Nanobiomaterials in Galenic Formulations and Cosmetics: Applications of Nanobiomaterials

products.

Chapter 1

Advances in nanobiomaterials for topical administrations: new galenic and cosmetic formulations

Patrícia Severino¹, Joana F. Fangueiro², Marco V. Chaud³, Juliana Cordeiro¹, Amélia M. Silva⁴,⁵ and Eliana B. Souto²,⁶,    ¹University of Tiradentes and Institute of Technology and Research, Aracaju, Brazil,    ²Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Coimbra, Portugal,    ³Laboratory for Development and Evaluation of Bioactive Substances, Sorocaba University (UNISO), São Paulo, Brazil,    ⁴Department of Biology and Environment, University of Trás-os Montes e Alto Douro, Vila Real, Portugal,    ⁵Centre for Research and Technology of Agro-Environmental and Biological Sciences (CITAB, UTAD), Vila Real, Portugal,    ⁶Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal

Abstract

Nanomaterials are systems with at least one external dimension in the size range of approximately 1–100 nm (or 10−9–10−7 m). Nanoscale modifies the chemical, physical, and biological properties of the raw material, resulting in a wide diversity of applications, for example, drug delivery, diagnostics, implants, biosensors, medical imaging, and tissue engineering. Among the cosmetic and galenic formulations for topical administration, nanomaterials are being employed with the purpose of protection of the active pharmaceutical ingredient (API) from degradation, to improve the local action and to avoid the API penetration into the bloodstream, thus reducing the risk of systemic effects and toxicity. The most popular nanomaterials for topical application are based on lipid or polymeric nanoparticles, while others containing metals are mainly used for diagnostic purposes and imaging analysis. Of particular relevance are those composed of biodegradable and biocompatible raw materials (so-called nanobiomaterials), making them attractive for the formulation of topical pharmaceuticals and cosmetics. This chapter summarizes the recent advances in nanobiomaterials and their applications in galenic and cosmetic formulations.

Keywords

Drug-delivery systems; cosmetic formulations; galenic formulations; nanobiomaterials; topical administration

1.1 Introduction

The use of biodegradable materials in the formulations of products for skin application has been carried out since the eighteenth century. This area is becoming even more popular with the development of innovative and cutting-edge materials with improved biodegradability and higher skin compatibility.

Cosmetic and galenic formulations for topical application allow a local action and may avoid penetration of active pharmaceutical ingredients (APIs) into the bloodstream. In certain cases, this strategy is desirable to avoid the systemic effects of powerful APIs, which cannot be achieved with oral and parenteral administration. Therefore, topical administration is able to maintain the therapeutic level of the bioactive in the site of action and reduce the administration frequency. Topical administration of APIs can have cosmetic or pharmaceutical purposes. Generally, formulations with cosmetic purposes are used for aesthetic reasons, for example, to modify the appearance of the skin, and to protect and clean the skin. Pharmaceutical formulations are those that cure, treat, mitigate/prevent disease or affect the structure or function of the human body to treat or cure some pathology. Due to the systematic combination of both in the same product, the term more appropriately adopted is cosmeceutical product, which has the major goals of improving skin condition and health. However, the Federal Food, Drug, and Cosmetic Act does not recognize this terminology, and the cosmetic industry uses the term cosmeceutical to refer to cosmetic products that have medicinal or drug-like benefits. Additionally, drugs are subject to a review and approval process by the Food and Drug Administration (FDA), while cosmetics are not approved (FDA, 2014).

The APIs mostly applied in cosmetic formulations include depigmenting agents (Leelapornpisid et al., 2010; Dadzie and Petit, 2009), antioxidants (Leelapornpisid et al., 2010; Gokce et al., 2012), skin renewal agents (Dashora, 2013), ultraviolet (UV)-blockers, and sunscreens (Severino et al., 2012b; Souto et al., 2005). The most common APIs delivered by pharmaceutical formulations to the skin include corticosteroids (Ramsing and Agner, 1995), retinoids (Moon et al., 1997), antimicrobial and antimycotic agents (El-Badry et al., 2014; Sahoo et al., 2014; Verma et al., 2014), immune-suppressants (Euvrard et al., 2004), anesthetics (Pathak and Nagarsenker, 2009), and antipruritic agents (Wahlgren et al., 1990).

