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Advances in cosmeceutical nanotechnology for hyperpigmentation treatment

Advances in cosmeceutical nanotechnology for hyperpigmentation treatment J Nanopart Res (2022) 24: 155 https://doi.org/10.1007/s11051-022-05534-z REVIEW Advances in cosmeceutical nanotechnology for hyperpigmentation treatment Mason Jarius Tangau · Yie Kie Chong  · Keng Yoon Yeong Received: 14 March 2022 / Accepted: 7 July 2022 / Published online: 20 July 2022 © The Author(s) 2022 Abstract Hyperpigmentation is a common and Lastly, a total of 44 reported patents and articles of major skin problem that affects people of all skin types. depigmenting compounds encapsulated by nanoparti- Despite the availability of various depigmentation cles were filed and analyzed. Overall, lipid nanoparti - active ingredients for skin hyperpigmentation disorder, cles were found to be the most widely used nanomate- none of them are completely satisfactory due to their rial in treating hyperpigmentation. poor permeability through the skin layer and signifi - cant toxicity, thereby causing severe side effects such Keywords Nanomaterials · Cosmeceuticals · as irritative dermatitis, erythema, itching, and skin Hyperpigmentation · Hydroquinone · Arbutin · flaking. Nanotechnology plays an important role in Kojic acid · Azelaic acid · Retinoic acid · Lipid advancing the cosmeceutical formulation by improving nanoparticles the solubility, stability, safety, loading efficiency, and dermal permeability of the active ingredients. The aim of this review is to offer a comprehensive discussion on Introduction the application of various nanomaterials in improving cosmeceutical formulations used to treat hyperpigmen- Over the past decades, technological advancements tation. Focus is placed on elucidating the advantages in cosmeceuticals are growing rapidly. The rise in the that nanotechnology can bring to some common hyper- usage of cosmeceuticals in skincare can be attributed to pigmentation active ingredients such as hydroquinone, an increase in consumer awareness of general skin health arbutin, kojic acid, azelaic acid, and retinoic acid to and physical esthetic attributes. Coupled with the rise of improve their efficacy in treating hyperpigmentation. awareness of a healthy lifestyle, the role of cosmeceuticals and cosmetics has become essential in a person’s daily routine [1]. It is estimated that the rise in the market value and sales for the beauty and personal care market to go Mason Jarius Tangau and Yie Kie Chong contribute beyond $716 billion dollars by 2025 [1]. With such rapid equally to this work. development in skincare products, more quality and sci- M. J. Tangau · Y. K. Chong (*) · K. Y. Yeong (*)  entific assessments are needed to improve its efficiency. School of Science, Monash University Malaysia Campus, Besides focusing on improving the efficacy of Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, individual active agents, scientists have also been Malaysia exploring more on how nanotechnology can improve e-mail: yiekie.chong@monash.edu the delivery and absorption of active ingredients to K. Y. Yeong  the skin [2, 3]. e-mail: yeong.kengyoon@monash.edu Vol.: (0123456789) 1 3 155 Page 2 of 18 J Nanopart Res (2022) 24: 155 Nanotechnology has become a promising addition to the Although the use of nanotechnology in cosmeceu- cosmetic industry due to its ability to enhance the properties ticals has been widely reported [4, 6, 19–21], specific of cosmetic products in general. Features such as absorption, details focusing on nanoparticles in improving the effi - texture, protection for active ingredients, and overall effi - cacy of depigmenting active ingredients have yet to be ciency could all be manipulated and improved upon using reviewed. Herein, we provide a general overview on the nanotechnology [4]. Nanotechnology utilizes nanoparticles use of nanotechnology and the advantages it brings in or nanomaterials which are naturally or synthetically derived improving the efficacy of anti-hyperpigmentation com - ranging from 1 to 100  nm [5]. The nano-sized particles pounds. Specifically, this review revisits common depig - are able to impart numerous important properties in topi- mentation active ingredients such as hydroquinone, cal applications. Firstly, the minuscule size of nanoparticles arbutin, kojic acid, azelaic acid, and retinoic acid and allows for a high surface area to volume ratio which enables elucidates new approaches where nanotechnology could greater exposure of active molecules per dose administrated improve their efficacy in treating hyperpigmentation. to the stratum corneum [6]. Secondly, nanoparticles are able to improve the absorption through the skin along with sus- Nanoparticles in cosmeceuticals tained release in order to increase blood circulation time of the encapsulated compound and improve the delivery of the The cosmeceutical industry uses various nanomateri- active ingredients to the targeted site [7]. Besides, nanomate- als, from lipid nanostructures to metal-based nanocar- rials may also provide better stability of cosmeceutical com- riers, nanocrystals, and even polymer-based nanocar- pounds of which may degrade due to oxidation or for other riers for various application (Fig. 2). reasons [8]. Figure 1 showed the outline of the improvement Recently, a variety of nanomaterials have been studied of cosmeceutical compounds by nanoparticles. in different in vivo models with outstanding and promis - Hyperpigmentation is one of the most notable skin ing outcomes [5]. Nanomaterials that are often studied maladies that is associated with discolorations or pig- alongside skin-based cosmetics can be divided into 2 main mentation problems [9]. Hormonal fluctuations, injury, categories, namely organic nanoparticles and inorganic skin inflammation, ultraviolet (UV) exposure, and nanoparticles as shown in Fig.  2. Organic nanoparticles improper medication are potential causes of hyperpig- are mainly used in lipid and polymer-based nanocarriers. mentation [10]. These events can trigger an over-produc- Inorganic nanoparticles are made up of metals and their tion of melanin by melanocytes within the skin layers oxides, and are generally water insoluble [1]. Organic which can result in dark spots or overall darkening of nanoparticles are mainly used in the formulation of active one’s skin tone [9]. Melanin is the natural pigment that ingredients by acting as carriers and absorption enhancers gives our skin, eyes, and hair color, and is essential for whereas inorganic nanoparticles are often used as bases the protection of human skin against radiation. How- for products that sit or act on the surface of the skin such ever, an abnormal increase in melanin production can as antimicrobial products or sunscreens. The main differ - result in pigmentation disorders, such as ephelides, mel- ence between the two lies with the sturdy nature of inor- asma, senile lentigines, and freckles [11]. Over the past ganic nanoparticles where their physical properties remain decade, several classes of tyrosinase inhibitors such as unchanged when applied topically [1]. Different classes of phenolics, steroids, flavonoids, terpenes, oxadiazole, and nanoparticles are further discussed below. bipiperidines have been reported to inhibit melanogen- esis and enzymatic browning [12–14]. Brightening or anti-hyperpigmentation agents such as, arbutin, azelaic Organic nanoparticles acid, kojic acid, and hydroquinone are commonly used in the market due to their ability to inhibit melanocytes or suppress melanin production [15–17]. However, these (1) Lipid and surfactant derived nanoparticles. depigmentation agents hardly showed inhibitory activity towards tyrosinase in intact melanocytes. Some are even considered to be cytotoxic and unstable over time [17, (a) Vesicular nanoparticles. 18]. With nanotechnology, the previously overlooked Lipid-based nanoparticles include vesicular nanopar- active ingredients could be further explored and formu- ticles such as niosomes and liposomes [1]. These lated into more effective and safer depigmenting agents. vesicular nanocarriers are spherical, in-closed Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 3 of 18 155 vesicles that are made up of naturally self-assem- their inherent tuneable microstructure, they are bly phospholipid bilayers or non-ionized syn- also utilized as emulsion stabilizers [24]. thetic amphiphilic lipids such as alkyl esters [6]. Liposomes range from 10 to 3000  nm, which is comparatively larger than niosomes which range (2) Polymeric nanoparticles. from 10 to 100 nm. These lipid-rich vesicles are Polymeric nanoparticles are categorized into nano- able to enhance the penetration of encapsulated capsules and nanospheres. Nanocapsules are active ingredients due to their amphiphilic nature, formed from a polymeric coating which shelters which in turn boosts their bioavailability. Moreo- a liquid core that contains either an oil or sur- ver, they are also biodegradable which is an envi- factant that is loaded with the active ingredient ronmental advantage. whereas nanospheres are matrixes which trap the (b) Non-vesicular nanoparticles. active ingredient within its network [6]. The main Non-vesicular carriers including nanoemulsions, benefit that comes from the use of polymeric solid lipid nanoparticles (SLN) and nano-based nanoparticles is their ability to encapsulate both lipid carriers (NLC) are mainly composed of dif- hydrophilic and lipophilic active ingredients. fering heterogenous systems that are dual-phased Moreover, they can extend the lifespan of unsta- (aqueous and lipophilic) and stabilized with ble compounds such as antioxidants and vola- emulsifiers and surfactants (NLC). Nanoemul - tile chemicals such as fragrances [1]. Generally, sions are dual-phase systems that contain oil an polymeric nanoparticles can be prepared using aqueous medium and emulsifying agents [22]. synthetic or natural polymer. Polyethylene glycol, Their ultrafine texture often leads to a silkier fin - polylactides, and poly(lactic-co-glycolic acid) ish, enhancing product absorption as well as pro- (PLGA) are examples of biodegradable synthetic viding a boost in skin hydration.