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Clay Minerals in Skin Drug Delivery

Published online by Cambridge University Press:  01 January 2024

César Viseras*
Affiliation:
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Campus of Cartuja, 18071 s/n, Granada, Spain Andalusian Institute of Earth Sciences, Consejo Superior de Investigaciones Científicas-University of Granada, Avda. de Las Palmeras 4, 18100 Armilla, Granada, Spain
Esperanza Carazo
Affiliation:
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Campus of Cartuja, 18071 s/n, Granada, Spain
Ana Borrego-Sánchez
Affiliation:
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Campus of Cartuja, 18071 s/n, Granada, Spain Andalusian Institute of Earth Sciences, Consejo Superior de Investigaciones Científicas-University of Granada, Avda. de Las Palmeras 4, 18100 Armilla, Granada, Spain
Fátima García-Villén
Affiliation:
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Campus of Cartuja, 18071 s/n, Granada, Spain
Rita Sánchez-Espejo
Affiliation:
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Campus of Cartuja, 18071 s/n, Granada, Spain
Pilar Cerezo
Affiliation:
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Campus of Cartuja, 18071 s/n, Granada, Spain
Carola Aguzzi
Affiliation:
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada, Campus of Cartuja, 18071 s/n, Granada, Spain
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Abstract

Clays have played an important role in medicine since the dawn of mankind and are still applied widely as active ingredients and/or excipients in pharmaceutical formulations. Due to their outstanding properties of large retention capacity, swelling and rheological properties, and relative low cost, they have been used widely as advanced carriers for the efficient delivery of drugs by modifying their release (rate and/or time), increasing the stability of the drug, improving the dissolution profile of a drug, or enhancing their intestinal permeability. In addition, recent studies have shed new light on the potential of clay minerals in the nanomedicine field due to their biocompatibility, beneficial effects of clay nanoparticles on cellular adhesion, proliferation, and differentiation. Use as active ingredients and excipients are exerted via the oral and topical administration pathways. Skin drug delivery represents an attractive alternative to the oral route, providing local and/or systemic drug delivery. Due to their complex structures, however, most drugs penetrate the human skin only with difficulty. Enormous efforts have been invested, therefore, in developing advanced drug delivery systems able to overcome the skin barrier. Most strategies require the use of singular materials with new properties. In particular, and on the basis of their inherent properties, clay minerals are ideal candidates for the development of intelligent skin drug delivery systems. In this article, the properties of clay materials and their use in the skin-addressed pharmaceutical field are reviewed. A brief introduction of skin physiology and biopharmaceutical features of penetration by a drug through the skin layers is also included and is designed to shed light on the optimum properties of ideal nanosystems for advanced skin drug delivery. Special attention is devoted to the pharmacological functions of clays and their biomedical applications in pelotherapy, wound healing, regenerative medicine, antimicrobial, and dermocosmetics.

Type
Research Article
Copyright
Copyright © Clay Minerals Society 2019

Introduction

The aim of this review was to provide a summary of recent research on clay mineral uses in advanced skin drug delivery; a future perspective is included to discuss challenges and prospects.

Because of their healing properties and global accessibility, use of clay minerals in the therapy of skin pathologies goes back to prehistoric times and continues to play a crucial role in the design of skin-addressed drug delivery systems. Clay minerals are used in conventional medicinal products as excipients or actives (Cornejo et al. Reference Cornejo, Galán and Ortega1990; López-Galindo & Viseras Reference López-Galindo and Viseras2004; Carretero et al. Reference Carretero, Gomes, Tateo, Bergaya, Theng and Lagaly2006; López-Galindo et al. Reference López-Galindo, Viseras, Aguzzi, Cerezo, Bergaya and Lagaly2011; Viseras et al. Reference Viseras, Aguzzi, Cerezo and Lopez-Galindo2007) as well as advanced materials developed to modify drug delivery features (Aguzzi et al. Reference Aguzzi, Cerezo, Viseras and Caramella2007, Reference Aguzzi, Sandri, Cerezo, Carazo and Viseras2016; Carazo et al. Reference Carazo, Borrego-Sánchez, García-Villén, Sánchez-Espejo, Cerezo, Aguzzi and Viseras2018; Sandri et al. Reference Sandri, Bonferoni, Rossi, Ferrari, Aguzzi, Viseras, Caramella and Ågren2016; Viseras et al. Reference Viseras, Aguzzi, Cerezo and Bedmar2008, Reference Viseras, Cerezo, Sanchez, Salcedo and Aguzzi2010, Reference Viseras, Aguzzi and Cerezo2015).

