspensions of these products resulted in more penetration of the active into the skin, as compared with a neutral-oil o/w emulsionc with identical coenzyme Q10 content.40 Within three years after the introduction of the first two products, additional cosmetic products containing lipid nanocarriers were launched.
On the other hand, despite some R&D and evaluation for the delivery of cosmetic active agents, few commercial products containing SLNs have appeared on the market. Before this novel carrier system is introduced to the market, additional research is required to provide a better understanding of the production of SLNs, including safe excipients, long-term stability and large-scale production; the effect of surfactants used for certain lipid modifications; and how lipid nanoparticles interact with the lipids of the SC and affect active delivery.53
The cosmetic industry has made efforts toward the development of nanotechnology, evidenced by the numerous nanotechnology patents held by cosmetic companies. In addition, the introduction of nanoparticles into cosmetic products has been an economic success. Depending on their intended use, nanoparticles can be designed to enhance or retard the penetration of active ingredients into the epidermis or deep dermis and beyond. The future trend for delivering actives may be improved nanoparticulate systems that can deliver their active molecules via triggered-release mechanisms.
Since cosmetic products are for external use and cannot make substantiated medical claims, they are not often subject to US Food and Drug Administration approval. In addition, the time from invention to market for cosmetic products is much faster than for drug delivery systems. Thus, with the growing commercialization of nanotechnology, consumer exposure via cosmetic products and potential adverse health effects are a concern. Therefore, further work is required to understand and evaluate the behavior and fate of topically applied nanomaterials. Further research, along with better regulation and reporting, will enable consumers to choose products with confidence and, in turn, benefit cosmetic companies.
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This content is adapted from an article in GCI Magazine. The original version can be found here.