[5] On the other polymers while poly(methyl methacrylate) and hand, SLNs and NLCs are made up of a lipid core polyacrylates are few of the non-biodegradable containing either solidified lipids or liquidized synthetic polymer which are frequently used to lipids respectively. In general, both lipid nanocar- deliver hydrophobic compounds in skin care for- riers can be used to deliver poorly water-soluble mulations [25]. Chitosan, gelatin, and albumin drugs and bioactive molecules [23]. Next, due to are natural polymers that are biodegradable and Fig. 1 Schematic outline for improvement of cosme- ceutical compounds using nanotechnology Vol.: (0123456789) 1 3 155 Page 4 of 18 J Nanopart Res (2022) 24: 155 Fig. 2 Schematic representation of nanomaterials in cosmeceutical biocompatible. Chitosan is commonly used natu- pounds. The results indicated that the surface ral polymer because it possesses great potential modified nanocrystal could increase surface for surface modification [ 26] and is suitable for hydrophobicity, emulsifying efficiency, stability, encapsulating negatively charged compounds as well as penetration depth through all skin lay- which can help in cellular internalization [25]. In ers with increasing drug accumulation [28]. comparison, synthetic polymers are more flexible as they were able to turn into various shapes and size compared to natural polymer [27]. (3) Nanocrystals. Inorganic nanoparticles Nanocrystal is another form of polymeric nanoparti- cles that are mainly used for the delivery of insol- Inorganic nanoparticles are commonly used as active uble active ingredients [22]. Nanocrystals possess substances, nanocarriers, and modifiers in cosmetic a large surface area which aids the absorption of products. Carbon-based nanotube, nanorod, noble otherwise insoluble active ingredients. Recently, metals, metal oxides, and mesoporous nanostructures Hiranphinyophat and co-workers reported a are several classes of inorganic nanoparticles used in poly(2-isopropoxy-2-oxo-1,3,2-dioxaphospho- commercial cosmetic products. Carbon-based nano- lane) (PIPP) modified cellulose nanocrystal as tubes are widely used for coloring hair, eyelashes, a vehicle for topical delivery of lipophilic com- and eyebrows due to its high resistance to various Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 5 of 18 155 shampoos and its heat dissipation abilities [29, 30]. Overall, these depigmenting compounds exhibit Mesoporous silica is a porous form of silica com- good efficacy. However, the severe side effects pre - posed of hexagonal array of nanoscale pores which vented these depigmenting agents from being used in can accommodate the active compounds and control numerous countries. Several studies have shown that its release [31]. Mesoporous silica encapsulated with the encapsulation of depigmenting compound in nan- octal methoxycinnamate (MCX) and benzophenone-3 oparticles could reduce its adverse effects, promotes (BZP) were reported to improve UV protection com- target delivery, and enhance its stability [60–64]. The pared to the non-encapsulated-free compounds alone. advantages on the use of nanotechnology in various [32, 33]. Apart from mesoporous silica, inorganic depigmenting compounds are deliberated below. oxides nanoparticles such as TiO , ZnO, CeO , and 2 2 ZrO are able to scatter and reflect UV radiations. Application of nanoparticles in depigmentation Due to this property, they are widely included in the compounds formulation of cosmetic sunscreen [34]. Studies on hydroquinone loaded nanoparticles Advantages and drawbacks of nanomaterials used Hydroquinone (Fig. 3) is often used in the production in cosmeceutical formulation of skin-lightening products as it functions to inhibit tyrosinase activity [65]. It is a known irritant whereby Based on the nanomaterials discussed, the advantages its side effects include skin irritation and erythema and disadvantages will be highlighted further specifi - [66]. In cosmetic applications, hydroquinone suffers cally for organic nanoparticles and inorganic nano- from instability due to rapid oxidation, insufficient particles in Table 1. skin penetration because of its hydrophilic structure, and encounter serious side effects due to systemic absorption. Several studies were aimed to load hyd- Topical depigmenting agents roquinone into nanoparticles to overcome the men- tioned drawbacks of depigmenting agents. Skin-lightening compounds, such as hydroquinone, Studies have shown that encapsulation of hyd- kojic acid, arbutin, azelaic acid, and retinoic acid, are roquinone in lipid nanoparticles were able to often used to treat hyperpigmentation disorder. The enhance the stability against oxidation and pos- mode of action of depigmentation agents can be clas- sess better skin penetration ability compared to the sified as follows: (i) inhibition of tyrosinase; (ii) inhibi - hydroquinone [60]. An in vitro rat skin penetration tion of melanosome transfer; (iii) scavenge active oxy- study showed approximately threefold higher drug gen and limiting oxidative damage to cell membrane accumulation and 6.5-fold lower drug entrance structure; and (iv) interaction with copper which nor- into receptor phase of Franz cell confirming the mally serve as a catalyst in the formation of pigment lower systemic absorption of drug using hydro- [35]. Table 2 shows the classification of the depigment - quinone loaded SLN compared with hydroquinone ing agents based on their mechanism of action. hydrogel. The lipoid nature of SLN colloidal car- However, these depigmenting compounds are rier is likely to enable penetrated drugs to local- associated with many adverse effects such as irri - ize in the skin. This may reduce toxic side effects tative dermatitis, erythema, itching, and skin flak - as systemic absorption is minimized. Moreover, ing due to their poor solubility, poor permeability another research group has also reported a better through the stratum corneum, as well as high toxic- skin penetration and enhanced protection towards ity [48]. The poor skin permeability of depigmenting UVA/UVB irradiation using hydroquinone in compounds is often the result of the overaccumula- nanostructured lipid carrier (NLC) compared to tion of the active ingredients and increment of skin hydroquinone alone [67]. In their in vitro artificial retention period which in turn escalates the likelihood skin permeation study showed that percutaneous of adverse effects mentioned above [ 49, 50]. Table  3 penetration ability of hydroquinone encapsulated depicts clinical studies on various topical depigment- in NLC was significantly greater than hydroqui- ing agents and their observed side effects. none only. Vol.: (0123456789) 1 3 155 Page 6 of 18 J Nanopart Res (2022) 24: 155 Table 1 Advantages and disadvantages of organic and inorganic nanoparticles in treating hyperpigmentation [19, 35–43] Advantages Drawbacks Organic nanoparticles Niosomes -Allows for controlled and tar- -Chance for leaking and hydroly- geted compound delivery sis of entrapped compound and -Increased dermal penetration reducing shelf life -Low toxicity, biocompatible and -Physically unstable nonimmunogenic -Tends to aggregate Liposomes -Increased stability for encapsu- -High production cost lated compound -Low solubility -Biocompatible and biodegrad- -Chance for leaking of entrapped able active ingredient -Increased efficacy of encapsu- lated active ingredient Nanostructured lipid carrier -Physically stable -Irritative and sensitizing actions (NLC) -Higher loading capacity com- caused by some surfactant that pared to SNL use to produce NLC -Extended release of drug -Insufficient studies in the prepara- tion of NLCs Solid lipid nanoparticles (SNL) -Possesses an occlusive nature -Poor drug loading capacity which aids in increasing skin -Burst release hydration -Not suitable for loading hydro- -Easy to upscale philic compound -Increased bioavailability of encapsulated active ingredient Nanoemulsion -Suitable for delivery of both -Low viscosity and spreadability lipophilic and hydrophilic -Higher chance for skin irritation compound -Low bioavailability -Increased rate of absorption -Can be formulated into creams, sprays, foams and so on Polymeric nanoparticles -Controlled and sustained release -Difficult to scale up -Good protection from enzymatic -Insufficient toxicity assessment in and chemical degradation literature -Low toxicity Nanocrystals -Can obtain high dosage of -Low stability entrapped active ingredient -Some active ingredients may not -Increased bioavailability be easily crystallized Inorganic Al O, TiO , ZnO, gold, silver, -Biocompatible -High toxicity (can damage 2 3 2 nanoparticles copper and carbon-based nano- -High physical and chemical pulmonary tissue and may have particles etc stability cytotoxic effects) In addition, it has been revealed that hydroqui- against oxidation [68]. The study showed a sustained none after loaded in cellulose nanocrystals are exhib- release profile of hydroquinone (80% of bound hydro - ited sustained release manners and showed stability quinone released in 4 h) which improved the efficacy Table 2 Classification of Mechanism of action Depigmenting compounds depigmenting agents based on their mechanism of i) Inhibition of tyrosinase Hydroquinone, azelaic acid, kojic action [44–47] acid, and arbutin ii) Inhibition of melanosome transfer Retinoids (including of retinoic acid) iii) Reactive oxygen species scavengers during melanin Ascorbic acid synthesis iv) Interaction with copper Kojic acid, ascorbic acid Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 7 of 18 155 Table 3 Summary of the findings and side effects of topical depigmenting agents Depigmenting Studies agents Hydroquinone Amer and Metwalli [51] Results: Patients with melasma, post-inflammatory hyperpigmentation, and freckles was achieved in good to excellent responses at 89.5%, 75%, and 44.4% respectively Side effects: Local irritation was found in most patients Ennes et al. [52] Results: 38% of patients showed total improvement, partial improvement in 57% and 5% of patients discontinued therapy Side effects: 28.6% of patients experienced adverse effects including contact dermatitis Haddad et al. [53] Results: 76.9% of melasma patients showed improvement Side effects: 25% of patients experienced irritation effect. It can trigger “confetti leukoderma” (a focal depigmen- tation of the skin) due to the destruction of melanocytes Arbutin Morag et al. [54] Results: 75.86% of female melasma patients and 56.00% of female lentigo solaris patients showed improvement Side effects: No side effects were observed Azelaic acid Baliña and Graupe [55] Results: 64.8% of melasma patients were observed a good to excellent result Side effects: 11% of patients were found to encounter local irritation Sarkar et al. [56] Results: 96.7% of melasma patients had good to excellent responses Side effects: 20% of patients were encountered side effect including burning, erythema and itching Kojic acid Monteiro et al. [57] Results: After the treatment, mean melasma area and severity index score was decreased by 2.403 Side effects: 3.3% of patients experienced erythema and burning sensation Retinoic acid Griffiths et al. [58] Results: 68% of melasma patients was observed a improved or much improved results Side effects: 88% of patient were encountered moderate cutaneous side effects Kimbrough-Green [59] Results: 32% of melasma patients were improved Side effects: 67% of patients occurred mild retinoid dermatitis and simultaneously reduced the adverse effects of