Clay minerals were likely used in the very first prehistoric remedies, probably including geophagy and wound treatments. Clay minerals have continued to be essential ingredients in medicinal products during human history. In Europe, ancient western medicine used “Terra sigillata” (Λημνία Γη) or Stamped earth with “trade mark” denominations (terra Armenica, Terra Florentina, terra Hierosolymitanae, terra Hispanica, terra Lemnia, terra Portugallica, terra Silesiaca, among others) (Macgregor Reference Macgregor, Duffin, Moody and Gardner-Thorpe2013; Mantle et al. Reference Mantle, Gok and Lennard2001). Clay minerals were mentioned in at least half of the most important historical texts constituting the European materia medica since the “Hippocratic Corpus” (5th–4th century BC) (De Vos Reference De Vos2010). During the nineteenth century, the presence of clay “simples” in western medicine continued (Medicamentarius, Reference Medicamentarius1866). In the first half of the twentieth century, the major Western pharmacopoeias included clay minerals in the substances used in medicinal products. Nowadays, the terms “Bentonite,” “Magnesium trisilicate,” “Magnesium aluminum silicate” (or “Aluminium Magnesium silicate”), and “Attapulgite” have their own monographs in the most important worldwide pharmacopeias (USP 41, 2018; BP, 2018; EP 5.0, 2015 (Pharmacopeia Reference Pharmacopeia2018; British Pharmacopoeia Commission 2018; Ministerio de Sanidad y Consumo 2015)).

Clay minerals have been classically used in the elaboration of topical semisolid products as pastes, poultices, or liniments. Two examples, still in vogue, are “Calamine Lotion,” indicated for treatment of skin irritations that include 25% w/w of “Bentonite magma” and “Titanium dioxide paste” formulated with 10% w/w of kaolin (USP 41, 2018; BP, 2018; EP 5.0, 2015 (Pharmacopeia, Reference Pharmacopeia2018; British Pharmacopoeia Commission 2018; Ministerio de Sanidad y Consumo 2015)).

Clay minerals are currently used mainly as excipients (any constituent of a medicinal product other than the active substance and the packaging material). Excipients represent the largest part of the medicines (up to 95%) and determine drug release and bioavailability. More than 1200 excipients from many origins (animal, vegetable, or mineral) are used in medicines. Clays account for ~5% of the global market for inorganic excipients. Most of the advances in pharmaceutical science and technology are related directly to inorganic excipients, the market for which should reach $433.7 million by 2020 (BCC Report 2016).

Skin Anatomy and Physiology

In order to understand fully the design and development of skin pharmaceuticals, the structure, composition, and functions of human skin must be reviewed. The skin, which is considered the largest organ of the human body, is a multistratified structure (epidermis, dermis, and hypodermis) with essential functions as temperature control and barrier against physical, chemical, and thermal aggressions (Ng & Lau, Reference Ng, Lau, Dragicevic and Maibach2015). The presence of appendages (hair follicles, sweat, and sebaceous glands) leads to several interesting properties. Human skin has an average surface area of 1.8 m2 and constitutes a cellular layer, named dermis or true skin, sandwiched between the epidermis (outer layer and boundary with the exterior) and hypodermis (inner layer). The thickness of the epidermis varies between 0.05 mm on the eyelids to 1.55 mm on palms and soles. The epidermis is divided into basale, spinosum, granulosum, lucidum (only in palms and soles), and corneum strata. Continuous cell renewal in the stratum basale generates different cell types, mainly keratinocytes, melanocytes, and merkel cells (associated with terminal filaments of cutaneous nerves). Replication rates (normal full skin renewal requires ~28 days) increase during inflammation or injury. Keratinocytes move through the strata to reach the stratum corneum as corneocytes. The stratum spinosum contains a large concentration of keratin filaments appearing as a “spiny” area where Langerhans cells (antigen-presenting cells with an immunologic role) are also frequent. Langerhans cells and melanocytes are connected to adjacent cells by desmosomes in the same way keratinocytes are connected to one another. In the stratum granulosum the keratinocytes become flattened, lose their nuclei, and secrete their contents to form a lipid barrier. One of the most determining layers of the skin in terms of permeation by control drugs is the stratum corneum (SC). The SC is the hardest barrier of the skin, comprising rows of corneocytes (matured keratinocytes lacking nuclei and having elongated and flattened shapes) organized on a “brick and mortar” structure: corneocytes (“bricks”) immersed in a lipid matrix (“mortar”) (Prow et al. Reference Prow, Grice, Lin, Faye, Butler, Becker and Roberts2011). The space between adjacent corneocytes is occupied by a mesophase (lyotropic liquid crystal) formed by phospholipid bilayers and with the presence of proteins. The dermis layer is much thicker than the epidermis. Blood vessels, nerves, and various appendages (sweat glands, hair follicles, and sebaceous glands) are also found, providing nutritional and structural support to the epidermis. The hypodermis obeys the main functions of energy supply and thermal insulation.

Routes and Targets on, into, and Through Skin Drug Delivery

Delivery of drugs on/into/through the skin enables either local or systemic actions and improvement of poor biopharmaceutics profiles of drugs administered via other administration paths, and becomes a useful strategy in situations in which other administration routes are not possible or inadvisable (Aulton & Taylor Reference Aulton and Taylor2017). With these backgrounds, the main goals of advanced skin drug delivery systems are improving drug biopharmaceutics and pharmacokinetics and obtaining targeted drug delivery based on interaction with skin appendages and skin lipids leading to a facilitated, sustained, and/or stimuli-induced release.

