Chitosan-based drug delivery systems for skin atopic dermatitis: recent advancements and patent trends

Abstract

Atopic dermatitis (AD) is a complex, relapsing inflammatory skin disease with a considerable social and economic burden globally. AD is primarily characterized by its chronic pattern and it can have important modifications in the quality of life of the patients and caretakers. One of the fastest-growing topics in translational medicine today is the exploration of new or repurposed functional biomaterials into drug delivery therapeutic applications. This area has gained a considerable amount of research which produced many innovative drug delivery systems for inflammatory skin diseases like AD. Chitosan, a polysaccharide, has attracted attention as a functional biopolymer for diverse applications, especially in pharmaceutics and medicine, and has been considered a promising candidate for AD treatment due to its antimicrobial, antioxidative, and inflammatory response modulation properties. The current pharmacological treatment for AD involves prescribing topical corticosteroid and calcineurin inhibitors. However, the adverse reactions associated with the long-term usage of these drugs such as itching, burning, or stinging sensation are also well documented. Innovative formulation strategies, including the use of micro- and nanoparticulate systems, biopolymer hydrogel composites, nanofibers, and textile fabrication are being extensively researched with an aim to produce a safe and effective delivery system for AD treatment with minimal side effects. This review outlines the recent development of various chitosan-based drug delivery systems for the treatment of AD published in the past 10 years (2012–2022). These chitosan-based delivery systems include hydrogels, films, micro-, and nanoparticulate systems as well as chitosan textile. The global patent trends on chitosan-based formulations for the AD are also discussed.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s13346-023-01307-w.

Introduction

Atopic dermatitis prevalence and incidence

Atopic dermatitis (AD) is a complex, chronic, and recurrent inflammatory itchy skin disorder. It usually begins in early childhood and can last throughout adulthood in the majority of cases [1]. Over the previous decade, the prevalence of AD has climbed by more than 20% in some countries and this continues to rise, affecting not only developed (e.g., Canada, United States, France, Germany, UK, Japan) but also developing countries (e.g., Columbia, Mexico, Saudi Arabia, Turkey, United Arab Emirates) particularly among infants and children [2, 3]. Infancy or childhood accounts for about 80% of disease cases, with the remaining 20% appearing in adulthood. The point prevalence for adults ranges from 2.1 to 4.9%, while that for children varies from 2.7 to 20.1% among nations [4]. An international, cross-sectional, web-based survey [3] of children and adolescents (6–18 years old) was conducted and the study reported that the overall pediatric prevalence of diagnosed AD was 9.8 and 15.1% in the United States (US) and Canada, respectively. In Europe, Germany had the lowest prevalence (8.4%), and the Southern European countries of Spain and Italy had the highest prevalence, 18.6% and 17.6%, respectively [3]. However, the prevalence in the United Kingdom (UK) was also only marginally lower at 15.3%. Interestingly, the rates in East Asia were similar in Japan (10.7%) and Taiwan (11.3%) [3]. According to the International Study of Asthma and Allergies in Childhood (ISAAC), the 12-month prevalence of AD among Malaysian children has increased from 9.5% in ISAAC-1 (1994–1995) to 12.6% in ISAAC-3v (2002–2003), with an average increase of 0.49% annually [5]. In developing nations (Malaysia, Indonesia, and the Philippines), the direct medical expenses for a child with AD have been estimated to cost between USD199 to 743 per child [6]. It was found that families for children with a high severity of AD were over six times more likely to have a low quality of life and parents of children with AD are known to be associated with depression and stress [7]. Therefore, having an effective and safe therapy for long-haul AD is crucial.

Skin barrier function and structure and its relevance to AD

The stratum corneum (SC), the outmost layer of the human skin epidermis, plays a significant role in the structure and composition of the skin barrier. The SC is comprised of a highly organized intercellular lipid matrix and corneocytes [8]. The SC lipid matrix is composed of three main types of lipids—cholesterol, free fatty acids, and ceramides. Corneocytes are flattened cells without nuclei that are filled with keratin filaments. SC structure is often referred to as the “brick and mortar” [9], with corneocytes representing the bricks and the lipids representing the mortar [10]. The lipid matrix, on the other hand, forms a highly ordered structure of densely packed lipid layers. This intercellular lipid matrix is the main pathway for substances traveling across the skin barrier. The primary function of the SC is to protect the body from excessive transepidermal water loss (TEWL), as well as to prevent the ingress of compounds into the body via epidermis [9]. In patients with AD, there is altered SC homeostasis which leads to increase in TEWL as well as penetration of allergens [11]. The total lipid levels are also decreased in AD, and as a consequence, the skin ability to act as a barrier is compromised and resulted in increased water permeability of SC and TEWL; thus, the skin becomes extremely dry. Clinically, AD is characterized by sensitive and dry skin with localized or disseminated eczematous lesions usually accompanied by a severe itching sensation [12]. When the skin is dry, the protective barrier function of the SC is compromised, and the skin readily develops AD in response to various external stimuli, such as dry air, sweat, and skin microflora [13]. This phenomenon results in various skin lesions characterized by pruritus, erythema, edema, excoriation, and thickening of the skin, and in severe cases, it leads to a significant impairment in the patient’s life [1, 2].

The AD is caused by complex interactions of genetic predispositions, environmental triggers and immune dysregulation leading to the epidermal barrier defect [14–17]. In AD, another key factor that can affect the structure and composition of the stratum corneum is the loss and reduced function of filaggrin protein. Filaggrin is a major epidermal protein and its mutation has been shown to be a key player in the pathogenesis of AD [18]. Filaggrin is a large (37 kD), histidine-rich protein named after its ability to aggregate keratin intermediate filaments (filament aggregating protein) in the skin [19, 20]. Filaggrin is specifically deaminated by peptidyl deiminase, then broken down into smaller peptides and free amino acids, creating natural moisturizing factor (NMF) such as carboxylic acid or urocanic acid [18]. NMF helps to avoid gaps between corneocytes, thus improving the integrity of the SC [3]. Structural proteins such as filaggrin are needed for the proper functioning skin. It was shown that AD patients with filaggrin mutations are more frequently affected by reduced health-related quality of life when compared with AD patients with wild-type filaggrin [20, 21].