hydroquinone. All of the above examples showed that nanotech- nology is a promising approach for topical admin- istration of hydroquinone to overcome hyperpig- mentation with a suitable skin penetration and low systemic absorption to reduce the adverse effects of hydroquinone. Studies on arbutin loaded nanoparticles Arbutin (Fig.  4) is commonly used as a skin-light- ening and brightening agent in skincare and cos- metic products [69]. The main mode of action for arbutin is inhibit the synthesis of melanin by act- ing as a tyrosinase inhibitor [70]. Besides, it is also Fig. 3 Chemical structure of hydroquinone Vol.: (0123456789) 1 3 155 Page 8 of 18 J Nanopart Res (2022) 24: 155 possesses anti-inflammatory and antioxidant prop - melanin) and their culture medium (extracellular mel- erties [71]. It is highly hydrophilic and hygroscopic anin), arbutin-GNP nanocomplex were able to inhibit due to its chemical structure which contains multiple the production of intracellular and extracellular mela- hydroxyl groups. Therefore, it usually suffers from nin of up to 22.7 and 47.7% respectively versus 21.8% poor absorption and penetrance through the stratum and 31.8% with arbutin alone. The study also reveals corneum [72]. The high lipid content of the skin ren- that arbutin-GNP nanocomplex exhibited better anti- ders arbutin difficult to permeate through it and dif - inflammatory activity and lower toxicity comparing fuse into the inner cells. A recent study indicated that to pure arbutin. the arbutin’s adverse effects is triggered by external Guar gum (GG)-based nanomaterials have been production of hydroquinone due to exposure of ultra- extensively used for skin and percutaneous admin- violet rays and skins microorganisms [66]. istration to controlled release and delivery enhance- One of the methods to mitigate the poor penetra- ment [76–78]. A cross-linked amphiphilic GG tion is by loading arbutin into chitosan polymeric nanocarriers loaded with arbutin was reported [79]. nanoparticles. Chitosan is a biodegradable polymer Through the modification of guar gum with hydro - made from de-acetylated chitin that possesses high phobic short-chain alkylglycerol, namely glycidol biocompatibility, non-toxic, and can interact with a butyl ether (GBE), the GBE-GG nanocomplex loaded large variety of polyanions [73]. When it is made into with arbutin imparted a higher degree of hydropho- a nanocarrier, positively charged chitosan nanoparti- bicity which increases its permeation through the cles (CNP) was able to increase permeation through stratum corneum. Besides, the results suggested the the skin due to the increased interaction with nega- absence of cellular toxicity and better cellular uptake tively charged cellular surfaces and eventual uptake across the cultured human keratinocyte HaCaT cells into melanocytes via endocytosis or phagocytosis that increase the biological membrane permeability, [74]. Ayumi et  al. reported that the α-arbutin and suggesting their potential as safe nanocarriers for top- β-arbutin chitosan nanoparticles demonstrated pro- ical delivery. longed rate of absorption by releasing the active com- Nanoemulsion of arbutin loaded with coumaric pound slowly over a sustained 52-h period [74]. acid has also been showed to improve the deliv- Gold nanoparticles (GNPs) have become prevalent ery and stability of arbutin [61]. Through the use of within the cosmeceutical industry due to their inert multi-phase (w/o/w) nanoemulsion, it was found that and non-toxic nature. Park et  al. described a novel the encapsulated arbutin achieved high stability and arbutin-GNP nanocomplex which possesses supe- high encapsulation efficiency using a hydrocolloid rior brightening properties compared to arbutin alone medium. Furthermore, the encapsulated arbutin was [75]. In their study, they measure the melanin con- able to exhibit sustained release (86%) due to the tent from both the tested melanocytes (intercellular nature of the gelatin hydrocolloid in compared to free Fig. 4 Chemical structure of arbutin Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 9 of 18 155 form of arbutin, which only resulted in a 5% overall drug retention and tyrosinase inhibition activity [86]. release over a period of 6 h. In their study, hyaluronic acid was used to formulate In conclusion, the application of different types of into nanoemulsion along with azelaic acid because nanotechnology has been able to overcome the weak hyaluronic acid was previously reported to signifi - permeating capability of arbutin by either encapsulat- cantly decrease the melanin synthesis due to improv- ing it via polymeric nanocarriers, complexing it with ing the interaction of nanoemulsion and melanocytes inorganic nanoparticles such as GNPs or formulating [87]. At last, with the help of nanotechnology and it within a nanoemulsion. hyaluronic acid, azelaic acid–loaded nanoemulsion showed lesser tyrosinase activity and permeated Studies on azelaic acid–loaded nanoparticles through the skin without showing cytotoxic activity. A study showed that the use of nanostruc- The main use of azelaic acid (Fig. 5) originates from tured lipid carriers (NLC) loaded with azelaic acid its antibacterial, anti-inflammatory, and skin bright - allowed for its enhancement towards its target- ening properties [80]. Its ability to treat hyperpigmen- ing sites such as melanocytes. This is due to their tation lies with its nature as a potent reversible inhibi- small particle size and its innate occlusive effect tor of the tyrosinase enzyme [81]. As azelaic acid that allows for better penetration through the stra- possess two carboxyl groups, it is easily ionized. The tum corneum [88]. When tested for their permeation ionized compounds tend to exhibit poorer skin per- capabilities, the release rates of azelaic acid-NLC, meability due to the hydrophobic nature of the skin azelaic acid gel, and azelaic acid in water was found [82, 83]. Thus, in response to azelaic acid’s poor per- to be 21%, 38%, and 78% respectively. Despite meability through the skin, azelaic acid encapsulated the slower release rates, azelaic acid-NLC exhib- by nanoparticles were able to increase absorption to ited a higher initial burst release of up to 5%. The exhibit significant therapeutic effect [ 82]. azelaic acid-NLC’s ability for sustained release and Nanocrystals have received considerable attention high initial burst release is advantageous for topical in cosmeceutical as they increased compound’s solu- application as it allows for a rapid onset of action bility, dissolution rate, and increased adhesion proper- and allows for a drug depot effect to take place in ties of nanocrystal to the skin [84, 85]. With the aims a localized area. The slower release of azelaic acid- to enhance the solubility and stability of azelaic acid, NLC also mitigated the occurrence of side effects as Tomic and co-workers reported the encapsulation of the skin was not exposed to high amounts of azelaic azelaic acid in nanocrystals suspended in Pluronic® acid over a period of time compared to azelaic acid F127 and hyaluronic acid (PHA). These azelaic acid gel and azelaic acid in water. nanocrystals showed improved aqueous solubility and In short, the use of nanotechnology is able amelio- dissolution rate [62]. The results suggested that the rate the drawbacks faced when formulating azelaic acid nanocrystal of azelaic acid and its incorporation in such as its poor aqueous solubility and occurrence of PHA hydrogel gave better skin bioavailability in com- dermal adverse effects. Examples including nanoe - parison to an azelaic acid–containing standard com- mulsions and nanocrystals allow better solubility of mercial product. azelaic acid and with the use of NLCs; the likelihood It has also been revealed that azelaic acid loaded of adverse effects is lowered due to the gradual release in nanoemulsion with hyaluronic acid exhibited better effect of azelaic acid–loaded NLC formulation. Fig. 5 Chemical structure of azelaic acid Vol.: (0123456789) 1 3 155 Page 10 of 18 J Nanopart Res (2022) 24: 155 Studies on kojic acid–loaded nanoparticles et al. reported the formulation of kojic acid loaded in NLCs were showed to have better release profile, and Kojic acid (Fig.  6) primarily functions as a skin- more potent tyrosinase inhibitory as well as antioxi- lightening agent by acting as an inhibitor for tyrosi- dant activities compared to the pure kojic acid [63]. nase [89]. The main mode of action for kojic acid Results of these studies indicated that kojic acid- as an inhibitor is through its ability to chelate to SLNs and kojic acid-NLCs with lipid excipients and the copper within the enzymes active site [90]. It is surfactant increase skin permeation. This implies the highly hydrophilic as its chemical structure contain- potential of nanotechnology for kojic acid delivery in ing of two hydroxyl group. The hydrophilic nature topical application. of the compound makes it difficult for kojic acid A very recent study on different formulations to penetrate through the stratum corneum and hin- of oil-in-water (O/W) kojic acid nanoemulsion for dered the accumulate of kojic acid in the target sites topical application [100]. The study revealed vari- [18, 91]. Several studies have reported the concern ous parameters to generate kinetically stable nanoe- of kojic acid regarding its toxicity [92], carcino- mulsion at a recommended pH range of pH 4.95 genicity, mutagenicity [93], irritancy [94], hepa- to 5.18 for 6  weeks storage. The results suggested tocarcinogenicity [95, 96], genotoxicity [97], and the suitability of the kojic acid emulsion for topical tumor-initiating activity [98]. Loading kojic acid in application. nanoparticle has been envisage to counteract these The above studies revealed that the loading of adverse effects. kojic acid in nanoparticles are able to reduce the Solid lipid nanoparticles (SLNs) and nanostruc- hydrophilic nature of kojic acid and thereby increase tured lipid carriers (NLCs) have been extensively its skin permeation and stability, by either loaded studied as way to bypass the hydrophilic nature of kojic acid with SLNs and NLCs or formulating it into kojic acid. Khezri et al. reported a kojic acid–loaded nanoemulsion. SLNs optimized by some lipid excipients and sur- factants in order to increase its loading. The results Studies on retinoic acid–loaded nanoparticles indicated that the kojic acid-SLNs dispersion can increase the dermal delivery of kojic acid with Retinoic acid (tretinoin; Fig. 7) is a metabolite of vita- higher concentration, better controlled release, and min A [101]. It is often used in the treatment of mel- more tyrosinase inhibition potency compare with asma and other pigmentation disorders [58]. When the free form of kojic acid [99]. Recently, Khezri used topically, it functions to increase the pigment Fig. 6 Chemical structure of kojic