Topical Dosage Form & Delivery System for Pigmentation Control: A Review

Hyperpigmentation is one of the most commonly seen skin disorders which is not a concerning health issues but it may affect the psychological aspect of a person. Hyperpigmentation is caused by the presence of excess melanin, which is the brown pigment of the skin. Products that aimed to reduce the pigmentations act by inhibiting the tyrosinase enzyme, which is the rate-limiting enzyme in the synthesis of melanin. There are many products that are currently available in the market that aims to reduce pigmentation of the skin. These products are conventionally formulated into different dosage forms such as cream, lotion and emulgel, which gains popularity due to its convenience on application. However, due to the drawbacks that these dosage forms possess such as poor stability and absorption, new formulations are presented which incorporate novel drug delivery system into the conventional dosage forms. These novel drug delivery systems are, inter alia, liposome, niosomes and microsphere. They carry benefits of controlled drug delivery, enhanced skin penetration and reduce drug toxicity as compared to the conventional dosage form, which resulted in the increase in marketed product diving into this pathway. This present article will discuss the various dosage forms, drug delivery system, its advantages, disadvantages and marketed product for pigmentation control.

Dosage forms, Drug delivery system, hyperpigmentation, anti-tyrosinase, skin-whitening, skin-lightening A Hyperpigmentation is one of the most commonly seen skin disorders which is not a concerning health issues but it may affect the psychological aspect of a person. Hyperpigmentation is caused by the presence of excess melanin, which is the brown pigment of the skin. Products that aimed to reduce the pigmentations act by inhibiting the tyrosinase enzyme, which is the rate-limiting enzyme in the synthesis of melanin. There are many products that are currently available in the market that aims to reduce pigmentation of the skin. These products are conventionally formulated into different dosage forms such as cream, lotion and emulgel, which gains popularity due to its convenience on application. However, due to the drawbacks that these dosage forms possess such as poor stability and absorption, new formulations are presented which incorporate novel drug delivery system into the conventional dosage forms. These novel drug delivery systems are, inter alia, liposome, niosomes and microsphere. They carry bene its of controlled drug delivery, enhanced skin penetration and reduce drug toxicity as compared to the conventional dosage form, which resulted in the increase in marketed product diving into this pathway. This present article will discuss the various dosage forms, drug delivery system, its advantages, disadvantages and marketed product for pigmentation control.

INTRODUCTION
Pigmentation is not a concerning health issue but is rather unpleasant aesthetically. Going back to the root that leads to pigmentation, it all arises from tyrosinase, being the rate-limiting enzyme to produce melanin, the brown pigmentation that causes pigmentation of the skin. Products that aimed to reduce pigmentation usually target at inhibiting the tyrosinase enzyme, which is the rate-limiting enzyme for the melanogenesis process.
The advancement of pharmaceutical technology has driven formulation scientist to explore into dosage forms other than parenteral or oral route, which is of more convenient and less invasive. Topical dosage form refers to the dosage form that aims to deliver the drug locally through anywhere in the body, such as ophthalmic, rectal or skin. Skin is the largest organ of the body and is also considered to be the main target for most topical dosage forms. Topical preparations can be used to target locally on the skin surface or even systemically. In this context, the excipients employed will play an important role in determining whether the preparation will act locally or systemically.
Dosage form indicates the physical form of the drug as solid, liquid or gas. It essentially refers to the end product in which the product is marketed for use, which includes the active ingredient, excipients as well as material that is neither an ingredient nor excipients such as capsule shell. On the other hand, drug delivery system refers to the way in which the active ingredients are administered in order to reach the site of action and achieve its therapeutic effect.
There are currently many topical dosage forms for cosmeceutical products that are available in the market, including cream, gel, lotion and emulsion. It is a widely accepted form of dosage form due to its non-invasiveness as well as convenience. Preparations applied topically can also bypass hepatic irst pass metabolism as well as the acidity of the gastric acid that orally administered drug would encounter. Not to mention, due to its conveniency, this will improve the user's compliance and acceptance on the product. The systemic toxicity caused by the active ingredient can also be held to the minimum with the use of topical dosage form (Malik et al., 2016).
However, the challenges in these conventional topical dosage forms are its stability, which largely depends upon its active ingredients as well as excipients, its ability to cross the lipophilic and tight skin barrier, thus relating to its lipophilicity, and not to mention, is whether it is accepted cosmetically, which for example, should be of less greasy (Bhowmik, 2016). These conventional formulations also possess certain drawbacks such as the low bioavailability (1 to 15%) although there is a high level of the pharmacological agent at the site of application.
Hence, in order to address the drawbacks brought upon by the conventional dosage forms, topical dosage forms are prepared using various delivery systems such as liposome, niosomes and microsphere. Depending on the formulations, these novel drug delivery systems are able to be incorporated into the conventional dosage forms, which carries advantages such as improved stability and improved skin penetration.