AD and immune response

Besides genetic determination, the epidermal barrier function also depends on the immune dysregulation. Type 2 immune cytokines, for example, interleukin (IL)-4 and IL-13, have demonstrated to play important roles in the chemokine production, skin barrier dysfunction, suppression of antimicrobial peptides (AMP), and allergic inflammation [22]. Disrupted epidermal barrier and environmental triggers also stimulate keratinocytes to release IL-1β, IL-25, IL-33, and macrophage-derived chemokines, which activate dendritic cells and Langerhans cells [23]. Activated dendritic cells stimulate T-helper 2 (Th2) cells to produce IL-4, IL-5, IL-13, IL-31, and IL-33, which leads to barrier dysfunction, decreased AMP production, impaired keratinocyte differentiation, and itchy symptoms [23, 24]. IL-4, IL-13, IL-3, and IL-33 downregulate the production of epidermal barrier proteins, including filaggrin, keratins, loricrin, involucrin, and cell adhesion molecules [24–26]. Furthermore, a damaged epidermal barrier not only leads to the development of AD, but also raises sensitization to allergens, thereby increasing the likelihood of developing food allergy and respiratory airway hyperreactivity [23].

It was shown that AD frequently leads to skin colonization with Staphylococcus aureus, which is able to produce virulence factors that perpetuate inflammation, even in normal-appearing skin [27]. Normally, the weakly acidic condition of healthy skin prevents colonization by S. aureus. However, the skin pH among patients with AD shifts toward neutrality, allowing S. aureus to grow and exacerbate the AD symptoms [28]. However, it is important to note that in regard to the skin immunity, the characteristics of AD-derived S. aureus strains differ from those of the standard S. aureus strains. A comparison of laboratory strains of S. aureus (standard strain) and clinical isolates from AD skin (AD strain) revealed that the AD strain alters the T cell responses via Langerhans cells, resulting in Th2-shifted immune responses. This in turn upregulates pro-inflammatory cytokines, such as thymic stromal lymphopoietin (TSLP), IL-4, IL-12, and IL-22, and stimulates mast cell degranulation, which results in skin inflammation [29, 30]. The impact of antimicrobial treatment on S. aureus colonization and the intensity of AD inflammation has been studied, with varying degrees of success. Topical and systemic antimicrobials were able to lower the colonization density and resulted in a partial improvement of skin lesions in various open or double-blind placebo-controlled trials [31, 32]. Therefore, the inclusion of antimicrobial substances imparting antimicrobial activity, in textiles or in emollients that are in direct contact with the skin surface, can be extremely helpful to these patients [33].

Conventional treatments for AD

Skin hydration and controlling the inflammation remain the mainstay for the management of AD. In mild AD, moisturizers or emollients have been shown to improve the epidermal barrier function and dryness leading to reduction in itchiness. In the case of moderate and severe AD, pharmacological interventions are warranted, including topical corticosteroids and calcineurin inhibitors [34]. The treatment choice in AD depends on the age of the patient, the site of skin lesions, chronicity of skin lesions, and severity of skin inflammation. However, these drugs tend to give rise to adverse reactions of itching, burning, or stinging sensation when used for more than 3–4 weeks [35]. Therefore, many formulation strategies, including the use of micro- and nanoparticulate systems, biopolymer composites, and textile fabrication, are being extensively researched with an aim to produce a safe and effective delivery system for the topical delivery of the drug compounds with minimal side effects [36–39].

Novel treatments for AD

Biopolymers are receiving increasing attention as alternatives to synthetic polymers in several technological processes ranging from environmental to food and health applications [40]. Among them, chitosan is one of the most promising biopolymers, being produced usually from heterogeneous alkaline N-deacetylation of chitin. Chitosan exhibits myriad of therapeutic properties, due to its homeostatic, coagulative, immunostimulative, and antimicrobial attributes [38]. Over the decades, chitosan has become the focus of lead biomaterials in bioactive delivery systems design. The amazing features of chitosan allow the use of chitosan as carriers of drugs, small RNAs, and biologics to treat various inflammatory diseases, especially brain diseases, tumors, and skin diseases such as AD [39, 41–43]. This review outlines the recent development of various forms of chitosan-based drug delivery systems for the treatment of AD from research articles published from years 2012 to 2022. These delivery systems include hydrogels, films, micro- and nanoparticulate systems, and chitosan textile. The patent trends and future perspective on chitosan-based formulations for the AD are also discussed.

Chitosan and its properties

Chitosan is mainly sourced from the abundantly occurring natural polymer, chitin, through the process of deacetylation [44, 45]. Theoretically, chemical N-deacetylation of chitin can take place in either acidic or alkali conditions [46]. However, a more pragmatic approach would entail the use of alkali conditions during the deacetylation of chitin as the glycosidic bonds present in the polymer are susceptible to hydrolysis in acidic conditions [46]. Aside from concentrated alkaline reaction conditions, high temperatures are also required to achieve heterogeneous N-deacetylation of chitin [46]. The use of chemical N-deacetylation is considered to be the most common approach in the commercial production of chitosan from chitin [46]. However, there are significant drawbacks to this method which poses a harm to the environment due to high energy usage and waste generation of highly concentrated alkali [46, 47]. Enzymatic deacetylation represents an alternative to chemical deacetylation in light of this issue [46, 47]. This method utilizes chitin deacetylase to produce chitosan from chitin by catalyzing the hydrolysis of N-acetamido bonds in the polymer. Chitosan oligosaccharides are mostly prepared using this method for commercial purposes [46, 47]. Although chitin can be found in many different sources, commercially available chitosan is normally obtained from animal-sourced chitin found in the exoskeleton of crustacean life (e.g., shrimp shells) [44, 45]. Recently, non-animal sources of chitosan, which uses chitin derived from plant sources such as fungal cell walls have become commercially available but at a much higher cost [44, 48]. More research will be required to shed light on the distinct differences between chitosan obtained from animal sources and plant sources. One study has found differences in the physical and biological properties of gels prepared using animal-sourced and plant-sourced chitosan [49]. Plant-sourced chitosan generally had lower viscosity values than animal-sourced chitosan [49]. Furthermore, gels formulated using the plant-sourced chitosan only exhibited antimicrobial activity against P. gingivalis while the animal-sourced chitosan showed activity against P. gingivalis, A. actinomycetemcomitans, and C. albicans [49].