acid Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 11 of 18 155 transfer to keratinocytes, as well as the rate at which retinoic acid, which proved to be more effective and skin cells are shed. It is also known to inhibit the pro- biocompatible than the marketed product [64]. duction of tyrosinase [102]. Further benefits from reti - A study by Shah et  al. (2007) showed improved noic acid also include their superior antioxidant and physical stability and dermal tolerability of retinoic antimicrobial capabilities. The use of retinoic acid acid with encapsulation of SLNs [106]. When tested in product formulation is often met with challenges for photodegradability, retinoic acid-SLNs proved due to its inherent lipophilicity, which results in poor to be superior when irradiated, retaining up to 71% aqueous solubility. This limits its ability to be formu- of the retinoic acid content in comparison to reti- lated in aqueous mediums and often results in the use noic acid in methanol which only retained 12%. The of harmful co-solvents such as ethanol and propylene irritating properties of retinoic acid has been stated glycol [103]. Furthermore, the unstable nature of reti- to originate from its acidic functionality (carboxyl noic acid has also led to a drop in its therapeutic effi - group) when it is contact with the skin. This problem cacy. This is due to increased liability and decreased can be possibly be overcome using retinoic acid-SLN, stability when exposed to light, heat, oxidation, and whereas Draize patch test on rabbits attained a lower changes to environmental pH [104, 105]. irritation score compared to the marketed retinoic Ourique et  al. (2011) describe the use of a lipid- acid formulation. core polymeric nanocapsules (LCNC) to encapsulate In summary, the studies above suggesting the retinoic acid in order to increase the photostability emerging of nanotechnology in retinoic acid able to and improve skin retention time. When tested for half- eliminate the drawbacks such as its poor aqueous sol- life and effects of photodegradation, the retinoic acid- ubility and photosensitivity. LCNC achieved a t of 26.6 h compared to marketed 1/2 gel containing retinoid acid which has a t of 3.8 h. Trends of patents and research papers on 1/2 Furthermore, the rate of degradation was significantly nanotechnology in hyperpigmentation treatment reduced in retinoic acid-LCNC compared to retinoic acid, from 68.64 to 24.17% [103]. In order to further study on the relevance and com- Vesicular nanocarriers such as liposomes have also mercial research of nanomaterials for the improve- been documented to aid retinoic acid to retain on the ment to the delivery and efficacy of the aforemen - skin. It also offers enhanced protection from UV radi - tioned depigmenting compounds (hydroquinone, ation. Furthermore, the use of phospholipids in the arbutin, azelaic acid, kojic acid, and retinoic acid), a creation of such nanocarriers offers a higher biocom - total of 44 patents and articles on the encapsulation patibility compared to traditional mediums such as of the active ingredients by nanoparticles were filed gels and creams, increasing retinoic acid’s therapeutic to date. Based on Fig.  8, only two patents and one efficacy. A study by Raza et al. demonstrated the use paper were published prior to 2010 compared to 44 of SLNs, NLCs, and liposomes to enhance the drug publications from 2010 to 2021. The rapid rise in the delivery of retinoic acid. The reported study indicates number of patents and papers can be attributed to the that nanoparticulate carriers could enhance the photo- exponential growth in the cosmetics industry. This stability, skin transport, and anti-psoriatic activity of provides opportunities to expand and investigate on Fig. 7 Chemical structure of retinoic acid Vol.: (0123456789) 1 3 155 Page 12 of 18 J Nanopart Res (2022) 24: 155 the use of nanocarriers in the formulation of the five to nanomaterials that are synthetic, insoluble, or not mentioned active ingredients. Among the depigment- readily biodegradable such as metals. Consequently, ing agents, arbutin remains to be the most studied materials that are soluble and biodegradable such as active ingredient in conjunction with nanotechnology. lipid-based nanoparticles (liposomes, NLC, and SLN) The extensive study of arbutin can be attributed by its are not considered as nanomaterials under the EC Reg- higher skin tolerance and reduced side effects com - ulation 1223/2009, which allowed for several indus- pared to traditional skin brightening agents such as tries including the cosmetic industry to utilize these hydroquinone, retinoic acid, and kojic acid [66, 107]. nanomaterials more extensively as they are not directly Nanotechnology-based cosmeceuticals continually regulated by the EC regulation and can be more freely gain attention over the past few decades. According to studied and marketed. In summary, increased cosmetic the market analysis by the Woodrow Wilson Interna- interest, government backing as well as decreased reg- tional Centre on Emerging Nanotechnology, 788 out ulation for certain types of nanomaterials has led to an of more than 1600 products were marketed as nano- overall increase in both patents and research towards technology products for cosmetic [108]. The European the use of nanotechnology for cosmetic products. Union (EU) revamped cosmetic regulation (Directive Based on the patents and research papers studied, 76/768/EEC) in 2009 under a new name, EC Regula- it was found that a vast majority of the discussed tion 1223/2009 [109], which included international papers researched on the use of lipid nanoparticles as guidelines in order to address issues in the technologi- nanocarriers in improving the efficacy of the depig - cal insufficiencies within the cosmetic industry and to menting active ingredients (14 out of the 25 listed include recent research developments towards formu- papers). In comparison, the least studied nanocarrier lating new nano-based cosmetics [110]. This gave the was found to be inorganic nanoparticles which only push towards the usage of research data in developing had 1 paper associated with treatment of depigment- more sophisticated nano-based products, increased ing agents based on Table 4. transparency when providing information towards cus- The rise in the popularity of lipid nanoparticles in tomers, and rigorous safety testing, especially within research is due to several important properties such as the EU countries. Notably, these guidelines only apply high skin penetration ability, safe for topical application, Fig. 8 Number of patents and published papers before 2010 (a) and 2010–2021 (b), corresponding to the 5 studied active ingredi- ents, hydroquinone, arbutin, azelaic acid, kojic acid, and retinoic acid Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 13 of 18 155 biocompatible, and biodegradable when used topically [119–121]. Further studies have also shown that the SLNs and NLCs can act as a physical ultraviolet ray blocker [22, 119]. This allows for the encapsulation of photosensitive materials such as retinoic acid. Unlike lipid nanoparticles, inorganic nanoparticles such as gold, titanium, and silica- based nanoparticles are considered to be insoluble parti- cles [1]. Thus, these materials are unlikely to degrade after topical application [122]. Moreover, there is high risk in utilizing these inorganic nanoparticles as they may have risks in terms of occupational, environmental, or even toxicity [123]. Furthermore, inorganic nanoparticles were more likely to use as active agents for UV protection rather than acting as nanocarriers for other active ingredients [1]. Conclusion Nanotechnology has recently received increased attention in cosmetic industry. Some advances have been widely applied such as in formulations for skin whitening but treating hyperpigmentation has often been overlooked. In this review, we have summaries how the current nanotech- nology helps in solving the problem of depigmentation agents, in particularly: improving the solubility; enhancing the stability; reducing its toxicity by controlling the release of active ingredient; and increasing its entrapment effi - ciency and dermal penetration of the active ingredient to reach the stratum corneum. From the 44 reported patents and articles, lipid nanoparticles were found to be the most widely use nanocosmeceutical in treating hyperpigmen- tation due to its high skin permeability, biocompatible, and biodegradable as well as its use as an ultraviolet ray blocker. Notably, less regulation for specific types of nano - material has also led to an overall increase in both patents and research towards the use of biodegradable lipid nano- particles for hyperpigmentation treatment. Meticulous studies on health hazard and safety profile of nanomateri - als used in cosmeceutical are required to fully understand the impact of mass usage of these materials. Ultimately, precise and stringent laws and guidelines for control of cosmetic products should be imposed to ensure the safety of cosmeceutical nanoparticles used. Acknowledgements The authors acknowledge the School of Science, Monash University Malaysia for supporting this work. Author contribution MJT: conceptualization, literature search, writing of manuscript; YKC: conceptualization, litera- ture search, writing, and editing manuscript; KYY: conceptual- ization, reviewing, and editing manuscript. Vol.: (0123456789) 1 3 Table 4 List of nanocarriers from research papers that utilized the five depigmenting agents Hydroquinone Arbutin Azelaic acid Kojic acid Retinoic acid Lipid nanoparticles SLN Ghanbarzadeh et al. [60] - - Khezri et al. [99]; Moham- Raza et al. [64]; Shah madi et al. [111]; et al. [106]; Bosk- abadi et al. [112] NLC Wu et al. [67] - Kumari et al. [88]; Lacatusu Khezri et al. [63] Raza et al. [64]; Asfour et al., Malik and Kaur et al., et al. [115] Arsenic et al. [84, 113, 114] Niosomes - Radmard et al. [116] - - - Liposomes - - - - Raza et al. [64] Polymeric nanoparticles Chitosan - Ayumi et al. (74) - - - Biodegradable poly- - - Reis et al. [117] - Ourique et al. [103] ester Silica - - - Lima et al. [118] - Guar gum - Bostanudin et al. [79] - - - Nanoemulsion - Huang et al. [61] Jacobus Berlitz et al. [86] Yun et al. [100] - Nanocrystal Taheri and Mohammadi et al. Tomic et al. [62] - - [68] Inorganic nanoparticles Gold - Park et al. [75] - - - 155 Page 14 of 18 J Nanopart Res (2022) 24: 155 Funding Open Access funding enabled and organized by hormonal regulation. Physiol Rev 84:1155–1228. https:// CAUL and its Member Institutionsdoi. org/ 10. 1152/ physr ev. 00044. 2003 12. Chang TS (2009) An updated review of tyrosinase inhib- Declarations itors. 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Advances in cosmeceutical nanotechnology for hyperpigmentation treatment

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Abstract