The advantages of using nanobiomaterials for skin delivery and targeting rely on the use of non-toxic, biodegradable, and biocompatible materials, with rapid and reversible onset of action, and that are pharmacologically inert (Souto et al., 2011, 2013). Additionally, nanobiomaterials enable an increase in bioactive skin exposure, decreasing the necessity for treatment frequency (Simeonova et al., 2003).

1.2 Skin as Site for Topical Delivery

The skin is the largest body organ and, due to its large area, remains an attractive site for the delivery of APIs (Souto and Müller, 2008). The skin is responsible for various functions, such as sensitivity, physical protection, immunological and microbiological control, temperature regulation, prevention of excessive water loss, and production of vitamin D. The human skin is composed of cells and cutaneous annexes (hair follicles, nails, and gland), and can be divided into three basic layers: the epidermal layer (the outer most layer, populated mostly by keratinocytes), the dermal layer (consisting of two regions, the papillary dermis and reticular dermis), and the hypodermis or subcutaneous fat layer (mostly composed of fibroblasts, adipose cells, and macrophages) (Mikesh et al., 2013).

Briefly, the epidermis (50–100 μm in thickness) is composed of epithelial cells distributed in layers which, from inside to outside, are classified as germinal or basal, spinous, and granular corneal layers, respectively. In the palmar and plantar regions, between the cornea and granulosa layers, lies the lucid layer (WHO, 2009). The germ layer gradually reaches the surface, undergoing changes in form and chemical composition to become anucleate, composing the stratum corneum (SC) and forming the outermost layer of the epidermis. The region below the SC, in which the cells proliferate and undergo changes, gives rise to dead cells of the SC, and is called viable epidermis (Venus et al., 2010).

The dermis (1–2 mm in thickness) is the tissue located beneath the epidermis. This layer is composed of glands, nerve endings, blood vessels, some cell types such as fibroblasts, collagen, and elastin fibers. The deepest layer is the hypodermis, with variable thickness and mostly formed by adipocytes (Zhai and Zhai, 2014).

The topical administration of galenic and cosmetic formulations based on nanobiomaterials seems to have high efficiency due to the large surface area of skin contributing to their adhesiveness, occlusion, and hydration capacity (Alvarez-Román et al., 2004). Therefore, it is necessary to consider physicochemical properties, such as zeta potential, polydispersity index, size, type of nanomaterial, loading efficiency, and administration route (Desai et al., 2010).

Depending on the effect required for a certain API, that is, local (epidermis) or systemic (dermis), its permeation could be modulated. Formulations for cosmetic purposes can only exert local action/effect in the skin surface such as make-up, film formers, sunscreens, insect repellents, antimicrobials, and antifungals. Other treatments include the interactions with the SC, which are related to the softness and stimulation of keratosis (keratolytic effect). In this case, it is expected that these substances do not reach the viable epidermis, because they should only affect the outermost layer of the skin, in contrast to bioactive substances such as anti-inflammatory, anesthetic, antipruritic, cytotoxic, and immunosuppressive agents, which should be able to reach the viable epidermis and dermis. Beside the skin layers, there are situations where substances need to target the skin appendages, such as glands (sebaceous and eccrine) and hair follicles (Schoellhammer et al., 2014).

The skin provides immunological, physical, and UV protection (Salmon et al., 1994). The first barrier of the skin, namely the SC, is highly impermeable mainly due to two factors: (1) SC is composed of keratinocytes which are arranged in a scaffold-like lattice, bound together by the fibrous proteins and (2) the intercellular spaces are filled with a lipid-rich matrix arranged in a laminar structure providing a robust and waterproofing barrier (Venus et al., 2010).

The immunological protection is provided by some of the cells that compose the skin and are responsible for defense against microorganisms. The mechanisms include (1) the production of antimicrobial peptides, which kill Gram-positive and Gram-negative organisms, fungi, and some viruses; (2) resident epidermal Langerhans cells that act as antigen-presenting cells; and (3) transient epidermal T-cells that protect against pathologies such as dermatitis, bullous disorders, psoriasis, and cutaneous T-cell lymphoma (Venus et al., 2010).