Physicochemical properties

Chitosan, the deacetylated derivative of chitin, is composed of repeating monomeric subunits of N-acetyl-2-amino-2-deoxy-d-glucose and 2-amino-2-deoxy-d-glucose in varying degrees [44, 45]. Due to the lower degree of N-acetyl groups in chitosan relative to chitin, a significant increase in the solubility in aqueous acidic media can be attained [50]. Fewer N-acetyl groups in chitosan allows a larger portion of primary amines to be protonated under acidic conditions which imparts a relatively higher degree of solubility [50]. The poor solubility of chitin in both organic solvents and aqueous media represents a limiting factor in its applications. Improving solubility properties of chitosan greatly expands the practical utility of this natural polymer in numerous fields such as food, cosmetic, textile, and pharmaceutical industries to name a few. Viscosity can be seen as another valuable property of chitosan when assessing its potential for engineering various materials including thin films, scaffolds, fibers, and hydrogels [50]. As with most polymers, the molecular weight of chitosan strongly influences its viscosity in solution, with higher molecular weights leading to higher viscosities and vice versa [51]. Deacetylation degree of chitosan also affects the viscosity of the polymer in solution. Higher deacetylation degrees have been found to produce higher viscosity values while lower deacetylation degrees led to lower viscosity values [51]. Compared to chitosan, chitin is mostly insoluble under aqueous conditions, and the reported viscosity of this polymer in the current literature uses organic solvents [52]. Similar concepts which govern the viscosity of chitosan can be applied to chitin. However, changes in viscosity of chitin can be strongly influenced with the formation of complexed moieties with other molecules in the solution [52]. At dilute concentrations, the reduced viscosity of chitin has been found to increase following an increase in chitin concentration. However, once the concentration exceeds the capacity of the system, the ratio of complexed to non-complexed chitin will decrease, leading to a decrease in reduced viscosity [52]. These properties can vary widely depending on the polymer molecular weight and deacetylation degree [50].

Structural conformation of chitosan significantly varies based on changes in both the degree of N-deacetylation and the distribution of N-acetylated d-glucosamine monomers [53]. In terms of the secondary structure, molecular dynamics have shown that decreasing the deacetylation degree leads to more rigidity with lesser conformational interchangeability in the polymer chain [53]. At 0% deacetylation (chitin), the polymer chain assumes an extended twofold helix structure stabilized by intra-chain hydrogen bonding with the asymmetric unit comprised of a glucosamine residue [53, 54]. A structure termed as a relaxed twofold helix becomes dominant upon 40% deacetylation distributed uniformly along the chain where the asymmetric unit consists of 4 glucosamine residues [53, 54]. Further increase in deacetylation degree to 60% with uniform distribution favors a fivefold helical structure with a single glucosamine residue as the repeating unit [53, 54]. Lastly, at 100% deacetylation, the relaxed twofold and fivefold conformations appear at a similar distribution frequency [53, 54]. Curiously, a block distribution of acetyl groups at 40% deacetylation and 60% deacetylation favors the fivefold and extended twofold conformation, respectively [53, 54].

It has been similarly shown that changes in deacetylation degree of chitosan further influences its biological properties [55]. Certainly, the helical conformation observed in chitin and chitosan is considered commonplace for biomacromolecules including naturally occurring polymers [56]. Subsequent biological properties of biopolymers and natural polymers with similar structures as chitin and chitosan have been proposed to be a partial result of this structural conformation [56]. However, it is difficult to directly infer the role of conformational modifications of chitosan with different deacetylation degrees from these observations. This is due to the cationic surface charge of chitosan which is greatly affected by deacetylation degree and is as likely to influence its biological properties as the structural conformation of the polymer [56].

Biological properties

Studies evaluating the therapeutic use of chitosan have consistently reported satisfying levels of safety and biocompatibility, including in the human skin cells [55, 57, 58]. Within the context of AD, chitosan possesses an impressive range of biological properties which makes it a promising candidate for developing therapeutic platforms [55]. Based on the current scientific literature, chitosan displays three different biological activities relevant to the treatment of AD [55]. These properties can be classified as antimicrobial, antioxidative, and inflammatory response modulation (Fig. 1) [55].

Fig. 1.

Physicochemical and biological properties of chitosan [46, 55]

Antimicrobial activity

Dysbiosis of the skin microbiota has gained more attention in the pathogenesis of AD recently [13, 59]. Significant reductions in microbiota diversity and abnormally high levels of S. aureus on the skin have been correlated with the occurrence of AD and during flare-ups [13, 59]. Chitosan has been shown to exert antimicrobial properties by numerous reports in the current literature [60–63]. By taking the advantage of the antimicrobial nature of chitosan, S. aureus levels on the skin can be potentially reduced in patients with AD [64, 65]. Many different mechanisms have been proposed as the antimicrobial mode of action of chitosan. By and large, most studies [61, 63] showed that the unique polycationic nature of chitosan plays an essential role in producing its antimicrobial effects. The interaction between the negatively charged bacterial cell wall with the positively charged chitosan polymer chains have been often quoted as one of the main ways of disrupting bacterial growth [61, 63]. Inhibitory activity from this interaction has been proposed to stem from the chelation of trace metals on cell walls, disruption of cell wall integrity, and disruption of membrane integrity [63, 66]. In addition, interference with DNA transcription and mRNA synthesis within the bacterial cell has also been thought to contribute to the antimicrobial nature of chitosan [63]. Lower molecular weight chitosan and chitosan nanoparticles have been found to be able to penetrate the cell wall of bacteria and subsequently binding to cytoplasmic DNA which then inhibits the synthesis of mRNA [63, 67].

Antioxidative activity

Oxidative stress and excessive levels of reactive oxygen species (ROS) due to skin inflammation stands as a significant problem during both acute and chronic dermatitis [68]. Overaccumulation of ROS during skin inflammation can lead to damage of skin cells through lipid peroxidation and further prolongation of inflammation by upregulating the release of pro-inflammatory cytokines including IL-33, TNF-α, and TSLP [68, 69]. Chitosan can be useful in this aspect as it has been found to show mild antioxidative properties. Unlike potent antioxidants such as polyphenols, the antioxidative effects exerted by chitosan is considerably lower in comparison, but still significant [70, 71]. By donating a hydrogen atom from either the hydroxyl or amino groups, chitosan can produce moderate free radical scavenging activity [72, 73]. This antioxidative effect is limited by the overall structure of the polymer chain. Intermolecular hydrogen bonding between different chitosan chains and intramolecular hydrogen bonding within individual chitosan chains reduces the free radical scavenging activity of the hydroxyl and amino groups [72, 73]. Despite this limitation, the mild level of antioxidation exerted by chitosan can still be beneficial in controlling the oxidative stress present on the inflamed skin of AD patients [74].

Inflammatory response modulation activity

Excessive levels of inflammation on the skin represents the hallmark of AD pathology [13]. Few studies are available which investigate the effects of chitosan on inflammatory pathways [75–77]. Interestingly, chitosan has been found to produce immunomodulatory activities which strongly depend on the physicochemical properties of the polymer being used [75]. Through the binding with CR3 and TLR4 receptors in macrophages, chitosan was shown to reduce the release of tumor necrosis factor (TNF)-α and IL-6, inducible nitric oxide synthase (iNOS) expression, and consequently nitric oxide (NO) production (Fig. 2) [75]. However, this was only observed in chitosan polymers with relatively higher molecular weights (156 kDa and 72 kDa) [75]. Chitosan chains possessing lower molecular weights (7.1 kDa and chitosan oligosaccharide) were found to exhibit pro-inflammatory effects in macrophages through the binding with CD14, TLR4, and CR3 receptors [75]. NO and iNOS have been implied to be involved in a number of signaling pathways relevant to AD [78, 79]. These pathways in turn can be anti-inflammatory or pro-inflammatory in nature by regulating the release of cytokines [78, 79]. Recent development of a NO donor, B244 by AOBiome Therapeutics, which underwent a phase 2b clinical trial for AD treatment further highlights the role of NO in AD management [80]. Hence, the usage of the appropriate form of chitosan would hold a promising potential to provide additional anti-inflammatory effects when designing a treatment for AD.