J Nanopart Res (2022) 24: 155 https://doi.org/10.1007/s11051-022-05534-z REVIEW Advances in cosmeceutical nanotechnology for hyperpigmentation treatment Mason Jarius Tangau · Yie Kie Chong  · Keng Yoon Yeong Received: 14 March 2022 / Accepted: 7 July 2022 / Published online: 20 July 2022 © The Author(s) 2022 Abstract Hyperpigmentation is a common and Lastly, a total of 44 reported patents and articles of major skin problem that affects people of all skin types. depigmenting compounds encapsulated by nanoparti- Despite the availability of various depigmentation cles were filed and analyzed. Overall, lipid nanoparti - active ingredients for skin hyperpigmentation disorder, cles were found to be the most widely used nanomate- none of them are completely satisfactory due to their rial in treating hyperpigmentation. poor permeability through the skin layer and signifi - cant toxicity, thereby causing severe side effects such Keywords Nanomaterials · Cosmeceuticals · as irritative dermatitis, erythema, itching, and skin Hyperpigmentation · Hydroquinone · Arbutin · flaking. Nanotechnology plays an important role in Kojic acid · Azelaic acid · Retinoic acid · Lipid advancing the cosmeceutical formulation by improving nanoparticles the solubility, stability, safety, loading efficiency, and dermal permeability of the active ingredients. The aim of this review is to offer a comprehensive discussion on Introduction the application of various nanomaterials in improving cosmeceutical formulations used to treat hyperpigmen- Over the past decades, technological advancements tation. Focus is placed on elucidating the advantages in cosmeceuticals are growing rapidly. The rise in the that nanotechnology can bring to some common hyper- usage of cosmeceuticals in skincare can be attributed to pigmentation active ingredients such as hydroquinone, an increase in consumer awareness of general skin health arbutin, kojic acid, azelaic acid, and retinoic acid to and physical esthetic attributes. Coupled with the rise of improve their efficacy in treating hyperpigmentation. awareness of a healthy lifestyle, the role of cosmeceuticals and cosmetics has become essential in a person’s daily routine [1]. It is estimated that the rise in the market value and sales for the beauty and personal care market to go Mason Jarius Tangau and Yie Kie Chong contribute beyond $716 billion dollars by 2025 [1]. With such rapid equally to this work. development in skincare products, more quality and sci- M. J. Tangau · Y. K. Chong (*) · K. Y. Yeong (*)  entific assessments are needed to improve its efficiency. School of Science, Monash University Malaysia Campus, Besides focusing on improving the efficacy of Jalan Lagoon Selatan, 47500 Bandar Sunway, Selangor, individual active agents, scientists have also been Malaysia exploring more on how nanotechnology can improve e-mail: yiekie.chong@monash.edu the delivery and absorption of active ingredients to K. Y. Yeong  the skin [2, 3]. e-mail: yeong.kengyoon@monash.edu Vol.: (0123456789) 1 3 155 Page 2 of 18 J Nanopart Res (2022) 24: 155 Nanotechnology has become a promising addition to the Although the use of nanotechnology in cosmeceu- cosmetic industry due to its ability to enhance the properties ticals has been widely reported [4, 6, 19–21], specific of cosmetic products in general. Features such as absorption, details focusing on nanoparticles in improving the effi - texture, protection for active ingredients, and overall effi - cacy of depigmenting active ingredients have yet to be ciency could all be manipulated and improved upon using reviewed. Herein, we provide a general overview on the nanotechnology [4]. Nanotechnology utilizes nanoparticles use of nanotechnology and the advantages it brings in or nanomaterials which are naturally or synthetically derived improving the efficacy of anti-hyperpigmentation com - ranging from 1 to 100  nm [5]. The nano-sized particles pounds. Specifically, this review revisits common depig - are able to impart numerous important properties in topi- mentation active ingredients such as hydroquinone, cal applications. Firstly, the minuscule size of nanoparticles arbutin, kojic acid, azelaic acid, and retinoic acid and allows for a high surface area to volume ratio which enables elucidates new approaches where nanotechnology could greater exposure of active molecules per dose administrated improve their efficacy in treating hyperpigmentation. to the stratum corneum [6]. Secondly, nanoparticles are able to improve the absorption through the skin along with sus- Nanoparticles in cosmeceuticals tained release in order to increase blood circulation time of the encapsulated compound and improve the delivery of the The cosmeceutical industry uses various nanomateri- active ingredients to the targeted site [7]. Besides, nanomate- als, from lipid nanostructures to metal-based nanocar- rials may also provide better stability of cosmeceutical com- riers, nanocrystals, and even polymer-based nanocar- pounds of which may degrade due to oxidation or for other riers for various application (Fig. 2). reasons [8]. Figure 1 showed the outline of the improvement Recently, a variety of nanomaterials have been studied of cosmeceutical compounds by nanoparticles. in different in vivo models with outstanding and promis - Hyperpigmentation is one of the most notable skin ing outcomes [5]. Nanomaterials that are often studied maladies that is associated with discolorations or pig- alongside skin-based cosmetics can be divided into 2 main mentation problems [9]. Hormonal fluctuations, injury, categories, namely organic nanoparticles and inorganic skin inflammation, ultraviolet (UV) exposure, and nanoparticles as shown in Fig.  2. Organic nanoparticles improper medication are potential causes of hyperpig- are mainly used in lipid and polymer-based nanocarriers. mentation [10]. These events can trigger an over-produc- Inorganic nanoparticles are made up of metals and their tion of melanin by melanocytes within the skin layers oxides, and are generally water insoluble [1]. Organic which can result in dark spots or overall darkening of nanoparticles are mainly used in the formulation of active one’s skin tone [9]. Melanin is the natural pigment that ingredients by acting as carriers and absorption enhancers gives our skin, eyes, and hair color, and is essential for whereas inorganic nanoparticles are often used as bases the protection of human skin against radiation. How- for products that sit or act on the surface of the skin such ever, an abnormal increase in melanin production can as antimicrobial products or sunscreens. The main differ - result in pigmentation disorders, such as ephelides, mel- ence between the two lies with the sturdy nature of inor- asma, senile lentigines, and freckles [11]. Over the past ganic nanoparticles where their physical properties remain decade, several classes of tyrosinase inhibitors such as unchanged when applied topically [1]. Different classes of phenolics, steroids, flavonoids, terpenes, oxadiazole, and nanoparticles are further discussed below. bipiperidines have been reported to inhibit melanogen- esis and enzymatic browning [12–14]. Brightening or anti-hyperpigmentation agents such as, arbutin, azelaic Organic nanoparticles acid, kojic acid, and hydroquinone are commonly used in the market due to their ability to inhibit melanocytes or suppress melanin production [15–17]. However, these (1) Lipid and surfactant derived nanoparticles. depigmentation agents hardly showed inhibitory activity towards tyrosinase in intact melanocytes. Some are even considered to be cytotoxic and unstable over time [17, (a) Vesicular nanoparticles. 18]. With nanotechnology, the previously overlooked Lipid-based nanoparticles include vesicular nanopar- active ingredients could be further explored and formu- ticles such as niosomes and liposomes [1]. These lated into more effective and safer depigmenting agents. vesicular nanocarriers are spherical, in-closed Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 3 of 18 155 vesicles that are made up of naturally self-assem- their inherent tuneable microstructure, they are bly phospholipid bilayers or non-ionized syn- also utilized as emulsion stabilizers [24]. thetic amphiphilic lipids such as alkyl esters [6]. Liposomes range from 10 to 3000  nm, which is comparatively larger than niosomes which range (2) Polymeric nanoparticles. from 10 to 100 nm. These lipid-rich vesicles are Polymeric nanoparticles are categorized into nano- able to enhance the penetration of encapsulated capsules and nanospheres. Nanocapsules are active ingredients due to their amphiphilic nature, formed from a polymeric coating which shelters which in turn boosts their bioavailability. Moreo- a liquid core that contains either an oil or sur- ver, they are also biodegradable which is an envi- factant that is loaded with the active ingredient ronmental advantage. whereas nanospheres are matrixes which trap the (b) Non-vesicular nanoparticles. active ingredient within its network [6]. The main Non-vesicular carriers including nanoemulsions, benefit that comes from the use of polymeric solid lipid nanoparticles (SLN) and nano-based nanoparticles is their ability to encapsulate both lipid carriers (NLC) are mainly composed of dif- hydrophilic and lipophilic active ingredients. fering heterogenous systems that are dual-phased Moreover, they can extend the lifespan of unsta- (aqueous and lipophilic) and stabilized with ble compounds such as antioxidants and vola- emulsifiers and surfactants (NLC). Nanoemul - tile chemicals such as fragrances [1]. Generally, sions are dual-phase systems that contain oil an polymeric nanoparticles can be prepared using aqueous medium and emulsifying agents [22]. synthetic or natural polymer. Polyethylene glycol, Their ultrafine texture often leads to a silkier fin - polylactides, and poly(lactic-co-glycolic acid) ish, enhancing product absorption as well as pro- (PLGA) are examples of biodegradable synthetic viding a boost in skin hydration.