The UV protection is essential to avoid damage to the skin and can act as a cocarcinogen with ultra violet B (UVB) radiation. The damage could lead to cancerous cells, and the oncogenic effect is a result of photochemical damage to epidermal cell DNA, damage to DNA repair mechanisms, and suppression of cell-mediated immunity (Kim and He, 2014). The protective layer that skin provides for UV radiation is mainly associated with two anatomical factors, namely (1) SC is able to reflect radiation and (2) the exposure to UV radiation increases melanocyte activity and melanin present in the epidermal keratinocytes, contributing to the absorption of UV radiation by DNA and cellular constituents (Venus et al., 2010).

Despite these anatomic and physiological barriers, skin is relatively permeable to many bioactive substances and aliphatic alcohols. The most impermeable molecules are those of polar character, such as water, sodium, potassium, and other ions in solution. Furthermore, different body sites are differentially permeable, the palms of the hand are the least permeable while the face, forehead, and dorsum of the hand are the most permeable (Venus et al., 2010; Schoellhammer et al., 2014).

1.3 Nanobiomaterials

Nanotechnology is an innovative technology dealing with the design, characterization, synthesis, and application of materials at atomic, molecular, and supramolecular levels (Yan et al., 2014). The control of the shape and size of nanomaterials allows their exploitation for human diagnostics and/or therapeutics (Cevc and Vierl, 2010; Yan et al., 2014). For human use the use of exclusively biotolerable materials is essential (Cevc and Vierl, 2010).

Topical formulations may be used to improve lubrication, smoothness, softness, adhesiveness, occlusion, and skin hydration (Magdassi and Touitou, 1998; Schoellhammer et al., 2014).

In order to increase drug bioavailability and residence time in the skin for its absorption or permeation, several approaches addressing nanotech aspects have been developed. The main advantages of nanocarrier use and incorporation into conventional galenic and cosmetic formulations are related to their capacity to encapsulate or incorporate poorly water-soluble molecules, protection of drugs from chemical and physical degradation and providing a controlled release, avoiding repeated administrations and providing greater patient compliance (Souto et al., 2011, 2013). The most frequently applied nanobiomaterials for topical administration are the liposomes (Gesztes and Mezei, 1988), solid lipid nanoparticle (SLN) (Mei et al., 2003), nanoemulsions (Dasgupta et al., 2014), polymeric nanoparticles (Guo et al., 2014), hydrogels (Sahoo et al., 2014), and microneedles (MNs) (Naguib et al., 2014).

The innovative and revolutionary nature of nanotechnology has gained considerable attention in the past few decades. Its application to pharmaceutical drug development is increasing with the increasing funding for nanotechnology-based products and patent applications.

1.3.1 Liposomes

Liposomes are amphiphilic molecules characterized by a hydrophilic and a hydrophobic part in its structure. These structures are able to organize themselves spontaneously into closed spherical shell-type structures under a certain concentration (critical micelle concentration). The vesicular structure form obtained is called a liposome when composed of phospholipids, such as phosphatidylcholine, phosphatidylserine, or phosphatidylethanolamine, and were discovered by Bangham in 1963 (Bangham and Horne, 1964). The most popular method of production of liposomes is the Bangham method, which consists of the solubilization of the phospholipids in an organic solvent, with posterior agitation and evaporation by rotary evaporator (Düzgüneş and Gregoriadis, 2005). Then, the film is rehydrated with aqueous solution to obtain vesicles. It is possible to obtain multilamellar (MLV) or unilamellar vesicles (ULV), depending on the passage of the formulation through extrusion equipment and the colloidal association of amphipathic lipids (Severino et al., 2012b). Additionally, ULV can be classified as small unilamellar vesicles (200–500 Å) and large unilamellar vesicles (0.1–10 μm) (Batista et al., 2007). Liposomes are capable of loading both hydrophilic and lipophilic APIs. The hydrophilic bioactives are entrapped in the inner core of the liposomes, while the lipophilics are placed within the acyl chains of the fatty acids linked to the glycerol of the phospholipids. Other methods described in the literature include microfluidization (Sorgi and Huang, 1996), reverse-phase evaporation (Szoka and Papahadjopoulos, 1978), French pressure (Hamilton et al., 1980), and solvent injection (Batista et al., 2007).