Fig. 2.

The schematic mechanism of action of chitosan on NO [75]

Chitosan hydrogels

Chitosan is a biopolymer that is widely explored for gel and hydrogel formation due to its ability to form a polymeric network with or without cross-linking. Gels and hydrogels are capable to imbibe a huge amount of water and biological fluids which presents as a desired properties to load drug solutions or absorb skin exudates [81]. These formulations are, therefore, suitable for dermal application owing to its hydrophilicity and flexibility. The advantages and disadvantages of chitosan hydrogels are summarized in Table 1.

Table 1.

Advantages and disadvantages of chitosan hydrogels, films, and nanofibers [82–84]

Formulation	Advantages	Disadvantages
Hydrogels (gels)	• Easy to prepare by simple mixing • Ready to be applied/used on the skin • Retain skin hydration (beneficial for drug permeation) • May increase drug thermodynamic activity upon drying after application	• Not occlusive • Require proper storage to avoid dehydration/evaporation • Easily wash off and contaminate clothing
Films	• Easy to prepare by simple mixing • Easy to store and better stability	• Require drying step during preparation • Require hydration/swelling for drug release
Nanofibers	• Better drug release and permeation due to smaller size • May present as a scaffold for tissue growth • Easy to store and better stability • Flexible and easy to be applied on the skin	• Require multiple steps or dedicated instruments (e.g., electrospinning) to prepare • Require hydration/swelling for drug release

A past study [85] developed chitosan-glycerol gel by simple mixing as a barrier formulation against metal contact dermatitis. The reactive amino and hydroxyl groups in chitosan chelated different heavy metal ions including nickel, chromium, cobalt, and palladium ions by forming metal-complexed chitosan. The chitosan-glycerol gel was shown to have the ability to reduce the percutaneous absorption of nickel ions in vitro. Chitosan gel was also prepared to accommodate topical steroid-loaded (0.1% of betamethasone 17-valerate or diflucortolone valerate) liposomes or lecithin/chitosan nanoparticles for in vivo evaluation in AD-induced rats [86]. Liposomes prepared using Phospholipon 90G (223.7–331.9 nm) showed a smaller size and lower entrapment efficiency (39.5–46.3%) than those using Lipoid S100 (size: 455.8–764.6 nm; entrapment efficiency: 53.4–58.8%), while lecithin/chitosan nanoparticles showed a similar size range (204.2–274.6 nm) but with a higher entrapment efficiency of up to ~88% [86]. The 6-h skin permeation studies using rat skin showed ~ 2–3-folds higher skin retention as compared to commercial creams for both gels with nanoformulations. Both gels showed a high proliferative effect on human fibroblast cells in vitro [86], while in vivo evaluation demonstrated a higher inhibition of paw edema and erythema (irritation) as well as an improved TEWL (skin barrier function) as compared with commercial cream with 10-time higher drug content [86].

Apart from liposome and chitosan nanoparticles, chitosan gel (cross-linked by glutaraldehyde) was used to incorporate solid lipid nanoparticles (SLN) loaded with ebastine (anti-histamine drug) [36]. The SLN prepared by cold dilution of microemulsion has zeta potential of 15.6 ± 2.4 mV, polydispersity index of 0.256 ± 0.03, and particle sizes of 155.2 ± 1.5 nm with a high drug entrapment efficiency (> 78%) [36]. The in vitro drug release from the SLN-loaded hydrogel was pH dependent and showed a sustained release of maximum 73.7% after 24 h. This contributed to a gradual permeation over 24 h with a cumulative amount of drug permeated of 70.76 μg/cm² [36]. The hydrogels were effective to alleviate the swelling, redness, thickness, and mast cells count of mice ear during in vivo allergic contact dermatitis studies. Also, the hydrogels were generally stable for 6 months and only induced slight irritation in mice [36].

Chatterjee and co-workers [87] attempted to design dual-responsive hydrogels by combining a thermo-responsive triblock copolymer of poly(ethylene oxide)-b-poly (propylene oxide)-b-poly(ethylene oxide) (PF127) and modified chitosan with pH-responsive properties loaded with traditional Chinese medicine, Cortex Moutan containing gallic acid (marker) [87]. Two different hydrogels were prepared using either N,N,N-trimethyl chitosan (TMC) and polyethylene-glycolated hyaluronic acid (PEG-HA) or polysaccharide-based conjugate that was chemically synthesized from pH-responsive cationic chitosan oligosaccharide lactate and anionic HA with alanine as a linker. The dual-responsive hydrogels exhibited reversible sol–gel transition at 37 °C and higher swelling ratio at pH 6.4 (close to the skin pH) [88]. Both modified chitosan hydrogels showed 76.5–86.5% of drug release (pH 6.4) after 5 days which were higher than the PF127 hydrogel (73.5%). Despite this, only ~ 0.6% of drug permeated after 48 h during in vitro permeation studies using porcine ear skin loaded with 0.5 mL of hydrogels (1.5%w/w) [88]. Nevertheless, these mechanically stable hydrogels have low in vitro cytotoxicity and strong antibacterial action against S. aureus which is a common infection in AD.

Chitosan is a flexible gelling agent and possibly a cross-linker which can be fabricated in different forms including gels. The current studies indicating the effectiveness of chitosan-designed platforms may not be entirely due to the presence of actives [36, 75, 85, 86]. Less is known about chitosan that the polymer itself can exert anti-inflammatory effects which probably through the same mechanism as AD [75]. This presents a great potential of using chitosan for this purpose.

Chitosan films

Due to the excellent film-forming ability, chitosan can be formulated as film as simple as by drying the gels formed aforementioned [89]. Chitosan films have been shown to have anti-inflammatory, antioxidant, and sunscreen effect which have been proven to benefit dermal application [44, 89, 90]. The benefits and shortfalls of chitosan films are listed in Table 1.