[5] On the other polymers while poly(methyl methacrylate) and hand, SLNs and NLCs are made up of a lipid core polyacrylates are few of the non-biodegradable containing either solidified lipids or liquidized synthetic polymer which are frequently used to lipids respectively. In general, both lipid nanocar- deliver hydrophobic compounds in skin care for- riers can be used to deliver poorly water-soluble mulations [25]. Chitosan, gelatin, and albumin drugs and bioactive molecules [23]. Next, due to are natural polymers that are biodegradable and Fig. 1 Schematic outline for improvement of cosme- ceutical compounds using nanotechnology Vol.: (0123456789) 1 3 155 Page 4 of 18 J Nanopart Res (2022) 24: 155 Fig. 2 Schematic representation of nanomaterials in cosmeceutical biocompatible. Chitosan is commonly used natu- pounds. The results indicated that the surface ral polymer because it possesses great potential modified nanocrystal could increase surface for surface modification [ 26] and is suitable for hydrophobicity, emulsifying efficiency, stability, encapsulating negatively charged compounds as well as penetration depth through all skin lay- which can help in cellular internalization [25]. In ers with increasing drug accumulation [28]. comparison, synthetic polymers are more flexible as they were able to turn into various shapes and size compared to natural polymer [27]. (3) Nanocrystals. Inorganic nanoparticles Nanocrystal is another form of polymeric nanoparti- cles that are mainly used for the delivery of insol- Inorganic nanoparticles are commonly used as active uble active ingredients [22]. Nanocrystals possess substances, nanocarriers, and modifiers in cosmetic a large surface area which aids the absorption of products. Carbon-based nanotube, nanorod, noble otherwise insoluble active ingredients. Recently, metals, metal oxides, and mesoporous nanostructures Hiranphinyophat and co-workers reported a are several classes of inorganic nanoparticles used in poly(2-isopropoxy-2-oxo-1,3,2-dioxaphospho- commercial cosmetic products. Carbon-based nano- lane) (PIPP) modified cellulose nanocrystal as tubes are widely used for coloring hair, eyelashes, a vehicle for topical delivery of lipophilic com- and eyebrows due to its high resistance to various Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 5 of 18 155 shampoos and its heat dissipation abilities [29, 30]. Overall, these depigmenting compounds exhibit Mesoporous silica is a porous form of silica com- good efficacy. However, the severe side effects pre - posed of hexagonal array of nanoscale pores which vented these depigmenting agents from being used in can accommodate the active compounds and control numerous countries. Several studies have shown that its release [31]. Mesoporous silica encapsulated with the encapsulation of depigmenting compound in nan- octal methoxycinnamate (MCX) and benzophenone-3 oparticles could reduce its adverse effects, promotes (BZP) were reported to improve UV protection com- target delivery, and enhance its stability [60–64]. The pared to the non-encapsulated-free compounds alone. advantages on the use of nanotechnology in various [32, 33]. Apart from mesoporous silica, inorganic depigmenting compounds are deliberated below. oxides nanoparticles such as TiO , ZnO, CeO , and 2 2 ZrO are able to scatter and reflect UV radiations. Application of nanoparticles in depigmentation Due to this property, they are widely included in the compounds formulation of cosmetic sunscreen [34]. Studies on hydroquinone loaded nanoparticles Advantages and drawbacks of nanomaterials used Hydroquinone (Fig. 3) is often used in the production in cosmeceutical formulation of skin-lightening products as it functions to inhibit tyrosinase activity [65]. It is a known irritant whereby Based on the nanomaterials discussed, the advantages its side effects include skin irritation and erythema and disadvantages will be highlighted further specifi - [66]. In cosmetic applications, hydroquinone suffers cally for organic nanoparticles and inorganic nano- from instability due to rapid oxidation, insufficient particles in Table 1. skin penetration because of its hydrophilic structure, and encounter serious side effects due to systemic absorption. Several studies were aimed to load hyd- Topical depigmenting agents roquinone into nanoparticles to overcome the men- tioned drawbacks of depigmenting agents. Skin-lightening compounds, such as hydroquinone, Studies have shown that encapsulation of hyd- kojic acid, arbutin, azelaic acid, and retinoic acid, are roquinone in lipid nanoparticles were able to often used to treat hyperpigmentation disorder. The enhance the stability against oxidation and pos- mode of action of depigmentation agents can be clas- sess better skin penetration ability compared to the sified as follows: (i) inhibition of tyrosinase; (ii) inhibi - hydroquinone [60]. An in vitro rat skin penetration tion of melanosome transfer; (iii) scavenge active oxy- study showed approximately threefold higher drug gen and limiting oxidative damage to cell membrane accumulation and 6.5-fold lower drug entrance structure; and (iv) interaction with copper which nor- into receptor phase of Franz cell confirming the mally serve as a catalyst in the formation of pigment lower systemic absorption of drug using hydro- [35]. Table 2 shows the classification of the depigment - quinone loaded SLN compared with hydroquinone ing agents based on their mechanism of action. hydrogel. The lipoid nature of SLN colloidal car- However, these depigmenting compounds are rier is likely to enable penetrated drugs to local- associated with many adverse effects such as irri - ize in the skin. This may reduce toxic side effects tative dermatitis, erythema, itching, and skin flak - as systemic absorption is minimized. Moreover, ing due to their poor solubility, poor permeability another research group has also reported a better through the stratum corneum, as well as high toxic- skin penetration and enhanced protection towards ity [48]. The poor skin permeability of depigmenting UVA/UVB irradiation using hydroquinone in compounds is often the result of the overaccumula- nanostructured lipid carrier (NLC) compared to tion of the active ingredients and increment of skin hydroquinone alone [67]. In their in vitro artificial retention period which in turn escalates the likelihood skin permeation study showed that percutaneous of adverse effects mentioned above [ 49, 50]. Table  3 penetration ability of hydroquinone encapsulated depicts clinical studies on various topical depigment- in NLC was significantly greater than hydroqui- ing agents and their observed side effects. none only. Vol.: (0123456789) 1 3 155 Page 6 of 18 J Nanopart Res (2022) 24: 155 Table 1 Advantages and disadvantages of organic and inorganic nanoparticles in treating hyperpigmentation [19, 35–43] Advantages Drawbacks Organic nanoparticles Niosomes -Allows for controlled and tar- -Chance for leaking and hydroly- geted compound delivery sis of entrapped compound and -Increased dermal penetration reducing shelf life -Low toxicity, biocompatible and -Physically unstable nonimmunogenic -Tends to aggregate Liposomes -Increased stability for encapsu- -High production cost lated compound -Low solubility -Biocompatible and biodegrad- -Chance for leaking of entrapped able active ingredient -Increased efficacy of encapsu- lated active ingredient Nanostructured lipid carrier -Physically stable -Irritative and sensitizing actions (NLC) -Higher loading capacity com- caused by some surfactant that pared to SNL use to produce NLC -Extended release of drug -Insufficient studies in the prepara- tion of NLCs Solid lipid nanoparticles (SNL) -Possesses an occlusive nature -Poor drug loading capacity which aids in increasing skin -Burst release hydration -Not suitable for loading hydro- -Easy to upscale philic compound -Increased bioavailability of encapsulated active ingredient Nanoemulsion -Suitable for delivery of both -Low viscosity and spreadability lipophilic and hydrophilic -Higher chance for skin irritation compound -Low bioavailability -Increased rate of absorption -Can be formulated into creams, sprays, foams and so on Polymeric nanoparticles -Controlled and sustained release -Difficult to scale up -Good protection from enzymatic -Insufficient toxicity assessment in and chemical degradation literature -Low toxicity Nanocrystals -Can obtain high dosage of -Low stability entrapped active ingredient -Some active ingredients may not -Increased bioavailability be easily crystallized Inorganic Al O, TiO , ZnO, gold, silver, -Biocompatible -High toxicity (can damage 2 3 2 nanoparticles copper and carbon-based nano- -High physical and chemical pulmonary tissue and may have particles etc stability cytotoxic effects) In addition, it has been revealed that hydroqui- against oxidation [68]. The study showed a sustained none after loaded in cellulose nanocrystals are exhib- release profile of hydroquinone (80% of bound hydro - ited sustained release manners and showed stability quinone released in 4 h) which improved the efficacy Table 2 Classification of Mechanism of action Depigmenting compounds depigmenting agents based on their mechanism of i) Inhibition of tyrosinase Hydroquinone, azelaic acid, kojic action [44–47] acid, and arbutin ii) Inhibition of melanosome transfer Retinoids (including of retinoic acid) iii) Reactive oxygen species scavengers during melanin Ascorbic acid synthesis iv) Interaction with copper Kojic acid, ascorbic acid Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 7 of 18 155 Table 3 Summary of the findings and side effects of topical depigmenting agents Depigmenting Studies agents Hydroquinone Amer and Metwalli [51] Results: Patients with melasma, post-inflammatory hyperpigmentation, and freckles was achieved in good to excellent responses at 89.5%, 75%, and 44.4% respectively Side effects: Local irritation was found in most patients Ennes et al. [52] Results: 38% of patients showed total improvement, partial improvement in 57% and 5% of patients discontinued therapy Side effects: 28.6% of patients experienced adverse effects including contact dermatitis Haddad et al. [53] Results: 76.9% of melasma patients showed improvement Side effects: 25% of patients experienced irritation effect. It can trigger “confetti leukoderma” (a focal depigmen- tation of the skin) due to the destruction of melanocytes Arbutin Morag et al. [54] Results: 75.86% of female melasma patients and 56.00% of female lentigo solaris patients showed improvement Side effects: No side effects were observed Azelaic acid Baliña and Graupe [55] Results: 64.8% of melasma patients were observed a good to excellent result Side effects: 11% of patients were found to encounter local irritation Sarkar et al. [56] Results: 96.7% of melasma patients had good to excellent responses Side effects: 20% of patients were encountered side effect including burning, erythema and itching Kojic acid Monteiro et al. [57] Results: After the treatment, mean melasma area and severity index score was decreased by 2.403 Side effects: 3.3% of patients experienced erythema and burning sensation Retinoic acid Griffiths et al. [58] Results: 68% of melasma patients was observed a improved or much improved results Side effects: 88% of patient were encountered moderate cutaneous side effects Kimbrough-Green [59] Results: 32% of melasma patients were improved Side effects: 67% of patients occurred mild retinoid dermatitis and simultaneously reduced the adverse effects of hydroquinone. All of the above examples showed that nanotech- nology is a promising approach for topical admin- istration of hydroquinone to overcome hyperpig- mentation with a