While all topical and transdermal compounds are applied to the skin, it is necessary to accentuate the fact that skin drug delivery can provide local (topical) or systemic (transdermal) therapeutic effects. The two principal routes of penetration are transappendageal (via the pores and shafts embracing sweat glands and hair follicles with their associated sebaceous glands) and transepidermal (diffusion through the stratum corneum). The transappendageal pathway is minor but preferred by ions and large polar molecules because the stratum corneum is not involved, whereas the transepidermal route is the dominant one and comprises two routes: transcellular, also known as intracellular, and intercellular (Fig. 1). Via the intracellular route, drug molecules repeatedly diffuse through corneocytes (keratin-filled; of an aqueous environment) and then partition into the intercellular lipid domains. This pathway is preferred by hydrophilic molecules. In contrast, the intercellular route implies that drug molecules diffuse via a tortuous route within the continuous lipid domain. Lipophilic molecules opt for this route. All drug molecules might use the three available routes; their physicochemical properties, however, determine the preferred pathway for finally reaching the capillaries at the epidermal–dermal junction.

Fig. 1 Skin layers and diverse routes of penetration

Quality and Performance of Topical Drug Products

Topically administered drug products include those applied for local action (exert their actions on the stratum corneum and/or modulate the function of the epidermis and/or the dermis) and those applied for systemic effects (transdermal drug delivery systems). Forms of topical dosage include solutions (for which release testing is not indicated), suspensions, emulsions (e.g. lotions), semisolids (e.g. foams, ointments, pastes, creams, and gels), solids (e.g. powders), and sprays (e.g. aerosols).

Two categories of tests, product quality tests and product performance tests, are performed with topical drug products. Product quality tests are performed to assess attributes such as assay, identification, content uniformity, pH, and microbial limits.

Product performance tests are conducted to assess drug release from the finished dosage form.

Quality tests ensure safety and efficacy (ICH guidelines Q6A, www.ich.org) and include general tests such as identification, assay, content uniformity, impurities, pH, water content, microbial limits, antimicrobial preservative content, antioxidant preservative content, and sterility (in some cases), and specific tests such as viscosity and particle-size determinations (USP 41, 2018; BP, 2018; EP 5.0, 2015).

Performance tests are particularly interesting and are designed to measure drug release from the finished dosage form and detect changes in drug release related to formulation and manufacturing variables as well as storage and aging effects.

The intercellular route represents the principal mode of entry for permeation of both hydrophilic and lipophilic drugs. A drug that penetrates the SC can reach the dermis and enter the bloodstream by passive diffusion which is considered to be the rate-limiting step for the transdermal transport of drug molecules and depends on the physicochemical properties of the substance (Couto et al., Reference Couto, Fernandes, Cordeiro, Reis, Ribeiro and Pessoa2014). This transport can be described by Fick’s First Law of Diffusion (Eq. 1).

(1) J = D δ C / δ x

where J is the flux, C is the concentration of diffusing drug, x is the space coordinate, and D is the diffusion coefficient of the drug. Fick’s Law assumes that diffusion occurs through an isotropic material, with the same structural and diffusional properties in all directions. Skin, however, is a heterogeneous structure so Fickian diffusion laws lead to approximations from transdermal drug delivery data.

In vitro protocols aim to mimic the in vivo situation. Several diffusion-type cell devices have been proposed as potential apparatus for drug release testing from topical drug products. However, only vertical diffusion cell systems (VDC, also named Franz Cells) have been normalized to measure drug release from semisolid dosage forms (<1724 > Semisolid Drug Products – Performance Tests. In the United States Pharmacopoeia and National Formulary USP 37–NF 32; the United States Pharmacopoeial Convention, Inc.: Rockville, Maryland, 2014, pp. 1273–84).

VDCs are made of a membrane (synthetic, animal, or human epidermis) separating two compartments. The drug in a vehicle is then applied to the uppermost membrane surface (‘donor’ solution). The other compartment contains a ‘receptor’ solution that provides sink conditions (near zero concentration) allowing a concentration gradient to exist between the donor and receptor phase, which is required for diffusion across the membrane.

Clay Mineral Functions in Topical Products

Inorganic excipients and in particular clay minerals may be used to overcome the traditional difficulties derived from topical drug administration and provide advanced functionalities (Carazo et al., Reference Carazo, Borrego-Sánchez, García-Villén, Sánchez-Espejo, Cerezo, Aguzzi and Viseras2018). Clay minerals have traditionally been included in topical products to improve technical properties and to increase the stability of emulsions and the viscosities of suspensions (Viseras et al. Reference Viseras, Aguzzi, Cerezo and Lopez-Galindo2007). In addition, clay minerals show advanced functionalities that made them essential ingredients in anti-inflammatory, antibacterial, and wound-healing products. Clay minerals also provide specific functions in some dermocosmetics. Figure 2 attempts to clarify the different locations, pathways, and advanced functions of clay minerals in topical products. The scope and uses of clay minerals administered on/into/through the skin, are listed in Table 1 and explained further in the text below.