The potential of the topical administration of liposomes was firstly exploited by Mezei and Gulasekharam (1980). Researchers observed that several factors were able to influence the drug release in the skin. These factors are the lamellarity, lipid composition and concentration, zeta potential, polydispersity index, and mean size (Mezei and Gulasekharam, 1980, Elsayed et al., 2007). Therefore, the release of APIs onto the skin surface from these phospholipid vesicles should be characterized by a phase transition temperature (Tc). When the phospholipid membrane is in a gel phase, the hydrocarbon lipid chain is in the ordered state, and if there is any change in the temperature a liquid-crystal phase is obtained. In this liquid-crystal phase, the molecules are in freer motion and grouped hydrophilic radicals become completely hydrated. The length and saturation of the lipid chain influence the Tc value. Thus, different membranes may comprise different lipids and can exhibit different levels of fluidity at the same temperature (El Maghraby et al., 2008). The permeability of liposomes is relatively low when the temperature is lower than its Tc.

The liposomes have many advantages, for example, the capacity of incorporation of both hydrophilic and lipophilic APIs, and are biocompatible, biodegradable, and non-immunogenic. In addition, they are highly versatile for wide range of research applications (El Maghraby et al., 2008). The greatest disadvantage is the limited residence time in the blood upon injection, because they are rapidly removed from the circulatory system by monocytes and macrophages in the spleen, bone marrow, liver, and lungs, causing a rapid localization in cells of the reticuloendothelial system (Barenholz, 2001). Additionally, the expensive cost of the raw materials is not attractive from a commercial point of view.

The greatest interest of liposomes for skin administration is related to their phospholipid bilayer structure identical to biological membranes. Depending on the lipid composition, liposomes present different skin permeation profiles. It is known that classical liposomes have no capacity to penetrate deeply into the skin, being limited to the upper layers of the SC (Elsayed et al., 2007). Conventional liposomes are usually composed of phospholipids and cholesterol, and surfactants are frequently added to enhance elasticity. Cholesterol tends to create liposomes that are more packed and surfactant with more fluids. The choice between surfactant and cholesterol depends on the final application. The highest bundled liposomes, the lowest loss of the bioactive substances and, consequently, highest stable system (Betz et al., 2005). Comparing MLV versus conventional liposomes, Betz et al. (2005) observed an increase in the water content of the skin (therefore improving skin hydration) with enhanced concentration of APIs in SC.

Rashes and itchy scales are commonly present in chronic skin diseases, such as atopic dermatitis. Topical administration of corticosteroids (e.g., betamethasone valerate, diflucortolone valerate) is usually the selected pharmacological approach. However, these drugs can induce skin atrophy, hypopigmentation, and transepidermal water loss increase. Betamethasone valerate and diflucortolone valerate have been loaded in liposomes with a mean size of 300 nm, which were then formulated into semisolid chitosan gels to achieve adequate consistency for topical administration. The results demonstrated that both drugs were located in the epidermis, while liposome-based formulations were more efficient than conventional semisolid dosage forms.

Liposomes have been used both to increase the incorporation of APIs into cells and to provide controlled release for topical administration (Magdassi and Touitou, 1998). Many of their applications include the prevention of hair loss, promotion of hair growth, slowing the aging process of the skin (Lee and Tsai, 2010), lightening skin pigmentation (Lee and Tsai, 2010), and prevention and treatment of gynoid lipodystrophy (Chorilli et al., 2013), sunscreen protection (Magdassi and Touitou, 1998), and damaged skin (Magdassi and Touitou, 1998).

Several studies (Gupta et al., 2010; Lee and Tsai, 2010; Değim et al., 2011; Aggarwal and Goindi, 2012; Raza et al., 2014) have reported that conventional liposomes are able to enhance skin deposition, with limited percutaneous absorption and no systemic absorption. No irritation, burning sensation, or erythema was attributed to liposomes, emphasizing the advantage of using these systems for topical API administration.

