Nanocosmeceuticals: facets and aspects

The global cosmetic market prized $532.43 billion USD in 2017 is expected to reach $805.61 billion USD by 2023, with a 7.14% compound annual growth rate. These figures have appealed to the cosmeceutical players for developing new and effective products containing advanced materials. Cosmetics incorporated with pharmaceutical actives, termed as ‘cosmeceuticals,’ are receiving an overwhelming response from cosmetic industry. Nowadays, the implementation of nanotechnology for enhanced effectiveness of cosmeceuticals is witnessing a huge success. These applications include remedies for hair damage, wrinkles, aging and skin dryness. Currently, there is a need to establish regulations and harmonized guidelines for nanotechnology-based products to assess their efficacy, safety and toxicity profiles. This review summarizes current development, applications, safety and regulations of nanocosmeceuticals.


Review
Nanocosmeceuticals Cosmeceuticals (cosmetics + API) Size reduction to nano scale Advantages Disadvantages *Active transport of API *Physical stability *Maximum efficiency *Controlled/targeted drug delivery *Environmental concern *Lack of uniform regulation *Toxicity issues *Absence of data  sized particles are unable to cross the SC layer, the transappendageal route appears to be the dominant pathway for the entry of nanoparticles into the skin ( Figure 2). Additionally, cutaneous penetration of the inorganic and polymeric nanoparticles can be facilitated using various passive and active permeation enhancement methods. The size, morphology, surface features, physicochemical properties of the nanomaterial along with their drug loading efficiency and lamellar arrangement defines the interactions between nanoparticles and skin to outline their delivery routes [18]. Lipid-based vesicular drug-delivery systems are preferred for the skin ailments. The polymeric nanoparticles comprising sunscreen agents permeate into the SC layer to deliver the encapsulated drug into the skin [19]. Inorganic nanoparticles like zinc oxide (ZnO) and titanium dioxide (TiO 2 ) are prime examples of the transparent and cosmetically desirable sunscreens [20]. Metallic/magnetic nanoparticles are useful in cell labeling or skin targeting for early diagnosis of skin ailments. They can passively penetrate the SC layer and hair follicles, reaching up to the stratum granulosum [21]. Quantum dot nanoparticles preferentially accumulate in the hair follicles as well as the upper SC layers. They can penetrate the skin through SC intracellular lipid layers [22].

Nanocosmeceuticals
Nanoparticles are the sub-micron sized particles in the size range of 1-100 nm ( Figure 3) [23,24]. Nanoscience and nanotechnology explores the distinct traits of the materials observed in nanosize. These remarkable traits have  reformed and transformed each and every field of basic and applied sciences [25]. Over the last three decades, nanoparticle-based technology is providing novel solutions to the treatment challenges associated with numerous acute and chronic ailments [26]. The nanoparticulate systems offer targeted delivery, painless remedies, customized therapies and simplified solutions over the conventional therapies [27]. Diverse forms of novel, sub-micron sized drug-delivery systems used in the delivery of cosmeceutical preparations comprise liposomes, nanostructured lipid carriers, solid lipid nanoparticles, niosomes, transferosomes, ethosomes, nanocapsules, nanoemulsions, gold nanoparticles, fullerenes, dendrimers and cubosomes ( Figure 3). These novel forms have been successfully developed and commercialized [27,28]. Nowadays, the use of nanotechnology is increasing steadily in the personal care industry with better entrapment, dispersibility, performance, quality, protection, penetration and patient compliance [29,30].
Liposomes were one of the first colloidal vesicular systems (consisting of single or multiple lipid phosphatidylcholine bilayers) explored in effective skin delivery. Modified lipid-based nano-sized delivery systems such as nanostructured lipid carriers, solid lipid nanoparticles, transferosomes, niosomes and ethosomes have been developed to enhance the skin permeation of various active molecules [18]. Jean et al. investigated stable, transparent, oil-in-water nanoemulsion for hair care [30,31]. This nanoemulsion was prepared using nonionic emulsifying agents and consistency increasing agents like ceteareth-20, ceteareth-12, glyceryl stearate, cetyl alcohol and cetyl palmitate. This nanoemulsion containing heat-sensitive active agents demonstrated a mean particle size in the range of 50-200 nm [31]. Alain et al. prepared stable nanoemulsion using an amphiphilic lipid system, comprising ester or a mixture of esters [32]. Gunjan  tract along with the hydrating and moisturizing effects [33]. Similar studies were carried using transfersomes [34]. Cauchard et al. patented a cosmetic formulation, which released the active agent, an amber extract (0.01 and 5% w/w) in a programmed manner for improving the skin firmness [35,36]. Similarly, many nanocosmetics have been commercialized and readily available in the market (Table 1).