Fig. 2 Places and routes of skin treatments and penetration with examples of clay mineral functions (modified from Barry Reference Barry1983)

Table 1 Applications of clay minerals in skin drug delivery

Anti-inflammatory

Pelotherapy is the topical administration of hot-muds known as peloids. Peloids are inorganic gels with optimal rheological and thermal properties composed of clay minerals and mineral-medicinal water aimed at treating arthro-rheumatic issues, bone-muscle traumatic damage, and dermatological pathologies. The optimum characteristics of a peloid depend on the required treatment and are related not only to the components of the peloid (mineromedicinal water and clay minerals) but also to the process of maturation (contact between the solid and water medium over a prolonged time period) (Veniale et al., Reference Veniale, Bettero, Jobstraibizer and Setti2007). Baschini and coworkers (Reference Baschini, Pettinari, Vallés, Aguzzi, Cerezo, López-Galindo and Viseras2010) used natural peloids from Copahue: “clayey–sulphurous mud,” a special type of therapeutic mud, the thermal properties of which are similar to those of other peloids but, due to the presence of sulfur, having special possibilities for the treatment of various pathologies. Portuguese clayey materials for medical hydrology applications were selected as candidates to be used in the preparation of tailored peloids (Rebelo et al., Reference Rebelo, Viseras, López-Galindo, Rocha and da Silva2011). Regulations and quality criteria for suitable therapeutic applications of peloids were reviewed (Quintela et al., Reference Quintela, Terroso, Da Silva and Rocha2012). The influence of “maturation” conditions (time and agitation) on aggregation states, gel structure, and rheological behavior of peloids made with a pharmaceutical-grade smectite, a sepiolite, and a medicinal mineral water from a Spanish thermal spring (Graena, Granada, Spain) were investigated (Aguzzi et al., Reference Aguzzi, Sánchez-Espejo, Cerezo, Machado, Bonferoni, Rossi and Viseras2013). A concise definition and a classification of peloids as well as a complete glossary of all the mud-therapy terms were proposed in order to compile the different terminology used in the course of time (Gomes et al., Reference Gomes, Carretero, Pozo, Maraver, Cantista, Armijo and Delgado2013). Five clay samples used in various spa centers of the southern European/Mediterranean area were subjected to ethnopharmaceutic research aimed at ascertaining the compositional characteristics that enable the establishment of quality attributes and corresponding requirements for peloids, including identity, purity, richness, and safety (Sánchez-Espejo et al., Reference Sánchez-Espejo, Aguzzi, Cerezo, Salcedo, Lopez-Galindo and Viseras2014). The suitability of eleven clay samples (green and brown) from five Tunisian medina markets, traditionally used in home-made mud-packs, was fully investigated (Khiari et al., Reference Khiari, Mefteh, Sánchez-Espejo, Cerezo, Aguzzi, López-Galindo and Viseras2014). Maturation increased the release of cations from therapeutic muds but did not improve their thermal properties, indicating that maturation could explain the differential chemical effects associated with the use of therapeutic muds compared to other thermotherapeutic agents (Sánchez-Espejo et al., Reference Sánchez-Espejo, Cerezo, Aguzzi, López-Galindo, Machado and Viseras2015). Therefore, the bacterial community in peloids changed mostly during the early stages of maturation and reached stability after 2 months (Pesciaroli et al., Reference Pesciaroli, Viseras, Aguzzi, Rodelas and González-López2016). The potentialities of seven selected kaolinite-rich samples from Egyptian Carboniferous sedimentary deposits were studied in order to evaluate their use in medicinal semisolid formulations as peloids focusing on the effect of particle geometry and kaolinite crystallite size (Awad et al., Reference Awad, López-Galindo, El-Rahmany, El-Desoky and Viseras2017). Peloids prepared with kaolin and saponite and medicinal mineral waters from Lanjarón Spa (Granada, Spain) were prepared and the optimum maturation time was investigated (Fernández-González et al., Reference Fernández-González, Martín-García, Delgado, Párraga, Carretero and Delgado2017).

Wound healing and treatment of skin lesions

The protective functions of the skin are compromised by injury. A wound can be defined as a defect or a break in the skin, resulting from mechanical or thermal damage, or the consequence of an underlying medical or physiological condition.

Wound-healing is a dynamic process in which the collaborative efforts of many different tissues and cell lines are required to recover the integrity of damaged tissue and replace lost tissue. It occurs in four stages: inflammation, migration, proliferation, and maturation. Healing is considered to be complete when the skin surface has reformed and re-established its tensile strength.

  1. (1) Inflammation: The body’s initial response to injury and involves both cellular and vascular responses resulting in vasodilation, increased capillary permeation, and stimulation of pain receptors. It occurs within a few minutes to 24 h of injury.

  2. (2) Migration: growth factors in the wound exudate promote the growth and migration of epithelial cells, broblasts, and keratinocytes to the injured area to replace damaged and lost tissue. It lasts for 2–3 d.

  3. (3) Proliferation: This involves the development of new tissue and occurs simultaneously or just after the migration phase. The network is important for developing the tensile strength of the skin. As proliferation continues, further epithelial-cell migration takes place across the wound, providing closure and visible wound contraction. During the proliferation stage, the wound is typically beefy red in colour and moist, but not exuding.

  4. (4) Maturation: This final phase of wound healing (also called the ‘remodeling phase’) involves the diminution of the vasculature and enlargement of collagen fibers, which increase the tensile strength of the repair.