Deformable liposomes have been used to enhance the skin penetration of ketotifen fumarate, under non-occlusive conditions (Elsayed et al., 2006). The mechanism involved in the drug absorption was attributed to the interaction between the lipid composition of the liposomes and the layers of SC, decreasing the intercellular packing and increasing the API partitioning in the skin (Essa et al., 2003; Kirjavainen et al., 1999). Depending on the physicochemical properties of the API, the degree of skin penetration increases either through a penetration-enhancing effect or through intact liposome permeation into the SC.

Hydrophilic drugs are more influenced by the penetration-enhancing effect than lipophilic drugs, as for many penetration enhancers, since hydrophilic drugs are slowly permeated (Elsayed et al., 2006; Williams and Barry, 1991).

Studies will continue to further improve skin delivery of drugs using liposomes. Liposomes rely on simple drug diffusion through the skin and are able to modulate drug transport through the barrier; therefore, they can ensure targeted delivery of APIs deep below the application site.

1.3.2 Solid Lipid Nanoparticle

SLNs were first investigated to circumvent physicochemical stability issues in biological media, offering the benefits of using lipids as drug carrier systems (Mueller et al., 2000). SLNs have been developed as an alternative to encapsulate drugs compared to traditional systems such as emulsions, liposomes, and polymeric nanoparticles. The great advantage of the SLNs is their physicochemical stability, which provides greater protection of drugs, including thermolability and susceptibility to chemical and physical degradation, such as proteins. Furthermore, SLNs promote sustained release and transport of drugs to target the desired site, thus increasing its therapeutic efficacy (Souto et al., 2013). The highlight of these systems is the use of physiological solid lipids which can incorporate mainly lipophilic drugs in its lipid layers and/or between the chains of fatty acids or even in previously induced imperfections in the physical structure after solidification of lipids. The lipids include glycerides, ceramides, waxes, or fatty acids (Souto et al., 2011, 2013). Through a combination of lipids and fatty acids, the release profile of drugs can be adjusted according to the specific need. Additionally, SLN dispersions have low cost, are cleared from organic solvents, and are composed of raw materials that are Generally Recognized as Safe by the FDA (Alvarez-Román et al., 2004).

The main characteristic of SLN dispersions is the capacity of the drug being molecularly dispersed in the lipid matrix, which provides higher protection and results in a sustained release and high API loading. Additionally, due to the nanometer size, the ratio of surface to area is increased and can be targeted for therapeutic purposes, increasing its efficiency (Mueller et al., 2000; Müller et al., 2002). These lipid systems are like emulsions; however the oil phase is replaced by solid lipids, and is stabilized by surfactants, constituting a two-phase system also. The lipophilic drug is usually dispersed in the lipid layers between the fatty acid chains of the glycerides or the fatty acids and also in the crystal imperfections when the lipids recrystallize (Souto et al., 2013). The method most commonly used to produce SLNs (i.e., high-pressure homogenization) is well described in the literature. This method allows manipulation of the size of SLNs, depending on the application and route of administration. Through a combination of lipids and fatty acids used, the release profile of the drug can be adjusted for a specific need (Müller et al., 2002). A second generation of lipid nanoparticles is the nanostructured lipid carriers (NLCs). NLCs are composed of a mixture of solid and liquid lipids, resulting in a more amorphous crystal structure. NLCs compared with SLNs are capable of accommodating higher amounts of API and also preventing their expulsion during storage. Because of the different polymorphic forms, both SLNs and NLCs can be used to modulate the release profiles of loaded APIs (Müller et al., 2002).

During the past 10 years various compounds have been incorporated into lipid nanoparticles (SLNs and NLCs). The lipophilic APIs are the most commonly loaded compounds in these systems; however, it is possible to encapsulate hydrophilic and thermolabile APIs, such as proteins and peptides (Severino et al., 2014; Fangueiro et al., 2013, 2014a,b).

Since the development of NLCs, these systems have mainly been used for cosmetic and dermatological purposes. This could be explained by the lower capacity of NLCs to penetrate human skin through its elasticity (Wissing et al., 2004).