Current regulations for nanocosmeceuticals
In these past years, there are many challenges witnessed in the regulation of the nanoparticulate systems. Numerous studies have been conducted to assess the discrepancies related to the safety of nanomaterials in cosmetics.

FDA
The FDA regulates a large number of products by Federal Food, Drug and Cosmetic Act. Cosmetic products are not directly regulated by the FDA [36]. Currently, cosmetics do not need any prior approval, but efforts must be undertaken to assure safety of cosmetics. It is the manufacturer who must be accountable for ensuring the safety of cosmetic products. In 2006, the FDA created internal nanotechnology task force to regulate the nanoparticle-based products. This step was taken to boost the development of innovative, safe and effective nanomaterials in cosmetic and pharmaceutical sectors [37]. In 2007, amendments were suggested by the FDA; numerous have been executed and several are in pipeline. In 2014, FDA issued three guidelines related to the safety of the nanoparticulate systems in the FDA-regulated products; two of these are associated with the cosmetics. The first guideline explained the determination of FDA-regulated products containing nanoparticles, based on the particle dimensions and the dimension-dependent phenomena. The second guideline addressed the safety of nanomaterials in cosmetic products. It is not made mandatory by the FDA to reveal the nanomaterials used for formulation on the finished product label [38]. The FDA in association with the Personal Care Products Council (DC, USA) devised numerous regulations for cosmetics, based on the Voluntary Cosmetic Registration Program for voluntary reporting of the ingredients and the adverse reactions [39,40]. The FDA constantly updates the manufacturers about the risks related to nanomaterials for continuous improvement in the safety of the cosmetic products. With this initiative, the manufactures are also benefited as they can restrict the use of unsafe nanocosmeceuticals [41].

EU
The EU regulations define nanomaterials as an insoluble or bio-persistent and intentionally manufactured material with one or more external dimensions, or an internal structure on the scale of 1-100 nm. It is necessary that all the nanomaterials must be indicated with the specific word 'nano' [42]. The information on product specification, toxicity, safety profile and undesirable effects needs to be informed 6 months prior to the market entry of nanoparticle-based products/nanocosmeceuticals. Premarket approval is required for the nanotechnology-derived sunscreens, colorants, cosmeceuticals and anti-aging products. Nanomaterials are covered under the European Commission Regulation Number 1907/2006, Registration, Evaluation, Authorization and Restriction of Chemical substances and Scientific Committee on Consumer Products safety [42][43][44].

India
The Government of India judiciously raised funds in the Nano Science and Technology Initiative, which provided well-organized set-ups in various universities, academic societies, national laboratories, start-ups as well as R&D units. The key performers in the national health research systems are the Council of Scientific and Industrial Research, Indian Council of Medical Research, Department of Science and Technology and Department of Biotechnology (all in New Delhi, India). The Ministry of Health and Family Welfare (New Delhi, India), plays a pivotal role in the prevention and control of the health-related hazards. Additionally, the Nanotechnology Sectional Committee, which involves experts affiliated to varied research institutes and organizations, work actively for the standardization of the nanotechnology-based products [41].

Nanocosmeceutical applications
Major applications of the nanocosmeceuticals are summarized in Figure 4 and discussed in the following sections.