Cream
Creams are dosage form that is intended to be applied on the skin. It has a consistency thicker than solution and is also known as a semi-solid emulsion being either water-in-oil or oil-in-water emulsion. Creams are used in cosmetics for cleansing, beautifying and are also used for therapeutic purposes. Active components incorporated into cream formulations are intended to provide a local effect, deliv-ering the component to a particular area beneath the skin layers, or the mucous membrane. Oil-inwater creams consist of small oil droplets dispersing in an external aqueous phase, while water-inoil creams consist of small water droplets dispersing in the external oily phase. In general, most of the creams used for cosmetic purposes are in the form of oil-in-water as it is less greasy, more comfortable and is accepted cosmetically. Most of the depigmentation products available in the market currently are in the form of cream. Hydroquinone, tretinoin, corticosteroids, azelaic acid, kojic acid, glycolic acid, zinc sulfate and some herbal extracts such as arbutin are the active ingredients employed in the formulation of topical bleaching cream. Based on the study conducted by Susan Farshi which compared 20% azelaic acid cream and 4% of hydroquinone cream in treating melasma, it was shown that 20% azelaic acid cream when applied two times a day is effective in treating mild melasma (Farshi, 2011). It is also reported that the triple combination therapy of 4% hydroquinone, 0.05% tretinoin and 0.01% luocinolone acetonide as an oil-in-water cream is more effective than monotherapy and is also tolerable by the patients who received the therapy (Malakooti, 2020).
Based on the study conducted by Nicholas J. Lowe et al. on the treatment of hyperpigmentation on the face with azelaic acid cream, it was shown that 20% azelaic acid cream is effective in reducing the hyperpigmentation and most of the study participants perceived the medicated cream used as nongreasy or slightly greasy (Lowe, 1998). In addition, none of the study participants rated the creams used as very or extremely drying. This is further supported by the study conducted by Jaya Gade and co-investigators on the formulation of herbal cream on 16 volunteers. In the study, it was reported that the formulation showed a good spreadibility, homogeneity, non greasy and function as an emollient (Gade et al., 2015). Besides, cream or topical dosage forms also have the advantage of less systemic absorption, resulting in lesser possibility of systemic toxicity. The table below (Table 1) summarizes the advantages and disadvantages of topical cream dosage form as well as the various marketed depigmentation cream (Table 2) Gel Pigmentation products in the market are also formulated in the form of gel. For example, PCA skin pigment gel and NEOSTRATA Enlighten Pigment Lightening Gel is in the form of gel dosage form (Table 2). Gel is classi ied as a semisolid, with the external solvent phase being either hydrophobic or hydrophilic and is immobilized within the space present in a three-dimensional network structure. Gels consist mostly of luid solvent, with a lesser percentage consisting of a solid matrix. The greatest difference between gel and cream is that gel consists of a higher water content, allowing a greater dissolution of drugs, and facilitate the movement of drug through the vesicle. The higher amount of aqueous component of gel enhances the dissolution of drug and eases the migration of drug through a liquid vehicle when compared with ointment or cream base.
The advantage of employing gel as a topical dosage form is due to it being colourless, thus high cosmetic acceptability, good homogeneity and spreadability, as well as smooth in texture which is reported in the study conducted by (Alzomor et al., 2014). The good quality of gel can also be seen in the study conducted by C-H. Hong on the preference for topical therapy by psoriasis patients. Most of the patients recruited in the study preferred gel over ointment and cream due it being non-greasy and free of odour (Hong, 2017). However, the drawback of gel can be seen in the study conducted by Donatas Grina, in which colour changes occur in all formulations of gel when it is stored in room temperature in a plastic container. The author concluded that the colour change may be attributed to the incompatibility of gel with the plastic container. In the same study, it can also be seen that gel preparation has instability issue as it has a greater tendency to undergo recrystallisation at room temperature as compare to cream and ointment dosage forms (Grina, 2011). The various advantages and disadvantages of gel are summarized in Table 1.