The need for regenerating injured skin rapidly and effectively has stimulated research into advanced therapies for wound care. Advanced wound dressings are designed to control the environment for wound healing. The role of clay minerals in the design of advanced wound dressings has been reviewed thoroughly (Sandri et al., Reference Sandri, Bonferoni, Rossi, Ferrari, Aguzzi, Viseras, Caramella and Ågren2016). Previous assessments were that not only was the use of clay minerals as nanocarriers of antimicrobial agents important for treating cutaneous bacterial infections, but also the ability of clays to physically adsorb and remove bacterial cells, toxins, and debris from the wound provided additional benefits aimed at wound healing (Otto & Haydel, Reference Otto, Haydel and Méndez-Vilas2013a, Reference Otto and Haydel2013b).

A functionalized montmorillonite with epidermal growth factor (EGF) demonstrated that EGF immobilized on montmorillonite can stimulate cell growth and migration in vitro, as is required in the proliferation step of the wound-healing process (Vaiana et al., Reference Vaiana, Leonard, Drummy, Singh, Bubulya, Vaia and Kadakia2011). A nanocomposite based on montmorillonite and chitosan loaded with silver sulfadiazine has been developed with the ability of not only protecting fibroblasts from the cytotoxic action of the drug but also improving its bacteriostatic and bactericidal properties, especially against Pseudomonas aeruginosa. This composite was assessed successfully for use as an advanced wound dressing (Sandri et al., Reference Sandri, Bonferoni, Ferrari, Rossi, Aguzzi, Mori and Caramella2014). A comprehensive and detailed study of the structure of the above-mentioned montmorilllonite-chitosan-silver sulfadiazine nanocomposite and the interactions involved was also reported by (Aguzzi et al., Reference Aguzzi, Sandri, Bonferoni, Cerezo, Rossi, Ferrari and Viseras2014)). Dário et al. (Reference Dário, da Silva, Gonçalves, Silveira, Junior, Angioletto and Bernardin2014) observed that the treatment made with a Brazilian clay allowed greater formation of collagen fibers and consequent regeneration of the deep dermis and re-epithelialization and continuous formation of granulation tissue when tested on rat models. Functionalized layered clays with amino acids (arginine, lysine, and leucine) promoted fibroblast proliferation and can be applied potentially as wound dressings to promote the wound-healing process (Ghadiri et al., Reference Ghadiri, Chrzanowski, Lee and Rohanizadeh2014). Antibacterial activity of clay–ciprofloxacin composites against the common skin bacteria Staphylococcus epidermidis and Propionibacterium acnes was demonstrated to be a potential delivery system for ciprofloxacin molecules aimed at designing novel wound dressings (Hamilton et al., Reference Hamilton, Hutcheon, Roberts and Gaskell2014). A methyl cellulose–sodium alginate–montmorillonite bionanocomposite film possesses interesting wound-healing properties based on both its ability to inhibit the growth of Enterococcus faecium and Pseudomonas aeruginosa and its potential wound-closure activities (Mishra et al., Reference Mishra, Ramasamy, Lim, Ismail and Majeed2014). A detailed review of the possibilities offered by various natural polymer/clay mineral composite scaffolds used for skin tissue engineering due to their enhanced wound-healing properties has been published (Ninan et al., Reference Ninan, Muthiah, Park, Wong, Thomas and Grohens2015). The potential use of montmorillonite-chitosan films loaded with chlorhexidine as a potential wound-dressing material to prevent microbial colonization in wounds was assayed and all the prepared films showed good antimicrobial activity (Ambrogi et al., Reference Ambrogi, Pietrella, Nocchetti, Casagrande, Moretti, De Marco and Ricci2017). A silicate (tourmaline)/chitosan composite film for wound-healing applications was obtained with improved cell adhesion and proliferation, larger numbers of newly formed and mature blood vessels, as well as faster regeneration of dermis when tested on porcine burn wounds (Zou et al., Reference Zou, Cai, Li, Li and Li2017). A nanocomposite made of chitosan oligosaccharide/halloysite was prepared and characterized successfully using advanced electron microscopy techniques. It was biocompatible in vitro towards normal human dermal fibroblasts; the results of an in vitro wound-healing test showed that it enhanced in vitro cell proliferation (cells in S-phase) rather than simple fibroblast migration. In vivo wound-healing murine model results were in agreement with the previous in vitro results, providing an early re-epithelialization process and an advanced degree of hemostasis and angiogenesis (Sandri et al., Reference Sandri, Aguzzi, Rossi, Bonferoni, Bruni, Boselli and Ferrari2017). Polymer films loaded with a carvacrol/clay hybrid for skin ulcer treatment were investigated. Different clays were considered: montmorrilonite, halloysite, and palygorskite; finally, a pharmaceutical-grade palygorskite was selected due to its ability to reduce carvacrol volatility and preservation of its antioxidant properties. The hybrid system provided improved antimicrobial properties against Staphylococcus aureus and Escherichia coli and cytocompatibility towards human fibroblasts (Tenci et al., Reference Tenci, Rossi, Aguzzi, Carazo, Sandri, Bonferoni and Ferrari2017). A new clay-based dermal patch system based on montmorillonite-betaine hydrochloride silver nitrate was evaluated for its potential use in first-degree burns and its anti-nociceptive activity (Rangappa et al., Reference Rangappa, Rangan, Sudarshan and Murthy2017). A novel responsive nanocomposite hydrogel based on poly(vinyl alcohol)/chitosan/honey/clay was designed and successfully evaluated for use as a novel wound dressing (Noori et al., Reference Noori, Kokabi and Hassan2018). The method of preparation of a burn ointment including montmorillonite aimed at promoting tissue regeneration and skin growth has been patented recently (Zhang et al., Reference Zhang, Zhang and Zhang2018).