Sunscreens
The prime use of sunscreens is to protect the skin from the short-term and long-term effects of UV radiation. The best sunscreen has a sun protection factor (commonly known as SPF) of at least 30 [42]. Nanoparticles used in the sunscreen cosmeceuticals do not form the typical, white, chalky layer on the skin as that of the conventional sunscreens. Nevertheless, the amount of established, sunscreen products applied on the skin can be minimized to a large extent with the help of nanoparticles. They also offer beneficial effects such as a less greasy appearance and odorless nature, which increase their aesthetic appeal [45]. Most used nanoparticles in sunscreen are TiO 2 , ZnO and para-aminobenzoic acid nanoparticles, which protect the skin from UV-A and UV-B rays [

Anti-aging products
Nanoparticle technology is most extensively utilized in anti-aging products. A very common anti-aging product which has a significant presence in the market is Revitalift R , manufactured by L'Oreal Company (Clichy, France). Revitalift uses nanosomes composed of pro-retinol A. The majority of anti-aging products work by moisturizing, lifting, toning and whitening the skin. Retinol A is known to increase the epidermal water content, epidermal hyperplasia with an enhanced collagen synthesis [47]. Additionally, retinol affects melanogenesis and inhibits the matrix metalloproteinase, which are responsible for collagen breakdown. Another example is Lancôme (Paris, France), who introduced Hydrazen Cream R , which is a nano-encapsulated triceramide formulation that rejuvenates skin health [48].

Moisturizer
Moisturizers are the most widely used cosmetic product, which also makes use of nanoparticles [49,50]. Water from the SC gets easily evaporated causing dryness and cracks. This can be treated with the help of the nanoparticles that form a thin humectant layer to prevent the rapid evaporation of water. Thus, the moisture content is retained resulting into better skin appearance [51]. Liposomes, nanoemulsions and solid lipid nanoparticles are the most widely used nanoparticulate in moisturizing formulations. They are useful in the treatment skin related diseases like dermatitis, psoriasis and pruritus [52].

Hair care products
The utilization of nanoparticles in the global hair care industry has recently emerged as an alternative to provide a better appearance and nutrition to the hair follicles. Additively, the use of nanoparticles in hair industry mainly focuses on the prophylaxis and the treatment of various types of alopecia [53]. Earlier, the common use of shampoos was restricted to cleansing only. Nowadays, nanoparticle-based shampoos are used as replacement therapies to provide nutrition essential for the proper growth of hair follicles. Silicone oil-based nanoparticles are used to diffuse inside the hair fibers without destroying their cuticle. This formulation offers more moisture and silkiness, as well as strengthens the hair owing to its nano size [54]. Nano size enables the penetration of silicone oil into the hydrolipid emulsion layer and prevents its accumulation on scalp.

Toxicity, safety & hazardous effects of nanocosmeceuticals
Toxicity associated with nanocosmeceuticals There is a continuous, rapid growth in the novel technologies and pharmaceutical preparations related to the nanoparticles. Along with these advances, there is also a risk factor associated with the development procedure and use of the nano-based products in society. Toxicity issues are the major limitations of nanotechnology, alongside technological and economic barriers [54]. In the past few years, a large number of case studies such as cell uptake, genotoxicity and oxidative cell damage have raised issues related to the safety of nanocosmeceuticals [55]. The particle size on the scale of nano range makes the surface of particles highly active. Penetration of such highly surface-active nanoparticles via the skin can lead to adverse reactions [56]. Nano-sized TiO 2 or ZnO (30-150 nm), up to 25% in concentration for the use in topical cosmetic products or sunscreens, are established as safe for protecting the skin from harmful solar radiations. Several reports have demonstrated that neither TiO 2 nor ZnO nanoparticles can penetrate beyond the SC layer of skin under different test conditions [57]. When explorative studies were performed on the gold nanoparticles, they were discovered to be safe with negligible toxicity. Later on, the changes in size of gold nanoparticles demonstrated potential toxicity. Nanoparticles, below 10 nm size, can easily penetrate deep inside the skin layer and nuclear membrane leading to potential genotoxicity. Further, nanoparticles in cosmetic products should be prepared considering the toxicity initiating parameters like morphology and concentration.
Despite the possible challenges associated with nanoparticles, it has a wide array of significant applications [58]. Fullerene nanoparticles are researched for diverse dermatological applications such as antiacne, anti-aging, brightening essence and sunscreens, owing to their excellent antioxidant properties [59]. Numerous case studies have highlighted that the carbon fullerene-based cosmeceuticals can cause brain damage in fishes [60,61]. In a recent study by Dhawan et al. the colloidal, C60 fullerenes have demonstrated genotoxicity [62].