Alves and colleagues [91] incorporated 1–5 wt% of a mineral component, bovine bone powder (5–60 μm) into biocomposite films prepared by physical cross-linking of chitosan (2%w/w) and polyvinyl alcohol (PVA) solutions (3:1) in tripolyphosphate solution. The addition of bovine bone powder increased the thermal stability and tensile strength of the biocomposite films but reduced their swelling properties [91]. The transparent biocomposite films have a low biodegradability and showed a unique pH- and temperature-dependent swelling behavior. The protonation of amine groups of chitosan (pH < 6) and the deprotonation of hydroxyl groups of PVA (pH > 8) contributed to the repulsions within the polymeric matrix due to same charge density that expanded the matrix and increased the swelling behavior [91]. Further investigations of the film (5wt% of bovine bone powder) application on 2,4-dinitrochlorobenzene-induced AD in mice showed the reduced scratching behavior among the mice with low itchiness and ear swelling as compared to the control film [91]. The anti-inflammatory potential was also confirmed by a decrease in myeloperoxidase activity that showed a low neutrophil and macrophage infiltration into the ear tissues [91].

Chitosan nanofibers

Nanofibers have attracted attention from researchers due to the remarkable properties as a dressing including high surface-to-volume ratio and porous structure [92]. The advantages and disadvantages of chitosan nanofibers are summarized in Table 1.

Izumi and co-workers [93] prepared chitin nanofibrils from their earlier work using α-chitin powder isolated from red snow crab [94] for suppressing skin inflammation in 2,4,6-trinitrochlorobenzene-induced AD in NC/Nga mice. The chitin nanofibrils were generated by performing multiple mechanical treatments on the ejected chitin slurry. The skin inflammation evaluation was performed on both developing and early stages of AD where the treatment was given either concurrently or 11 days after induction of AD, respectively [93]. Reduction in nuclear factor κB, cyclooxygenase-2 (COX-2), and iNOS in the epithelial cells of the skin which was involved in the adaptive type-2 allergic inflammation pathway was reported in both models [93]. In addition, the suppressed skin inflammation and immunoglobulin E (IgE) serum levels were noted in the early stage of AD. Such observation was similar to a steroid treatment (prednisolone valerate acetate) but less side effects with the use on chitin nanofibrils [93].

More recently, Shams and colleagues [95] electrospun chitosan-PVA mixture with self-microemulsifying drug delivery system (SMEDDS) incorporated with tacrolimus for nanofibrous membrane generation to treat AD. Owing to its polycationic nature in solution, rigid chemical structure, and specific intra- and intermolecular interactions, especially strong intramolecular hydrogen bonds of chitosan that greatly restricts its electrospinnability, chitosan is usually mixed with other polymers [96]. The SMEDDS component was prepared by adding tacrolimus (0.8%) in ethyl oleate with surfactant-cosurfactant mixture (solutol HS 15 and glycofurol). PVA (10%w/v) solution was mixed with chitosan (2%w/v) solution at 80:20 to form a polymer mixture to be mixed with SMEDDS at different ratios (80:20, 90:10, 95:5) [95]. At the ratio of 90:10, the fiber diameter was homogeneous (574.2 ± 79.6 nm) with smooth surface and the drug was probably in the amorphous state. Nevertheless, the in vitro release was the lowest (22.5%) at 72 h [95]. This nanofibrous membrane attenuated the pathological signs and lesions in mice models with 2,4-dinitrochlorobenzene-induced AD as compared to a control and drug-free membrane [95]. The SC on the epidermis was thinner although the epidermal thickness remained the same. These results were similar to that with the application of a tacrolimus (0.03%) ointment [95].

Chitosan nanoparticles as drug carriers

Chitosan nanoparticles (CSNPs) are widely used in drug delivery for AD due to its ease of preparation and versatile features. The most commonly employed method of preparation is ionotropic gelation using a cross-linking agent, which is often a negatively charged compound such as tripolyphosphate or PVA. The high-pressure homogenization-solvent evaporation method is sometimes used in large-scale production. In this section, CSNPs used for AD are reported to be in the range of around 100 to 250 nm. The small size and the positive charge of the CSNPs are exploited for increased penetration and retention into the skin. This is not surprising as nanoparticles below 100 nm have been widely reported to have increased skin penetration as the intercellular space of the stratum corneum are typically 50–100 nm [97]. In AD, alteration in cohesion between keratinocytes takes place and results in enlarged intercellular spaces [98], allowing slightly larger sizes of nanoparticles to be used, with reported literature size range below 250 nm. Moreover, chitosan has been reported to be able to open up epidermal tight junctions, giving rise to the additional benefit as a penetration enhancer [99]. Its cationic nature allows better interaction with the negative charge of the cells in the tight junctions [100]. Chitosan has been demonstrated to significantly change the secondary structure of keratin and increase water content in the SC, decreasing human keratinocyte cell membrane potential and enhancing cell membrane fluidity [101]. Chitosan can interact with both SC lipids and proteins, leading to the disorganization of lipid lamella and the formation of larger aqueous pores and fluidized lipid bilayered membrane that bring about greater permeation of drugs through the intercellular and transcellular routes [102]. As such, chitosan can be used as a building material of nanoparticles or as coating to improve delivery of drug compounds through the skin for AD (Fig. 3, Table 2). Chitosan was used to prepare nanoparticles encapsulating the following compounds for AD: Hydrocortisone (HC), and Hydroxytyrosol (HT) combination, Betamethasone (BMV), and Tacrolimus.

Fig. 3.

Application of chitosan-based nanoparticles in AD (produced using biorender.com)

Table 2.

The use of chitosan in chitosan-based nanoparticles in the treatment of AD

	Chitosan nanoparticles as a delivery vehicle	Chitosan as a coating for nanoparticles
Main building materials for the nanoparticles	Chitosan	Can be any materials
Chitosan location	Chitosan acts as the main building block and can be found throughout the body of the nanoparticles	Chitosan is only decorated on the surface of the nanoparticles
Properties of chitosan	Chitosan can be utilized for its permeation enhancing properties	Chitosan can be utilized for its permeation enhancing properties