Ointment
Ointment is a semisolid dosage form that is intended to be applied externally on the skin or mucous membrane. The active ingredients and excipients are dissolved, suspended or emulsi ied in the ointment base. However, its greasiness resulted in a lesser aesthetic acceptability as well as poor spreadability which were shown in the study conducted by (Grina, 2011). In the study conducted by C-H. Hong on 213 patients with psoriasis, it was shown that ointment resulted in poor consumer satisfaction, with a poor score in the section 'not greasy', 'dried quickly', 'no staining' and 'quickly absorbed' (Hong, 2017). Although tacrolimus ointment were used mainly for atopic eczema, however a study conducted by N Al-Mutairi showed that tacrolimus ointment has promising effect on the treatment of Lichen planus pigmentation (Al-Mutairi and El-Khalawany, 2010). In addition to those mentioned earlier, other ben-e its and drawbacks of ointment dosage form are listed in Table 3.

Emulgel
Although gels can provide faster drug release compared with ointments and creams, the delivery of hydrophobic drugs has been a major problem due to the high amount of aqueous or hydroalcoholic liquid in the gel formulation. A combination of emulsions and gels termed as emulgel has shown enhanced stability at high temperature. The incorporation of a gelling agent into the aqeous phase of emulsion converts the conventional emulsion into emulgel. In a study conducted by LuanaPerioli and coinvestigator, it can be seen that depending on the formulation, emulgel can result in a good consistency and stability. In vivo test conducted in this study has also showed that emulgel possess good tolerability, comfortable and is not irritating. In addition, emulgel also exhibits bene its when applied topically, such as grease-free, good spreadability, good stability and it is accepted cosmetically. Azelaic acid that has been known for its ability to treat acne and hyperpigmentation has been formulated in the form of emulgel to solve its poor permeability and solubility issue. Emulgel has also shown to improve the release of lycopene extracted from the fruit of S. Lycopersicum based on the study conducted by M. Sohail and coinvestigator (Sohail, 2018). However, the drawback of emulgel is that it is better suited for hydrophobic drug, the possibility of bubble formation during formulation and poor absorption of large drug particles when applied topically (Table 4) (Baibhav, 2011). Example of several available depigmentation emulgel products are listed in Table 5.

Lotion
According to USP35 Chapter <1151>, lotions are de ined as an "emulsi ied liquid dosage form generally intended for external application to the skin". In terms of characteristic, lotion and creams shares many similarities. However, the major difference is that lotion being a liquid dosage form is more luid in nature as compared to cream which is a semisolid. As a result, lotion exhibits a greater spreadability than cream. The bene it of lotion is that it is not greasy and evaporates rapidly, leaving a cooling sensation when rubbed onto the skin. On the other hand, due to its luidity, it is easily washed or rubbed off, resulting in a short contact time. Preservatives that are added may also cause irritation to the skin (Table 4). Examples of several depigmentation lotions currently available in the market are listed in Table 5.