Cell adhesion, proliferation, and differentiation: Skin engineering and regenerative medicine

Adhesion and proliferation of cells on biomaterials are crucial points in tissue engineering and biotechnology. Studies endeavoring to assess cell proliferation and adhesion to clay minerals are currently a matter of interest. The most studied clay minerals are Laponite, montmorillonite, cloisite, and halloysite (Sandri et al., Reference Sandri, Bonferoni, Rossi, Ferrari, Aguzzi, Viseras, Caramella and Ågren2016). Mousa and coworkers recently reviewed and compiled the beneficial effects of clay nanoparticles on cellular adhesion, proliferation, and differentiation. In addition, their attractive mechanical or rheological properties highlight the striking potential of clays for the creation and development of new bioactive scaffolds that may be used in skin-regenerative medicine (Mousa et al., Reference Mousa, Evans, Oreffo and Dawson2018). Early studies on sepiolite-collagen complexes observed normal fibroblast proliferation and outgrowth of skin fibroblasts from explants (Lizarbe et al., Reference Lizarbe, Olmo and Gavilanes1987; Olmo et al., Reference Olmo, Lizarbe and Gavilanes1987). Fibroblast attachment and spreading was improved by montmorillonite and halloysite, and cells maintained their phenoptype (Kommireddy et al., Reference Kommireddy, Ichinose, Lvov and Mills2005). The addition of montmorillonite to chitosan enhanced the adhesion of osteoblasts (Katti et al., Reference Katti, Katti and Dash2008) and fibroblasts (Popryadukhin et al., Reference Popryadukhin, Dobrovolskaya, Yudin, Ivan'kova, Smolyaninov and Smirnova2012). Da Silva et al. (Reference Da Silva, Da Silva-Cunha, Vieira, Silva, Ayres, Oréfice and Behar-Cohen2013) developed a biocompatible and biodegradable retinal scaffold based on a montmorillonite/polyurethane nanocomposite. The biocompatibility and cell proliferation of montmorillonite have been evaluated in cultured normal human dermal fibroblasts (Sandri et al., Reference Sandri, Bonferoni, Ferrari, Rossi, Aguzzi, Mori and Caramella2014). A nanocomposite based on montmorillonite and silk fibroin has been developed as biomaterial for bone tissue formation (Mieszawska et al., Reference Mieszawska, Llamas, Vaiana, Kadakia, Naik and Kaplan2011). A novel composite scaffold based on chitosan-gelatin/nanohydroxyapatite-montmorillonite with improved properties for use in tissue engineering applications was accurately prepared (Olad & Azhar, Reference Olad and Azhar2014). Montmorillonite-reinforced hydrogels, based on a peptidomimetic polyamidoamine carrying guanidine pendants were successfully used as substrates for the osteo-induction of osteoblast precursor cells (Mauro et al., Reference Mauro, Chiellini, Bartoli, Gazzarri, Laus, Antonioli and Ferruti2017). Cell viability tests showed that newly developed chitosan-montmorillonite triclosan loaded films are compatible with human dermal fibroblasts (Chen et al., Reference Chen, Ye, Sun, Li, Shi, Hu and Wang2018). A strontium (Sr2+) modified chitosan/montmorillonite composite scaffold has been developed recently with enhanced properties for use in bone tissue engineering (Demir et al., Reference Demir, Elçin and Elçin2018). A full and comprehensive study of the features provided by halloysite nanotubes in tissue engineering was reported (Fakhrullin & Lvov, Reference Fakhrullin and Lvov2016). Alginate-halloysite composite scaffolds were prepared with enhanced fibroblast attachment and proliferation attributed to the increase in the surface roughness due to the incorporation of halloysite (Liu et al., Reference Liu, Dai, Shi, Xiong and Zhou2015). Chitosan-gelatine-agarose doped halloysite scaffolds prepared were promising candidates for tissue engineering applications due to their in vitro and in vivo biocompatibility; their ability to enable neo-vascularization in newly formed connective tissue placed near the scaffold permitted the complete restoration of blood flow (Naumenko et al., Reference Naumenko, Guryanov, Yendluri, Lvov and Fakhrullin2016). A tri-component hydrogel, based on gellan gum, glycerol, and halloysite nanotubes, was designed for soft tissue engineering applications (Bonifacio et al., Reference Bonifacio, Gentile, Ferreira, Cometa and De Giglio2017). Cross-linked Laponite was able to maintain both the adhesion and proliferation of HepG2, skin fibroblast, and human umbilical vein endothelial in a manner strongly associated with the concentration of clay in the hydrogel (Haraguchi et al., Reference Haraguchi, Takehisa and Ebato2006; Liu et al., Reference Liu, Zhang, Wu, Xiong and Zhou2012). Wang et al. (Reference Wang, Castro, An, Song, Luo, Shen and Shi2012) used Laponite to develop poly(lactic-co-glycolic acid; PLGA) nanofibers with promoted fibroblast adhesion and proliferation. Similarly, attapulgite was included in PLGA nanofibers as a scaffolding material for osteogenic differentiation of stem cells (Wang et al., Reference Wang, Zhao, Luo, Wang, Shen, Tomás and Shi2015). A biocomposite scaffold composed of carboxymethyl chitosan, gelatin, and laponite nanoparticles via freeze drying was prepared with potential use in bone tissue engineering (Tao et al., Reference Tao, Zhonglong, Ming, Zezheng, Zhiyuan, Xiaojun and Jinwu2017).