Hydrocortisone

Hussain et al. have developed HC-loaded CSNPs for antidermatitis effects [103]. In an ex vivo permeation analysis on full-thickness NC/Nga mouse skin, HC-loaded CSNPs applied with a commercial aqueous cream (QV cream) as vehicle base significantly reduced corresponding flux [∼24 μg/(cm²/h)] and permeation coefficient (∼4.8 × 10⁻³ cm/h) of HC across the skin. It also recorded a higher epidermal (1610 ± 42 μg/g of skin) and dermal (910 ± 46 μg/g of skin) accumulation of HC compared to the control group of HC without NPs. This shows the advantage of CSNPs in increasing efficiency for topical delivery with a minimal systemic absorption. The HC-loaded CSNPs efficiently controlled TEWL [15 ± 2 g/(m²/h)], erythema intensity (232 ± 12), dermatitis index (mild), and thickness of skin (456 ± 27 μm) in vivo. Results from histopathological examination showed anti-inflammatory and antifibrotic activity against AD lesions induced in mice. In another study, the authors further evaluated the efficacy of the developed HC-CSNPs in the NC/Nga mice with AD [104]. Through in vivo Dino-Lite^® microscopic assessment, HC-CSNPs had demonstrated remarkable reduction in the severity of the pathological features of AD with a dermatitis index of 3.0, whereby the dermatitis index/score was established according to the following criteria: (1) erythema/hemorrhage, (2) dryness/scaling, (3) edema/swelling, and (4) erosion/excoriation, each of which was scored as 0 (none), 1 (mild), 2 (moderate), or 3 (severe) [104]. The observation was attributed to IgE production, histamine release, prostaglandin-E2, and vascular endothelial growth factor-α expression in the sera and skin of the mice. The HC-CSNPs were also shown to inhibit cytokine expression in the skin lesions, including IL-4, IL-5, IL-6, IL-13, IL-12p70, interferon-γ, and tumor necrosis factor-α in both the serum and skin homogenates of the mice [104]. The HC-CSNP formulations also inhibited fibroblast infiltration and fragmentation of elastic fibers, showing its ability to maintain the integrity of elastic connective tissues [104].

Hydrocortisone and hydroxytyrosol

In another study, CSNPs co-loaded with HC and HT (a potent antioxidant) was developed in the quest to alleviate systemic adverse effects of the HC and to provide additional anti-inflammatory and antioxidant benefits through HT for AD [105]. The co-loaded CSNPs were prepared using ionic gelation method through cross-linking between chitosan and sodium tripolyphosphate [65]. The CSNPs were reported to have different particle sizes, zeta potential (measurement of electrical charge as an indication of particle stability), loading efficiency, and morphology, when chitosan solutions of pH 3.0–7.0 were used [105]. The formulated HC-HT CSNPs significantly reduced the corresponding flux (17.04 μg/cm²/h) and permeation coefficient (3.4 × 10 − 3 cm/h) of HC across full-thickness NC/Nga mouse skin using Franz diffusion cells [105]. Delivery of HC in the co-loaded CSNPs also showed higher epidermal (1560 ± 31 μg/g of skin) and dermal (880 ± 28 μg/g of skin) accumulation of HC compared to commercial HC formulation [105]. In an in vivo study using an NC/Nga mouse model, the group treated with the HC-HT CSNPs showed better results in TEWL (13 ± 2 g/m²/h), intensity of erythema (207 ± 12), and mild dermatitis index [105].

Siddique et al. [106] formulated CSNPs via ionic cross-linking use TPP to encapsulate HC and HT to improve the efficacy against AD [106]. The HC-HT co-loaded CSNP had a reported size of 235 ± 9 nm and zeta potential of + 39.2 ± 1.6 mV. In vivo study on female Albino Wistar rats showed that this nanoencapsulation method significantly reduced the toxic effects of HC. The formulated CSNPs were incorporated into aqueous cream and applied onto the dorsal area of the animal after removal of fur. Results showed that HC–HT CSNPs did not cause skin irritation, as determined by Tewameter^® (measures transepidermal water loss), Mexameter^® (measures skin melanin and erythema by reflectance), and also visual observation [106]. Moreover, there was also reported no-observed adverse-effect level (NOAEL) of body weight, organ weight, feed consumption, blood hematological and biochemical, urinalysis, and histopathological parameters at a dose of 1000 mg/body surface area per day of HC–HT CSNPs for 28 days. It is expected that long-term use of HC-HT-loaded CSNPs could prevent local and systemic side effects caused by HC [106].

The same authors also reported significantly improved drug penetration by HC-HT CSNPs into the epidermal and dermal layers of albino Wistar rat skin without saturation [39]. A 2.46-fold deeper penetration than commercial formulation was reported, and the CSNPs had greater affinity and retention at the skin target site further confirming their safety benefits [39]. This was also supported by the observed lower levels of epidermal barrier flux through the SC. No evidence of toxicity was observed in repeated dermal application toxicity studies, while commercial formulation was found to induce skin atrophy and elevate liver enzyme levels [39].

Following the promising in vivo results, the authors further tested repeated applications of HC-HT CSNPs on healthy human volunteers for 28 days [107]. The TEWL and erythema intensity for 28-day application showed no signs of local irritation, redness, and toxicity. These were further confirmed by normal Draize skin irritation scoring system and skin hematoxylin and eosin (H&E) staining results [107]. There was also absence of swelling and edema. Results of blood hematology, blood biochemistry, and adrenal cortico-thyroid hormone level pre- and post-treatment showed no significant difference, further proving that the formulation is non-toxic [107]. This human study is an important milestone on the use of chitosan-based nanoparticles for AD, proving its safety and tolerability in the long-term use [107]. Further studies on the efficacy of the formulations would bring the nanoparticles a step closer to being marketed for use in patients [107].

Betamethasone

Md et al. (2019) prepared CSNPs from chitosan and PVA using the high-pressure homogenization-solvent evaporation method [108]. A common medium strength steroid according to the British corticosteroid classification, betamethasone (BMV) was encapsulated in the nanoparticles as BMV-CSNPs. The nanoparticles have size of < 250 ± 28 nm, zeta potential of + 58 ± 8 mV, entrapment efficiency of 86 ± 5.6%, and loading capacity of 34 ± 7.2%. In an in vitro drug release test, the HA-BMV-CSNPs followed Fickian diffusion release in a simulated skin surface of pH 5.5. BMV was also found to be retained in the epidermis and dermis about 1.9 times higher with BMV-CSNPs than that of BMV solution in an ex vivo drug permeation efficiency study using excised full-thickness skin from Wister albino rats. This demonstrated the superiority of using CSNPs to deliver BMV for acute dermatitis. In another study, BMV-CSNPs coated with HA were prepared using the same method [109]. Coating with HA has previously been shown to have skin penetration enhancer effect [110]. The optimized HA-BMV-CSNPs recorded a particle size of 282 ± 17 nm, zeta potential of 59.4 ± 3.39 mV, % entrapment efficiency of 78.67 ± 8.3%, and loading capacity of 29 ± 5.39%. Ex vivo drug permeation study was conducted with excised skin from Wister albino rats, and HA-BMV-CSNPs delivered and retained a comparatively higher amount of BMV into the epidermis and dermis layer compared to BMV-CSNPs without HA [109]. This was attributed to the mucoadhesive effects of HA and chitosan, causing the HA-BMV-CSNPs to remain attached to the skin appendages and release BMV locally in a controlled manner [109]. The prolonged residence of BMV at the target site could potentially improve therapeutic efficacy and reduce the frequency of drug application.