Liposome
Liposomes are human-made spherical shaped microscopic vesicle. It consists of phospholipids which are arranged into one or more concentric bilayers. It is arranged in such a way that the hydrophilic portion faces outwards towards the environment as well as inwards in the vesicle, surrounding the hydrophobic portion which is sandwiched between the outer and inner hydrophilic portion. With these characteristics, hydrophilic, lipophilic as well as amphiphilic substances are able to be carried by liposomes, resulting in a large number of potential applications.
The use of liposomes is able to improve the delivery of drug topically via two mechanisms, improving the penetration through the skin and by the entry of the intact vesicle through the stratum corneum. This was shown when the cumulative ketotifen that permeated the skin was signi icantly increased when encapsulated in deformable liposomes as compared to control group (Elsayed, 2006). Stability of drugs can also be improved by encapsulating with liposome. For example, free curcumin which degrades rapidly (16% remaining) when it is incubated for 3 hours was fully protected when it is encapsulated with liposome after incubating at 37 o C for 3 hours (Chen, 2009). When salicylic acid is entrapped in liposome, it was shown that the cumulative amount of salicylic acid permeating is lesser in liposomal salicylic acid, thus indicating that the application of liposome is able to prolong the release of active ingredient. Since salicylic acid produces irritating effect to the skin, the controlled release of active ingredient is able to reduce its irritant effect (Bhalerao and Harshal, 2003). Not to mention, since liposome is made up of phospholipid, it is biodegradable and biocompatible in nature. Nevertheless, liposome does possess some drawback as well. One of it includes it is not suited for encapsulating highly sensitive substances due to the exposure to high mechanical stress during production as well as possible harmful chemicals (Mozafari, 2005). Adding on to that, liposome prepared by sonication method is susceptible to oxidation and hydrolysis of the fatty acid chains of phospholipid (Uhumwangho and Okor, 2005). Osmotic sensitivity of liposome can also be seen when dioleoylphosphatidylcholine(DOPC) vesicle showed a change in hydrodynamic radius when subjected to hyperosmotic sodium chloride solutions (Table 6) (Pencer et al., 2001).
Pigmentation cream containing liposomeencapsulated 4-n-butylresorcinol and resveratrol has reported to reduce lesional melanin index and improve melasma without causing serious adverse effects (Kwon, 2020). A study conducted by Shrotriya et al. which involved the incorporation of curcumin solid lipid nanoparticles into the Carbopol gel has shown better in vitro tyrosinase inhibitory activity compared with the reference kojic acid and curcumin plain gel, suggesting the potential of the formulated gel for skin depigmentation (Davis and Callender, 2010). Moreover, the liposomal formulation of linoleic acid (LA) in hydrogel has also demonstrated a signi icant skin whitening effect compared to the free LA in ethanol and nonliposomal LA in hydrogel (Shigeta, 2004). Marketed depigmentation product containing liposomes are shown in Table 7.

Niosome
Niosomes are nanoparticles similar to liposomes, however it is made up of non-ionic surfactant instead of phospholipid and may or may not have cholesterol or their lipids being incorporated. The arrangement of the surfactant is similar to that of liposome, forming a bilayer in aqeous medium. The structure of the vesicle is maintained by forces acting from within the vesicle, such as van der waals forces and repulsive forces between the surfactant molecules. Based on the characteristic describe, the non-ionic surfactant employed must therefore possess hydrophilic and hydrophobic portion in order to form a niosome. The dialkyl ether chain surfactant has been found to more closely resemble phospholipid, and is of less toxic and less permeable to entrap solutes than surfactant containing single alkyl ether chain. Surfactant that contains ester linkage however are susceptible to degradation by esterases and therefore is important to prevent the carrier from accumulating in the cell, hence causing it to be less toxic than ether-linked surfactant. The use of niosome is able to overcome the disadvantages of liposome mentioned above, such as the high cost and susceptibility to oxidation and hydrolysis.
N-acetyl glucosamine (NAG) which is an amino sugar that is present naturally in human tissue is well known for its effect in improving hydration due to it being the precursor of hyaluronic acid. It was also found that NAG produces a dose dependant decrease in the amount of melanin when it is applied topically onto cell cultures, thereby showing a promising effect on depigmentation (Bissett, 2007). M.A. Shatalebi et al had encapsulated NAG into niosome and study its penetration across the skin of rat using Franz diffusion cells. It was found that the encapsulation of NAG in a niosome resulted in an improved localization of NAG in the skin as compared to hydroalcoholic solution. The skin permeation of NAG was also much greater from hydroalcoholic solution than from niosome, which resulted in a greater systemic absorption, and thus niosome can help reduce the side effect of drug as a result of systemic absorption (Shatalebi et al., 2010). Some advantages and disadvantages of niosomes are mentioned below (Table 8), and the marketed whitening product containing niosome are mentioned in Table 9.