Safety of the nanocosmeceuticals
As per the Scientific Committee on Consumer Products safety and European Commission, the safety of the cosmeceutical products is governed by the safety of their ingredients [63]. On the other hand, the FDA does not require cosmetic products and their ingredients to have FDA approval before marketing. The FDA states that the manufacturers can explore the safety data of the specific ingredients or products with comparable formulations to judge the safety of nanocosmeceuticals [64]. Likewise, the Personal Care Products Council measures and compares the safety of nanocosmeceuticals with the previously marketed formulations [65]. Individual ingredients safety facts and data are accessible through various resources such as the FDA's Generally Recognized As Safe database and the European Commission's Cosmetic Ingredient Database. An ingredient is grouped under Generally Recognized As Safe by a panel of qualified experts after being classed as 'having adequate safety under the conditions of its intended use' [66]. Even though this database mainly evaluates the ingredients such as the food additives, it also provides valuable safety inputs on the ingredients present in the personal care, as well as cosmetic products. Besides, the Cosmetic Ingredient Review (DC, USA) is an independent body involved in evaluating the safety of the individual ingredients used in cosmetics. Cosmetic Ingredient Review evaluates the ingredients using standardized procedures and specifies the recommendations as shown in Figure 5 [67].

Methods for assessing safety of the nanocosmeceuticals products
The active Scientific Committee on Emerging and Newly Identified Health Risks (Brussels, Belgium) controls and regulates the risk assessment methodologies, accessible for measuring the adverse health effects of the   nanotechnology-based products [68]. The key factors that are judged for the safety of the nanomaterials are summarized in Table 3 [56,58].

Conclusion
There is always a growing demand for cosmetics in the world. Continuous development in cosmetic products and nanotechnology has led to the evolution of cosmeceuticals into nanocosmeceuticals. The use of nanotechnology in cosmetics is increasing tremendously. However, few toxic events have been reported with these nanocosmeceuticals. Thus, the safety and efficacy of these nanocosmeceuticals needs to be evaluated prior to their marketing. Various guidelines from diverse countries to regulate such products need to be harmonized. Looking at the future development and market potential, nanocosmeceuticals need more attention and awareness.

Future perspective
Nanocosmeceuticals are expanding rapidly across the globe. Cosmeceuticals integrated with nanotechnology have shown their valuable implications in the therapy of many skin ailments. In absence of the specific guidelines, these products are undergoing fast commercialization and earning huge profits in the personal care product industry. There is an increased awareness regarding environmental concerns and risk of the side effects related to the nanoparticulate systems. Thus, there is a need for precise, harmonized guidelines and strict regulations over the future use and the advertisements of nanocosmeceuticals. Nanocosmeceuticals, a blend of cosmetics and pharmaceuticals is highly recommended for more safe and economic products for the consumers.

Executive summary
• Cosmetics integrated with the therapeutically active agents at the nanoscale or encapsulated in the nano-sized carriers, termed as 'nanocosmeceuticals' are rapidly expanding in the skin care products. • At present, the nanocosmeceutical products are occupying a major share of cosmetic market owing to their claimed benefits. • Various novel, sub-micron sized drug-delivery systems comprising of the lipid-based carriers, polymeric nanoparticles, nanoemulsions, inorganic nanoparticles, fullerenes and dendrimers are explored for the delivery of the cosmeceutical preparations in the skin. • Nanocosmeceuticals exhibit different topical and transdermal mechanisms of action based on the nature, type and size of the carrier and/or actives. • Major applications of the nanocosmeceuticals are in the sunscreens, moisturizers, hair care products, antimicrobials, anti-aging and antiwrinkle creams. • Several scientific organizations and regulatory agencies like the US FDA and European Commission have raised the health concerns and environmental risks associated with the nanocosmeceuticals. • Thus, evidence-based safety evaluation of the nanocosmeceuticals in context of the harmonized, globally accepted guidelines, prior to product commercialization has become essential.
Author contributions V Dhapte-Pawar drafted the manuscript, performed the literature search and revised the manuscript. PP Kenjale integrated the data along with manuscript editing; S Kadam and S Saptarsi provided discussion.

Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

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