Tacrolimus

A hybrid skin targeting system based on nicotinamide (NIC) and CSNPs was developed to encapsulate tacrolimus (FK506) (FK506-NIC-CSNPs) [111], which took advantages of both of NIC and CSNPs to obtain the synergetic effects. The CSNPs were prepared with TPP using an ionotropic gelation method. The optimized FK506-NIC-CSNPs had reported size of 110.2 ± 7.9 nm, PDI of 0.2 ± 0.02, zeta potential of 19.7 ± 0.8 mV, and encapsulation efficiency of 92.2 ± 2.2%. In vitro (Franz cell) and in vivo (Sprague Dawley rats) skin permeation studies demonstrated that NIC-CSNP system significantly enhanced FK506 permeation through and into the skin, causing greater deposition of FK506 into the skin. AD-like skin lesions were constructed with BALB/c mice induced by 1-chloro-2,4-dinitrobenzene (DNCB). FK506-NIC-CSNPs containing different doses of FK506 were topically administered to the AD-like skin lesions, using Protopic^® ointment as the comparison [111]. Based on the clinical symptoms, histological analysis, and molecular biology of the AD-mice, NIC-CSNPs with a lower dose (FK506 dose was about 1/3 dose of Protopic^® ointment) had better effects than Protopic^® ointment. NIC-CSNPs vehicle also exhibited moderate anti-AD effects, demonstrating enhancement in treatment efficacy by the nanoparticles. Apart from the size of the nanoparticles that contributed to the better treatment outcome, chitosan also works as a permeation enhancer due to its positive charges and mucoadhesive properties [111].

Chitosan as a coating to nanoparticles

Chitosan can be used as a coating on nanoparticles to improve delivery of compounds for AD. In a study by Jung et al. (2015), chitosan-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Chi-PLGA/Cer) were developed to deliver ceramide for SC regeneration in AD [112]. This aims to overcome the serious drawbacks of low dispersion properties of ceramide in the hydrophilic phase and its side effects upon excessive treatment. Factors affecting the release of ceramide from the nanoparticles include pH, temperature, and chitosan coats. In particular, chitosan coating was shown to enhance initial adherence to the skin and prevent the initial burst of ceramide. The degradation of chitosan by the weakly acidic skin gave rise to the controlled release of ceramide. Fluorescent imaging revealed that the nanoparticles penetrated into the SC and accumulated at the boundary between the epidermis and the dermis. The authors attributed the enhanced penetration to the chitosan coating, which increases the hydrophilicity of the nanoparticles, contributing to an enhanced penetration through aqueous route in the intercellular space of the skin barrier [113]. The Chi-PLGA/Cer was found to be non-cytotoxic and able to regenerate the SC in a rat AD model. The rat skin thickness was found to be significantly increased following the treatment with Chi-PLGA/Cer, further proving its efficacy in AD treatment [112].

Overall, the review of studies has demonstrated significant advantages of chitosan-based NP formulations in drug delivery for AD. These studies have collectively proven that chitosan-based NPs are safe and effective; at the same time, they allow better penetration into the skin due to better diffusion and interaction with the negative charge of the skin [114, 115]. The use of CSNPs not only leads to improved treatment efficacy, but also enables dose and frequency reduction in drug administration. Another important finding is that the CSNPs tend to retain in between the epidermis and dermis layer [114, 115]. This is especially important not only from a controlled release point of view, but also acts to minimize systemic absorption and the consequential side effects [114, 115]. Since treatment of AD has always revolved around the use of corticosteroids and immunosuppressants, avoidance of systemic exposure is vital, especially if patients are on long-term treatment [114, 115].

Chitosan-based textile

Disease management for AD requires an integrated approach. Clothing fabrics act as a physical barrier and shape the cutaneous microenvironment [116]. In the European guideline for treatment of AD, fabric selection targets to avoid primary skin irritation. Smooth clothing such as super- and ultrafine merino wool, traditional cotton, and silk fabrics appears to improve AD symptoms while occlusive clothing and fabric with irritating fibers (e.g., large diameter wool) are to be avoided [116, 117]. Due to the pre-existing epidermal barrier dysfunction, invasion of environmental allergens induces allergic responses, increased microbial colonization, and chronic inflammation. The use of chitosan in textiles is highly favored due to its dual functionality as antimicrobial agent and drug carrier. In a review by Costa and colleagues, the existing work suggested a strong inhibitory effect of chitosan-coated fabrics against S. aureus, Escherichia coli, Klebsiella pneumoniae, Candida albicans, and Bacillus subtilis [33].

As a drug delivery system, chitosan forms water-rich polymeric structures with a high biocompatibility and biodegradability. Ideally, fabrics suitable for AD patients should increase hydration, improve penetration, and provide sustained release of active ingredients, apart from being an absorbent, non-occlusive, comfortable, and lightweight [116]. Table 3 summarized studies conducted using chitosan-based delivery systems used as textiles.

Table 3.

Chitosan delivery system in textile engineering

Delivery system	Type of polymer	Active ingredient	Cross-linker	Concentration	Formulation method	Fabric	Reference
Microencapsulation	Chitosan–sodium alginate	PentaHerbs extract	Glutaraldehye	8% w/w	Cross-linking method	Cotton	[119]
	Chitosan	Cortex Moutan	Glutaraldehye	Core–shell ratio 1:1 to 1:3	Cross-linking method	Cotton	[118]
	Chitosan–sodium alginate	Cortex Moutan	Glutaraldehye	Core–shell ratio 1:1 to 1:3	Cross-linking method	Cotton	[120]
Stimuli-responsive hydrogel delivery system	Pluronic F-127/N,N,N-trimethyl chitosan/polyethylene-glycolated hyaluronic acid	Gallic acid	Polyethylene-glycolated hyaluronic acid	Drug-to-polymer weight ratio (w/w) of 1:9	Conjugation and ultra-sonication cross-linking	Cotton	[121, 122]
	Poly N-isopropyl acryl amide/chitosan hydrogel	n/a	N,Nmethylenebis-acrylamide	n/a	Surfactant-free emulsion polymerization	Cotton	[124–128]

Chitosan-sodium alginate (CSA) microcapsules were investigated as carriers for traditional Chinese medicine PentaHerbs extracts for textile engineering [118, 119]. Microcapsules sized between 3 and 18 μm were prepared at 8% w/w of PentaHerbs extract and were grafted onto cotton fabrics using textile binders. Scanning electron microscopy (SEM) confirmed grafting of microcapsules on cotton fibers. In vitro study showed drug release from microcapsules up to 80% within the first 24 h. It was postulated that the released drug adsorbs directly onto skin for clinical efficacy. Similar delivery system was studied to deliver herbal medicine Cortex Moutan using chitosan alone [120] or chitosan-sodium alginate conjugates [118]. In comparison, chitosan-sodium alginate microcapsules showed a higher rate of release at a lower pH, while rate of drug release from chitosan microcapsules was less affected by the pH.