Microparticle delivery system
Microparticulate drug delivery system possesses advantages such as the ability to produce a modi ied and targeted drug release and delivery, to improve the stability of the preparation and also to produce a more expected pharmacokinetic. The polymer in which the ingredients are loaded into protects them from the surrounding (such as temperature, pH) or even protects the body from the potentially irritating substance. Different types of microparticulate drug delivery system can be prepared, depending on whether the drug is in the free form, conined within a cavity or is homogenously dispersed, resulting in microparticle, microcapsule and microsphere respectively (Padalkar and Shahi, 2011).
Microparticles are particles having the size of 1-1000 µm. Microcapsules are small spheres encapsulating the drugs within a uniform wall and a microcapsule has a size of about 1µm to 7mm. Microcapsule can be used to enclose solid, liquid and gaseous material. However, it may affect the size and shape of the microcapsule. Microspheres are a matrix system consisting of homogeneously dispersed drugs, either being dissolved or homogeneously suspended. It is a reservoir, present in microscopic size, surrounded by polymer which controls the release of the content from the reservoir (Lengyel, 2019).
"Microsponges are polymeric delivery systems composed of porous microspheres." Microsponges are biologically inert polymer particles that absorb, trap, or bind drugs or other chemical compounds. The macroporous beads, which are 10 to 25µm in diameter, release its content over time or in response to particular stimuli, such as change in pH or temperature. For drugs that are water insoluble can be incorporated into these beads, which are very small and hence resulting in a large surface and an increased solubility. Microsponge also    Liposomes also need ultrapure raw materials for quality control, which makes them more expensive, unlike microsponge technology.
Besides, the novel drug delivery system of microsponge with the formulation of hydroquinone 4% and retinol 0.15% was also employed in the treatment of melasma and post-in lammatory hyperpigmentation. The gradual and prolonged drug release from the microsponges has proven to be effective in improving hyperpigmentation with well patient tolerability (Bhowmik, 2016).
The advantages and disadvantages of microparticulate drug delivery system are summarized in the table below (Table 10), while the examples of marketed whitening product containing microparticles are listed in Table 11.

DISCUSSION
Other types of existing topical dosage forms that are currently not available for the treatment of pigmentation includes pastes. Pastes are semisolid dosage form often containing 50% or more of inely dispersed solid. They are less luid in nature and do not low under normal body temperature. It is also opaque, resulting in a poor cosmetic acceptability. Hence, less or no formulations for depigmentation are available in the form of pastes.
Dosage form in the form of patches or plaster can also be tapped in the future in which the active ingredients for resolving pigmentation can be applied onto the patch and plaster, which is then adhere to the pigmented area. This can prevent the formulation being rubbed or washed away unintentionally.
Another form of nanoparticle is known as dendrimers. Traditionally, more focus was placed on linear macromolecules which may or may not con-  tain some smaller or longer branches. However, sometime later, highly branched macromolecules was found to have properties different from the conventional polymers. Dendrimers are formed by the engraftment of successive series of branches on a core, resulting in a three-dimentional spherical structure. Dendrimers are classi ied into generations based on the total number of series of branches. For example, dendrimers consisting of one series of branches are considered to be the irst-generation, two series of branches are secondgeneration (Klajnert and Bryszewska, 2015). The biocompatibility of dendrimers, the ability to control its degradation and the ability to control its molecular weight and size shows potential in formulating it into a depigmentation product.

CONCLUSIONS
Most of the depigmentation product currently available in the market is in the form of cream or gel because of its non-greasiness and have a high cosmetic acceptability. Although ointment is one of the well-known conventional dosage forms, however there are few or no depigmentation ointment in the market due to its greasy after-feeling and it may also leave stains. Due to the limitations of the conventional topical dosage form such as instability and bioavailability problem, novel drug delivery system has been developed in order to overcome these problems. Nanoparticle drug delivery system such as liposomes and niosomes are more widely adopted into novel depigmentation product as compared to microparticulate drug delivery system, probably due to it being smaller in size, and hence a larger surface area and loading capacity.