Antibacterial Purposes

As mentioned above, skin acts as a physical barrier to avoid the invasion of external pathogens. The desiccated, nutrient-poor, acidic environment, contributes to the adversity that microorganisms must deal with to colonize human skin (Byrd, Belkaid, & Segre, Reference Byrd, Belkaid and Segre2018). Besides, topical antimicrobial therapy emerges as an attractive route for the treatment of infectious diseases due to the increased resistance to oral-administered systemic antimicrobial therapy (Lam et al., Reference Lam, Lee, Wong, Cheng, Bian, Chui and Gambari2018).

Natural Antibacterial Clays

Natural antibacterial clays when hydrated and applied topically are able to kill human pathogens, including the antibiotic-resistant strains proliferating worldwide. Only certain clays are bactericidal ((Morrison et al., Reference Morrison, Misra and Williams2016); Williams, 2019, this issue). Examples of clays and soils being used for the treatment of cutaneous bacterial infections are well known (Carretero, Reference Carretero2002; Ferrell, Reference Ferrell2008; Friedlander et al., Reference Friedlander, Puri, Schoonen and Karzai2015; Williams et al., Reference Williams, Holland, Eberl, Brunet and Brunet de Courrsou2004; Williams et al., Reference Williams, Haydel, Giese and Eberl2008; Williams et al., Reference Williams, Metge, Eberl, Harvey, Turner, Prapaipong and Poret-Peterson2011). Antibacterial activity of natural clay minerals is the result of two types of actions: biotic and abiotic (Otto, Reference Otto2014; Otto & Haydel, Reference Otto, Haydel and Méndez-Vilas2013a). A good example of biotic activity is the Jordan red clays, the antimicrobial activity of which is explained by the proliferation of bacteria naturally present within the clays and their concomitant production of antimicrobial compounds (Falkinham et al., Reference Falkinham, Wall, Tanner, Tawaha, Alali, Li and Oberlies2009). Other biotic influences, including protozoan or mycobacterial predation, lytic microorganisms, and bacteriophages, may also be responsible for controlling bacterial growth. Additionally, abiotic processes are also responsible for the antimicrobial activity of some clays (Otto & Haydel, Reference Otto, Haydel and Méndez-Vilas2013a). Clays bind toxic metals to their surface due to their net negative charge and then release those exchangeable metal ions from the clay surface. The antibacterial activity of these natural clays thus depends on microbiocidal activities of the desorbed metal ions (Otto & Haydel, Reference Otto and Haydel2013b; Otto et al., Reference Otto, Koehl, Solanky and Haydel2014, Reference Otto, Kilbourne and Haydel2016).

Antibiotics-loaded Nanoclays

Clays act as topical delivery agents for various antimicrobial products. A natural zeolite was exchanged with inorganic Zn2+. The micronized composite was subsequently charged with erythromycin to investigate the antimicrobial efficacy against erythromycin-resistant Propionibacterium strains. A 99.5% reduction in P. acnes viability was observed (Bonferoni et al., Reference Bonferoni, Cerri, De'Gennaro, Juliano and Caramella2007; Cerri et al., Reference Cerri, De'Gennaro, Bonferoni and Caramella2004, Reference Cerri, de'Gennaro, Bonferoni, Caramella and Juliano2006). Furthermore, chlorhexidine intercalated into a montmorillonite had the aim of being useful in skin pathologies due to its successful inhibition of the growth of a wide range of microorganisms including both Staphylococcus aureus and Escherichia coli (Saha et al., Reference Saha, Butola and Joshi2014). An organo-modified bentonite for gentamicin topical application was developed with sustained antibacterial activity and enhanced drug permeation rate (Iannuccelli et al., Reference Iannuccelli, Maretti, Bellini, Malferrari, Ori, Montorsi and Leo2018). A topical ointment consisting of the clay minerals smectite, illite, and rectorite alone or in combination has been patented recently aimed at treating bacterially caused skin infections and skin diseases (Tuba, Reference Tuba2018). A multifunctional smectite-zwitterion-silver-analgesic system with both antimicrobial and pain relieving properties has been patented (Mukhopadhyay et al., Reference Mukhopadhyay, Rangan and Sudarshan2018). A chitosan-montmorillonite nanocomposite film was loaded with the antibiotic triclosan and an intelligent pH responsive long-term release was obtained. High sterilization efficiency of the films was found against Staphylococcus aureus, Escherichia coli, and Staphylococcus epidermidis. Furthermore, cell biocompatibility measurements toward L929 fibroblasts and human lens epithelial cells showed no adverse effects of the multilayer film (Chen et al., Reference Chen, Ye, Sun, Li, Shi, Hu and Wang2018).