SLNs have several advantages over conventional systems and also in comparison to liposomes and nanoemulsions. The more important advantages include (1) the physical and chemical stability, providing greater protection against degradation of labile drugs, (2) biotolerability and biodegradability associated with low toxicity due to the physiological lipid composition, and (3) the lipid matrix provides a controlled release. The main disadvantage of SLNs is mainly related to the expulsion of the drug after polymorphic transition and output in very dilute dispersions (70–99% water) (Wissing et al., 2004).

The factors that most influence the bioactive substances released by SLNs are: (1) the physicochemical characteristics of the active encapsulated/incorporated, (2) its distribution in the lipid matrix, (3) the size and distribution of the particle, (4) the composition of the lipid matrix, (5) the types of surfactants used, and (6) the method and parameters used in the production (Mehnert and Mäder, 2001).

The method of preparation should be chosen according to the drug encapsulated and also with the desired final goals. In addition, the release of a drug is dependent on the lipid matrix and on the production method. Several techniques have been developed for the production of SLNs. The most promising incorporation of bioactive substance is through the techniques of high-pressure homogenization at high and low temperatures (Alvarez-Román et al., 2004), the method of microemulsions, supercritical fluid (Battaglia et al., 2014), ultrasonication or high-speed homogenization (Hosny and Aljaeid, 2014), double-emulsion method (Severino et al., 2014), and the spray drying method (Ezzati Nazhad Dolatabadi et al., 2014). Techniques can produce SLNs and NLCs depending on the lipid composition.

The main research applications of these lipid nanoparticles describe the encapsulation of antibiotics (Hao et al., 2011), anti-inflammatory drugs (Schlupp et al., 2011), sunscreens (Gulbake et al., 2010), antiaging APIs (Pardeike et al., 2010; Brugè et al., 2013), hydration and elasticity products (Junyaprasert et al., 2009) to increase skin permeability (Pardeike et al., 2010; Müller et al., 2002). Examples of APIs loaded in SLNs for topic use described in the literature are: chloramphenicol (Hao et al., 2011), gatifloxacin (Kalam et al., 2010), penciclovir (Betz et al., 2005), p-methoxycinnamate (Nesseem, 2011), minoxidil (Padois et al., 2011), lutein (Mitri et al., 2011), tocopherol (Fangueiro et al., 2011; De Carvalho et al., 2013), resverastrol (Mitri et al., 2011), oxide zinc (Mitri et al., 2011), clotrimazole (Souto et al., 2004), loratadine (Üner et al., 2014), minoxidil and finasteride (Gomes et al., 2014), caffeine (Puglia et al., 2014), adapalene (Jain et al., 2014), retinoic acid (Silva et al., 2015), and triamcinolone acetonide (Pradhan et al., 2014).

1.3.3 Polymeric Nanoparticles

Polymeric nanoparticles are carrier systems within the submicron size (lower than 1 µm) and are composed of natural or synthetic polymers (Souto et al., 2012). Among polymeric nanoparticles, one may distinguish nanocapsules and nanospheres. The nanocapsules consist of spherical structures composed by an oily core surrounded by a polymeric shell; the drug may be dissolved in the core and/or adsorbed to the polymer wall (Hosseinkhani et al., 2014). The nanospheres are monolithic systems containing no oil, composed only of a polymeric matrix where the drug can be entrapped or adsorbed (Rodríguez-Cruz et al., 2013). The polymeric nanoparticles are one of the most used systems nowadays, where APIs can be entrapped, dispersed, and dissolved within the matrix or adsorbed onto the surface of nanoparticles. The exploitation of these nanoparticles for pharmaceutical and cosmetic uses started in the 1990s. Later, in 1995, the first polymeric nanocapsules were introduced in the market by L’Oréal (Guterres et al., 2007).