suitable skin penetration and low systemic absorption to reduce the adverse effects of hydroquinone. Studies on arbutin loaded nanoparticles Arbutin (Fig.  4) is commonly used as a skin-light- ening and brightening agent in skincare and cos- metic products [69]. The main mode of action for arbutin is inhibit the synthesis of melanin by act- ing as a tyrosinase inhibitor [70]. Besides, it is also Fig. 3 Chemical structure of hydroquinone Vol.: (0123456789) 1 3 155 Page 8 of 18 J Nanopart Res (2022) 24: 155 possesses anti-inflammatory and antioxidant prop - melanin) and their culture medium (extracellular mel- erties [71]. It is highly hydrophilic and hygroscopic anin), arbutin-GNP nanocomplex were able to inhibit due to its chemical structure which contains multiple the production of intracellular and extracellular mela- hydroxyl groups. Therefore, it usually suffers from nin of up to 22.7 and 47.7% respectively versus 21.8% poor absorption and penetrance through the stratum and 31.8% with arbutin alone. The study also reveals corneum [72]. The high lipid content of the skin ren- that arbutin-GNP nanocomplex exhibited better anti- ders arbutin difficult to permeate through it and dif - inflammatory activity and lower toxicity comparing fuse into the inner cells. A recent study indicated that to pure arbutin. the arbutin’s adverse effects is triggered by external Guar gum (GG)-based nanomaterials have been production of hydroquinone due to exposure of ultra- extensively used for skin and percutaneous admin- violet rays and skins microorganisms [66]. istration to controlled release and delivery enhance- One of the methods to mitigate the poor penetra- ment [76–78]. A cross-linked amphiphilic GG tion is by loading arbutin into chitosan polymeric nanocarriers loaded with arbutin was reported [79]. nanoparticles. Chitosan is a biodegradable polymer Through the modification of guar gum with hydro - made from de-acetylated chitin that possesses high phobic short-chain alkylglycerol, namely glycidol biocompatibility, non-toxic, and can interact with a butyl ether (GBE), the GBE-GG nanocomplex loaded large variety of polyanions [73]. When it is made into with arbutin imparted a higher degree of hydropho- a nanocarrier, positively charged chitosan nanoparti- bicity which increases its permeation through the cles (CNP) was able to increase permeation through stratum corneum. Besides, the results suggested the the skin due to the increased interaction with nega- absence of cellular toxicity and better cellular uptake tively charged cellular surfaces and eventual uptake across the cultured human keratinocyte HaCaT cells into melanocytes via endocytosis or phagocytosis that increase the biological membrane permeability, [74]. Ayumi et  al. reported that the α-arbutin and suggesting their potential as safe nanocarriers for top- β-arbutin chitosan nanoparticles demonstrated pro- ical delivery. longed rate of absorption by releasing the active com- Nanoemulsion of arbutin loaded with coumaric pound slowly over a sustained 52-h period [74]. acid has also been showed to improve the deliv- Gold nanoparticles (GNPs) have become prevalent ery and stability of arbutin [61]. Through the use of within the cosmeceutical industry due to their inert multi-phase (w/o/w) nanoemulsion, it was found that and non-toxic nature. Park et  al. described a novel the encapsulated arbutin achieved high stability and arbutin-GNP nanocomplex which possesses supe- high encapsulation efficiency using a hydrocolloid rior brightening properties compared to arbutin alone medium. Furthermore, the encapsulated arbutin was [75]. In their study, they measure the melanin con- able to exhibit sustained release (86%) due to the tent from both the tested melanocytes (intercellular nature of the gelatin hydrocolloid in compared to free Fig. 4 Chemical structure of arbutin Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 9 of 18 155 form of arbutin, which only resulted in a 5% overall drug retention and tyrosinase inhibition activity [86]. release over a period of 6 h. In their study, hyaluronic acid was used to formulate In conclusion, the application of different types of into nanoemulsion along with azelaic acid because nanotechnology has been able to overcome the weak hyaluronic acid was previously reported to signifi - permeating capability of arbutin by either encapsulat- cantly decrease the melanin synthesis due to improv- ing it via polymeric nanocarriers, complexing it with ing the interaction of nanoemulsion and melanocytes inorganic nanoparticles such as GNPs or formulating [87]. At last, with the help of nanotechnology and it within a nanoemulsion. hyaluronic acid, azelaic acid–loaded nanoemulsion showed lesser tyrosinase activity and permeated Studies on azelaic acid–loaded nanoparticles through the skin without showing cytotoxic activity. A study showed that the use of nanostruc- The main use of azelaic acid (Fig. 5) originates from tured lipid carriers (NLC) loaded with azelaic acid its antibacterial, anti-inflammatory, and skin bright - allowed for its enhancement towards its target- ening properties [80]. Its ability to treat hyperpigmen- ing sites such as melanocytes. This is due to their tation lies with its nature as a potent reversible inhibi- small particle size and its innate occlusive effect tor of the tyrosinase enzyme [81]. As azelaic acid that allows for better penetration through the stra- possess two carboxyl groups, it is easily ionized. The tum corneum [88]. When tested for their permeation ionized compounds tend to exhibit poorer skin per- capabilities, the release rates of azelaic acid-NLC, meability due to the hydrophobic nature of the skin azelaic acid gel, and azelaic acid in water was found [82, 83]. Thus, in response to azelaic acid’s poor per- to be 21%, 38%, and 78% respectively. Despite meability through the skin, azelaic acid encapsulated the slower release rates, azelaic acid-NLC exhib- by nanoparticles were able to increase absorption to ited a higher initial burst release of up to 5%. The exhibit significant therapeutic effect [ 82]. azelaic acid-NLC’s ability for sustained release and Nanocrystals have received considerable attention high initial burst release is advantageous for topical in cosmeceutical as they increased compound’s solu- application as it allows for a rapid onset of action bility, dissolution rate, and increased adhesion proper- and allows for a drug depot effect to take place in ties of nanocrystal to the skin [84, 85]. With the aims a localized area. The slower release of azelaic acid- to enhance the solubility and stability of azelaic acid, NLC also mitigated the occurrence of side effects as Tomic and co-workers reported the encapsulation of the skin was not exposed to high amounts of azelaic azelaic acid in nanocrystals suspended in Pluronic® acid over a period of time compared to azelaic acid F127 and hyaluronic acid (PHA). These azelaic acid gel and azelaic acid in water. nanocrystals showed improved aqueous solubility and In short, the use of nanotechnology is able amelio- dissolution rate [62]. The results suggested that the rate the drawbacks faced when formulating azelaic acid nanocrystal of azelaic acid and its incorporation in such as its poor aqueous solubility and occurrence of PHA hydrogel gave better skin bioavailability in com- dermal adverse effects. Examples including nanoe - parison to an azelaic acid–containing standard com- mulsions and nanocrystals allow better solubility of mercial product. azelaic acid and with the use of NLCs; the likelihood It has also been revealed that azelaic acid loaded of adverse effects is lowered due to the gradual release in nanoemulsion with hyaluronic acid exhibited better effect of azelaic acid–loaded NLC formulation. Fig. 5 Chemical structure of azelaic acid Vol.: (0123456789) 1 3 155 Page 10 of 18 J Nanopart Res (2022) 24: 155 Studies on kojic acid–loaded nanoparticles et al. reported the formulation of kojic acid loaded in NLCs were showed to have better release profile, and Kojic acid (Fig.  6) primarily functions as a skin- more potent tyrosinase inhibitory as well as antioxi- lightening agent by acting as an inhibitor for tyrosi- dant activities compared to the pure kojic acid [63]. nase [89]. The main mode of action for kojic acid Results of these studies indicated that kojic acid- as an inhibitor is through its ability to chelate to SLNs and kojic acid-NLCs with lipid excipients and the copper within the enzymes active site [90]. It is surfactant increase skin permeation. This implies the highly hydrophilic as its chemical structure contain- potential of nanotechnology for kojic acid delivery in ing of two hydroxyl group. The hydrophilic nature topical application. of the compound makes it difficult for kojic acid A very recent study on different formulations to penetrate through the stratum corneum and hin- of oil-in-water (O/W) kojic acid nanoemulsion for dered the accumulate of kojic acid in the target sites topical application [100]. The study revealed vari- [18, 91]. Several studies have reported the concern ous parameters to generate kinetically stable nanoe- of kojic acid regarding its toxicity [92], carcino- mulsion at a recommended pH range of pH 4.95 genicity, mutagenicity [93], irritancy [94], hepa- to 5.18 for 6  weeks storage. The results suggested tocarcinogenicity [95, 96], genotoxicity [97], and the suitability of the kojic acid emulsion for topical tumor-initiating activity [98]. Loading kojic acid in application. nanoparticle has been envisage to counteract these The above studies revealed that the loading of adverse effects. kojic acid in nanoparticles are able to reduce the Solid lipid nanoparticles (SLNs) and nanostruc- hydrophilic nature of kojic acid and thereby increase tured lipid carriers (NLCs) have been extensively its skin permeation and stability, by either loaded studied as way to bypass the hydrophilic nature of kojic acid with SLNs and NLCs or formulating it into kojic acid. Khezri et al. reported a kojic acid–loaded nanoemulsion. SLNs optimized by some lipid excipients and sur- factants in order to increase its loading. The results Studies on retinoic acid–loaded nanoparticles indicated that the kojic acid-SLNs dispersion can increase the dermal delivery of kojic acid with Retinoic acid (tretinoin; Fig. 7) is a metabolite of vita- higher concentration, better controlled release, and min A [101]. It is often used in the treatment of mel- more tyrosinase inhibition potency compare with asma and other pigmentation disorders [58]. When the free form of kojic acid [99]. Recently, Khezri used topically, it functions to increase the pigment Fig. 6 Chemical structure of kojic acid Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 11 of 18 155 transfer to keratinocytes, as well as the rate at which retinoic acid, which proved to be more effective and