Dermocosmetics

Clay minerals are part of a large variety of dermocosmetic products, such as facial creams, sunscreen, for skin cleansing, shampoos, and makeup items (liquid and powder foundations, eye shadow, facial masks, lipsticks, etc.) either as dermatological active ingredients or as excipients (López-Galindo et al., Reference López-Galindo, Viseras and Cerezo2007; Viseras et al., Reference Viseras, Aguzzi, Cerezo and Lopez-Galindo2007).

Most of the important properties attributed to clays for dermocosmetic applications are related to their surface properties (surface area, cation exchange capacity, layer charge, among others); rheological properties (thixotrophy, rheopecty, viscosity, plasticity); and other physical and mechanical properties including particle size and shape, color, softness, opacity, reflectance, iridescence, and so on (Moraes et al., Reference Moraes, Bertolino, Cuffini, Ducart, Bretzke and Leonardi2017).

Sunscreens

The detrimental effects of ultraviolet A and B radiations (UVA and UVB) on the skin can lead to the development of malignant carcinomas in cutaneous tissue. Sunscreens are thus dermocosmetic products of great importance to skin health. Thanks to their excellent optical barrier properties, some clay minerals have been included in dermocosmetic formulations of sunscreens, acting as a barrier to block solar radiation and, thus, protect cellular nucleic acids. Clay minerals must have a high index of refraction and optimal light dispersion properties to be used as sunscreens. Bentonite and hectorite meet the required specifications and are already being used as sunscreen (Ghadiri et al., Reference Ghadiri, Chrzanowski and Rohanizadeh2015; Mattioli et al., Reference Mattioli, Giardini, Roselli and Desideri2015). A mineral-based sunscreen containing activated clay combined with a dispersing agent and one or more inorganic sunscreen actives was patented, resulting in a mineral sunscreen having high UVB/UVA protection and exceptional spreadability that is non-whitening. (Timothy et al., Reference Timothy, Cziryak and Kljuic2015). A composition for cosmetics which has a UV shielding effect and good dispersibility is provided. The composition includes microparticulate titanium dioxide, magnesium and/or calcium hydroxide, and a clay mineral. The clay mineral suitable for the present invention has no limitation imposed upon it, as long as it can be used as a powder to be employed in ordinary cosmetics. Examples are boron nitride, sericite, natural mica, calcined mica, synthetic mica, synthetic sericite, alumina, mica, talc, kaolin, bentonite, and smectite (Ijiri et al., Reference Ijiri, Sato, Suzuki and Hasegawa2015).

Other Clay-Based Cosmetic Products

A wide range of cosmetic products containing clay minerals in their composition have been designed throughout time, and most of them have their patent registered (Viseras et al., Reference Viseras, Aguzzi, Cerezo and Lopez-Galindo2007). The use of clays as emulgents or emulsifiers in cosmetic products is well known. The use of talc as an emulgent in “make-up preparations” because of its large surface area, is notable (Gabriel, Reference Gabriel1973). Bentonite was used as an emulsifier in a nail-enamel remover (Carter, Reference Carter1940), in oil-in-water make-up (Gabriel, Reference Gabriel1973), in vanishing low oil-content creams (Alexander, Reference Alexander1973), and in cleansing lotions (Sarfaraz, Reference Sarfaraz2004). The optimization of a peel-off facial mask formulation containing green clay and aloe vera was studied (Beringhs et al., Reference Beringhs, Rosa, Stulzer, Budal and Sonaglio2013). More recently, a dry shampoo composition comprising a smectite, natural starches, and a natural oil absorbent was developed and was subsequently patented (Perfitt & Carimbocas, Reference Perfitt and Carimbocas2017). An emulsion of bio-minerals (phyllosilicate, inosilicate, cyclosilicate, tectosilicate, neosilicate, or sorosilicate) was created using a unique process that allows the combination of ingredients to be emulsified in a cold, chemical-free environment to create a product that is more stable and requires less energy and time to prepare and has been registered (Rochette et al., Reference Rochette, Doyon and Elkurdi2017).

Summary and Outlook

Topical and transdermal products including clay minerals have a long history and remain key formulations for delivering drugs not only onto the skin for local purposes, but also through it for systemic action. Skin is a widely used route of delivery for local and systemic drugs and is potentially a route for their delivery as nanoparticles. Among the wide range of nanoparticles available, clay minerals have been used since ancient times, both as actives and excipients in the treatment of skin illness. The use of nanoclays alone and/or in combination with biopolymers and/or drug in treating local skin and systemic diseases is of interest. In this review, recent work in the field of clay minerals-based nanoparticle delivery to the skin, and future directions currently being explored, is discussed. Once this attempt to summarize and highlight the possibilities offered by clay minerals in advanced skin drug delivery is finished, the final goal is to provide a greater understanding of the countless benefits derived from both this administration path and these types of nanosystems.

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Figure 0

Fig. 1 Skin layers and diverse routes of penetration

Figure 1

Fig. 2 Places and routes of skin treatments and penetration with examples of clay mineral functions (modified from Barry 1983)

Figure 2

Table 1 Applications of clay minerals in skin drug delivery