Polymeric nanoparticles can be composed of biodegradable or of non-biodegradable polymers. Biodegradable polymers have advantages over non-biodegradable, since the former do not need to be surgically removed after the end of the action (Sionkowska, 2011). Examples of synthetic polymers of non-biodegradable nature are polystyrene and polyacrylamide, whereas those of biodegradable nature are the polyalkylcyanoacrylates and aliphatic polyesters. The advantages of using synthetic polymers over non-synthetic are the well-known and controlled chemical composition; however, residues/impurities of synthesis may remain in the final product (Sionkowska, 2011). Natural polymers are usually biocompatible and biodegradable; however, they show less predictable composition and could be mildly immunogenic. Examples are chitin, chitosan (Dash et al., 2011), alginate (Bowey et al., 2013), hyaluronic acid (Choi et al., 2010), pullulan (Grenha and Rodrigues, 2013), gliadin, collagen (Mathieu et al., 2014), keratin (Xu et al., 2014), silk (Lammel et al., 2010), and elastin (Oliveira et al., 2011). The choice of material to be applied must comply with the physicochemical characteristics, such as viscosity, hygroscopicity, biocompatiblity, and ability to release completely the solvent or other materials used during the encapsulation process (Guterres et al., 2007; Alvarez-Román et al., 2004).

The greatest advantage of these particles is the possibility to chemically modify the polymer structure, including the synthesis of copolymers. This modification can reduce the toxicity of polymers and can target the particles to specific spots (Kumari et al., 2010). In addition, the enhanced polymer stability and durability may prolong storage at room temperature and increase the shelf life of the API. Also, the low production cost of these particles compared to others (e.g., liposomes) is pointed out as an additional advantage. The most relevant limitation of these particles is related to the potential risk of residual organic solvent used in the production of these particles, leading to possible cytotoxicity problems. The scaling of the production process is also a possible problem (Kumari et al., 2010).

Various methods for preparing polymer micro- and nanoparticles described in the literature can be classified into two main categories: one that requires a polymerization reaction (Souto et al., 2012) or those in which a macromolecule is used directly or a preformed polymer (Tiyaboonchai, 2013). When choosing the production process, one should consider the simplicity, reproducibility, and feasibility of scaling up. Polymeric nanoparticles—nanospheres or nanocapsules—are systems that exhibit promising topical applications, providing a reservoir system for release in skin (Naik et al., 2004).

The main methods of production shown in literature are ionotropic gelation (Severino et al., 2012a), spray dried (Severino et al., 2012a), fluid supercritical (Machado Jr et al., 2014), emulsion solvent evaporation (Staff et al., 2013), and nanoprecipitation (Petrova et al., 2014; de Oliveira et al., 2013).

The polymeric nanoparticles, nanocapsules and nanospheres, are systems that exhibit promising topical applications for treatment of a wide range of diseases, such as nosocomial infections (Lboutounne et al., 2002), contact dermatitis (Fontana et al., 2011), inflammation (Abdel-Mottaleb et al., 2012), acne vulgaris, ichthyosis, psoriasis (Ridolfi et al., 2012), and neoplasias (Ourique et al., 2008; Chatterjee et al., 2008). Therefore, in personal care they are used mainly as sunscreens (Perugini et al., 2002), antiwrinkles (Kim et al., 2006), and for skin photodamage prevention (Ainbinder and Touitou, 2010; Weiss-Angeli et al., 2008).

Sunscreens have been widely studied (Abd El Gawad, 2014; Alvarez-Roman et al., 2001; Jiménez et al., 2004) for the loading of several APIs since polymeric nanocapsules are able to load highly lipophilic substances, increase the solubility of APIs in aqueous media, and modify their biodistribution in the skin, while increasing the API adhesion to the skin surface. Hosseinkhani et al. (2014) developed nanocapsules loading fragrances for slow release on human skin. The aim of encapsulation was to promote slow release and achieve a stable formulation due to poor aqueous solubility and instability of fragrance molecules. Fragrance was loaded in polylactide acid nanocapsules by nanoprecipitation method and results showed a great innovation in cosmetic applications.

Capsaicin is widely used for patients with chronic pain, but it causes skin irritation and it is often necessary to interrupt the treatment. To overcome this difficulty, the use of Eudragit® RS 100 by deposition of a preformed polymer method has been proposed. Chitosan hydrogel was used as a vehicle for nanocapsules, and the formulation was tested in volunteers. Irritation was evaluated by erythema probe and on a visual scale. Results showed that nanocapsules significantly reduced irritation compared to commercial and free drug (Contri et al., 2014; Table