skin cells are shed. It is also known to inhibit the pro- biocompatible than the marketed product [64]. duction of tyrosinase [102]. Further benefits from reti - A study by Shah et  al. (2007) showed improved noic acid also include their superior antioxidant and physical stability and dermal tolerability of retinoic antimicrobial capabilities. The use of retinoic acid acid with encapsulation of SLNs [106]. When tested in product formulation is often met with challenges for photodegradability, retinoic acid-SLNs proved due to its inherent lipophilicity, which results in poor to be superior when irradiated, retaining up to 71% aqueous solubility. This limits its ability to be formu- of the retinoic acid content in comparison to reti- lated in aqueous mediums and often results in the use noic acid in methanol which only retained 12%. The of harmful co-solvents such as ethanol and propylene irritating properties of retinoic acid has been stated glycol [103]. Furthermore, the unstable nature of reti- to originate from its acidic functionality (carboxyl noic acid has also led to a drop in its therapeutic effi - group) when it is contact with the skin. This problem cacy. This is due to increased liability and decreased can be possibly be overcome using retinoic acid-SLN, stability when exposed to light, heat, oxidation, and whereas Draize patch test on rabbits attained a lower changes to environmental pH [104, 105]. irritation score compared to the marketed retinoic Ourique et  al. (2011) describe the use of a lipid- acid formulation. core polymeric nanocapsules (LCNC) to encapsulate In summary, the studies above suggesting the retinoic acid in order to increase the photostability emerging of nanotechnology in retinoic acid able to and improve skin retention time. When tested for half- eliminate the drawbacks such as its poor aqueous sol- life and effects of photodegradation, the retinoic acid- ubility and photosensitivity. LCNC achieved a t of 26.6 h compared to marketed 1/2 gel containing retinoid acid which has a t of 3.8 h. Trends of patents and research papers on 1/2 Furthermore, the rate of degradation was significantly nanotechnology in hyperpigmentation treatment reduced in retinoic acid-LCNC compared to retinoic acid, from 68.64 to 24.17% [103]. In order to further study on the relevance and com- Vesicular nanocarriers such as liposomes have also mercial research of nanomaterials for the improve- been documented to aid retinoic acid to retain on the ment to the delivery and efficacy of the aforemen - skin. It also offers enhanced protection from UV radi - tioned depigmenting compounds (hydroquinone, ation. Furthermore, the use of phospholipids in the arbutin, azelaic acid, kojic acid, and retinoic acid), a creation of such nanocarriers offers a higher biocom - total of 44 patents and articles on the encapsulation patibility compared to traditional mediums such as of the active ingredients by nanoparticles were filed gels and creams, increasing retinoic acid’s therapeutic to date. Based on Fig.  8, only two patents and one efficacy. A study by Raza et al. demonstrated the use paper were published prior to 2010 compared to 44 of SLNs, NLCs, and liposomes to enhance the drug publications from 2010 to 2021. The rapid rise in the delivery of retinoic acid. The reported study indicates number of patents and papers can be attributed to the that nanoparticulate carriers could enhance the photo- exponential growth in the cosmetics industry. This stability, skin transport, and anti-psoriatic activity of provides opportunities to expand and investigate on Fig. 7 Chemical structure of retinoic acid Vol.: (0123456789) 1 3 155 Page 12 of 18 J Nanopart Res (2022) 24: 155 the use of nanocarriers in the formulation of the five to nanomaterials that are synthetic, insoluble, or not mentioned active ingredients. Among the depigment- readily biodegradable such as metals. Consequently, ing agents, arbutin remains to be the most studied materials that are soluble and biodegradable such as active ingredient in conjunction with nanotechnology. lipid-based nanoparticles (liposomes, NLC, and SLN) The extensive study of arbutin can be attributed by its are not considered as nanomaterials under the EC Reg- higher skin tolerance and reduced side effects com - ulation 1223/2009, which allowed for several indus- pared to traditional skin brightening agents such as tries including the cosmetic industry to utilize these hydroquinone, retinoic acid, and kojic acid [66, 107]. nanomaterials more extensively as they are not directly Nanotechnology-based cosmeceuticals continually regulated by the EC regulation and can be more freely gain attention over the past few decades. According to studied and marketed. In summary, increased cosmetic the market analysis by the Woodrow Wilson Interna- interest, government backing as well as decreased reg- tional Centre on Emerging Nanotechnology, 788 out ulation for certain types of nanomaterials has led to an of more than 1600 products were marketed as nano- overall increase in both patents and research towards technology products for cosmetic [108]. The European the use of nanotechnology for cosmetic products. Union (EU) revamped cosmetic regulation (Directive Based on the patents and research papers studied, 76/768/EEC) in 2009 under a new name, EC Regula- it was found that a vast majority of the discussed tion 1223/2009 [109], which included international papers researched on the use of lipid nanoparticles as guidelines in order to address issues in the technologi- nanocarriers in improving the efficacy of the depig - cal insufficiencies within the cosmetic industry and to menting active ingredients (14 out of the 25 listed include recent research developments towards formu- papers). In comparison, the least studied nanocarrier lating new nano-based cosmetics [110]. This gave the was found to be inorganic nanoparticles which only push towards the usage of research data in developing had 1 paper associated with treatment of depigment- more sophisticated nano-based products, increased ing agents based on Table 4. transparency when providing information towards cus- The rise in the popularity of lipid nanoparticles in tomers, and rigorous safety testing, especially within research is due to several important properties such as the EU countries. Notably, these guidelines only apply high skin penetration ability, safe for topical application, Fig. 8 Number of patents and published papers before 2010 (a) and 2010–2021 (b), corresponding to the 5 studied active ingredi- ents, hydroquinone, arbutin, azelaic acid, kojic acid, and retinoic acid Vol:. (1234567890) 1 3 J Nanopart Res (2022) 24: 155 Page 13 of 18 155 biocompatible, and biodegradable when used topically [119–121]. Further studies have also shown that the SLNs and NLCs can act as a physical ultraviolet ray blocker [22, 119]. This allows for the encapsulation of photosensitive materials such as retinoic acid. Unlike lipid nanoparticles, inorganic nanoparticles such as gold, titanium, and silica- based nanoparticles are considered to be insoluble parti- cles [1]. Thus, these materials are unlikely to degrade after topical application [122]. Moreover, there is high risk in utilizing these inorganic nanoparticles as they may have risks in terms of occupational, environmental, or even toxicity [123]. Furthermore, inorganic nanoparticles were more likely to use as active agents for UV protection rather than acting as nanocarriers for other active ingredients [1]. Conclusion Nanotechnology has recently received increased attention in cosmetic industry. Some advances have been widely applied such as in formulations for skin whitening but treating hyperpigmentation has often been overlooked. In this review, we have summaries how the current nanotech- nology helps in solving the problem of depigmentation agents, in particularly: improving the solubility; enhancing the stability; reducing its toxicity by controlling the release of active ingredient; and increasing its entrapment effi - ciency and dermal penetration of the active ingredient to reach the stratum corneum. From the 44 reported patents and articles, lipid nanoparticles were found to be the most widely use nanocosmeceutical in treating hyperpigmen- tation due to its high skin permeability, biocompatible, and biodegradable as well as its use as an ultraviolet ray blocker. Notably, less regulation for specific types of nano - material has also led to an overall increase in both patents and research towards the use of biodegradable lipid nano- particles for hyperpigmentation treatment. Meticulous studies on health hazard and safety profile of nanomateri - als used in cosmeceutical are required to fully understand the impact of mass usage of these materials. Ultimately, precise and stringent laws and guidelines for control of cosmetic products should be imposed to ensure the safety of cosmeceutical nanoparticles used. Acknowledgements The authors acknowledge the School of Science, Monash University Malaysia for supporting this work. Author contribution MJT: conceptualization, literature search, writing of manuscript; YKC: conceptualization, litera- ture search, writing, and editing manuscript; KYY: conceptual- ization, reviewing, and editing manuscript. Vol.: (0123456789) 1 3 Table 4 List of nanocarriers from research papers that utilized the five depigmenting agents Hydroquinone Arbutin Azelaic acid Kojic acid Retinoic acid Lipid nanoparticles SLN Ghanbarzadeh et al. [60] - - Khezri et al. [99]; Moham- Raza et al. [64]; Shah madi et al. [111]; et al. [106]; Bosk- abadi et al. [112] NLC Wu et al. [67] - Kumari et al. [88]; Lacatusu Khezri et al. [63] Raza et al. [64]; Asfour et al., Malik and Kaur et al., et al. [115] Arsenic et al. [84, 113, 114] Niosomes - Radmard et al. [116] - - - Liposomes - - - - Raza et al. [64] Polymeric nanoparticles Chitosan - Ayumi et al. (74) - - - Biodegradable poly- - - Reis et al. [117] - Ourique et al. [103] ester Silica - - - Lima et al. [118] - Guar gum - Bostanudin et al. [79] - - - Nanoemulsion - Huang et al. [61] Jacobus Berlitz et al. [86] Yun et al. [100] - Nanocrystal Taheri and Mohammadi et al. Tomic et al. [62] - - [68] Inorganic nanoparticles Gold - Park et al. [75] - - - 155 Page 14 of 18 J Nanopart Res (2022) 24: 155 Funding Open Access funding enabled and organized by hormonal regulation. Physiol Rev 84:1155–1228. https:// CAUL and its Member Institutionsdoi. org/ 10. 1152/ physr ev. 00044. 2003 12. Chang TS (2009) An updated review of tyrosinase inhib- Declarations itors. 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Journal

Journal of Nanoparticle Research – Springer Journals

Published: Aug 1, 2022

Keywords: Nanomaterials; Cosmeceuticals; Hyperpigmentation; Hydroquinone; Arbutin; Kojic acid; Azelaic acid; Retinoic acid; Lipid nanoparticles

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