One unique attribute of chitosan is the presence of cationic amino groups that allow surface modification for the development of stimuli-responsive delivery systems. Studies by Chaterjee and colleagues [121, 122] described a chitosan/HA/pluronic F-127 hydrogel system for transdermal delivery of gallic acid. As mentioned above, gallic acid is a polyphenol and a major component of Chinese herb Cortex Moutan shown to relieve AD via reduced skin inflammation and immune modulation [123]. Inflection of dynamic viscosity suggested the thermoresponsive property of the delivery system with sol–gel transition starting at 30 °C. Swelling studies indicated the pH responsiveness of the hydrogel system. Stable swelling was observed in neutral (pH 7.4) and mild acidic (pH 6.4) conditions, while acidic environment (pH 5.4) triggered a complete disintegration of the hydrogel system [123].

Dual stimuli-responsive chitosan hydrogel system was also developed using poly(N-isopropylacrylamide), incorporated into cotton fabrics in the form of microparticulate [124] and nanoparticulate [125] systems. The transition temperature of this delivery system was shown to be dependent on pH, increasing from 26 to 33 °C at pH between 2 and 9 [126]. Incorporation of microgels at 1 and 3% was observed under SEM [127] and confirmed via elemental analysis using X-ray photoelectronic spectroscopy [126]. Incorporated fabric was further evaluated for water vapor permeability, moisture content, crease recovery angle, and whiteness index [127].

One important feature of a functionalized textile in AD is to minimize allergic responses [33, 37]. Collective results from available studies suggested that chitosan delivery systems are potentially non-toxic to keratinocytes [122] and human epidermal equivalent models in vitro [119]. In summary, studies about chitosan delivery system in textiles successfully derived the benefits of chitosan as a natural and versatile polymer. Copolymerization with a complementary polymer helps to circumvent the intrinsic limitations of chitosan, including high molecular weight, high viscosity, and low solubility in water [33].

Current patents trends

Research into patents can help to predict upcoming trends in technology in related fields. Through patent research, this review was able to gather data on the recent development of the chitosan-based topical formulations intended for AD treatment. A scientific prospect was made from 2012 to 2022 using international patent search website lens.org, which included the patent offices of the US, Canada, Europe, and Asia. The database were searched using search queries (i) “chitosan” in [Title/Abstract/Claims] and “atopic dermatitis” in [Title/Abstract/Claims] and (ii) “chitosan” in [Title/Abstract/Claims] and “atopic eczema” in [Title/Abstract/Claims]. Subsequently, potential hits were extracted from the entire patent document specifically by focusing abstract and patent claims to retrieve technological information pertaining to chitosan-based formulations. The search yielded 96 documents and the results are shown in Fig. 4. The patents applied and granted are low (< 10 per year) but show an upward trend from 2012 to 2019 indicating growing interests in the area. However, the tapered number of applications from 2020 till 2022 may be due to the COVID-19 pandemic which may have shifted the focus away from AD. In the following section, only the patents granted between 2012 and 2022 were reviewed.

Fig. 4.

The granted patent and patent application trends (2012–2022) of chitosan-based AD formulation (produced from lens.org)

Table 4 summarizes the patents containing chitosan as the formulation ingredient for the treatment of AD granted for the past 10 years (2012–2022) and only 11 patents were found. Majority of the patents (54%) were granted in the US, 36% in Europe and only 1 patent was granted for Malaysia. The chitosan formulations patented range from conventional formulation such as gel, cream, foam, and nail lacquer to advanced nanoparticles. Chitosan is a biopolymer that can be subjected to various chemical reactions (esterification, carboxymethylation, cross-linking, graft copolymerization, etherification, and others) to obtain its derivatives having diversified applications which include topical applications. Discussed below are some of the patented chitosan derivatives claiming AD therapeutic activity.

Table 4.

Patents granted in 2012–2022 in relation to chitosan-based drug delivery system for the treatment of AD

No.	Patent no.	Year	Patent title	Inventor(s)	Formulation type	Reference
1	EP 1889608 B1	2012	Therapeutic hydrogel for atopic dermatitis and preparation method	Nho et al.	Gel	[90]
2	US 8324356 B2	2012	Polysaccharide derivatives of lipoic acid, and their preparation and use as skin cosmetics and devices	Fabrizio et al.	Cream	[96]
3	US 8636982 B2	2014	Wax foamable vehicle and pharmaceutical compositions	Dov et al.	Foam	[93]
4	MY 169467 A	2019	Chitosan-based skin targeted nanoparticle drug delivery system	Haliza and Shariza	Nanoparticles	[91]
5	US 10111835 B2	2018	Microparticles for encapsulating probiotics, production and uses	Maite et al.	Microparticles	[92]
6	US 10201490 B2	2019	Use of chitosans for the treatment of nail inflammatory diseases	Federico	Nail Lacquer	[94]
7	US 10226483 B2	2019	Topical compositions and methods of using the same	Ryan and Jian	Gel	[95]
8	US 10443033 B2	2019	Lactobacillus rhamnosus RHT-3201 conjugated to polysaccharide polymer binder for prevention or treatment of atopic diseases	Lee et al.	Gel	[98]
9	EP 3429691 B1	2020	Non-aqueous Topical Compositions comprising a halogenated salicylanilide	Alexander et al.	Gel	[100]
10	EP 2968209 B1	2020	Metadichol R liquid and gel nanoparticle formulations	Palayakotai et al.	Nanoparticles	[99]
11	EP 3429600 B1	2021	New Immunobiological products	Igor and Liudmila	Hydrocolloid	[97]

Patent EP 1889608 B1 was granted in 2012 for a hydrogel comprising chitosan polymer, polyalcohol, and a medicinal plant extract from selected plants sources consisting of Houttuynia cordata, elm, persimmon leaves, celandine, pine tree leaves, Canavalia gladiata, a herb, and combinations because it was demonstrated to prevent the inflammatory progression of AD over 7 days [129]. A nanoparticle-based formulation MY 169,467 A comprising of CSNPs loaded with HC and HT shows excellent skin absorption ability in the treatment of AD has obtained patent approval in 2019 [130]. Microparticles comprising a matrix formed by casein and chitosan, and probiotic bacteria were developed by Maite and co-workers for the treatment of allergy-associated diseases including AD with patent no. US 10,111,835 B2 [131]. Tamarkin and co-workers invented a wax foam formulation (US 8,636,982 B2) for the treatment of skin diseases including AD. The foamable compositions are a wax, a stabilizer component which include chitosan polymers, water, and a propellant [132]. A formulation targeted at the dermatitis around the nail consisting of chitosan and its derivatives in the form of nail lacquer was also granted patent US 10201490 B2 [133]. Another formulation (US 10226483 B2) intended for skin inflammation such as dermatitis comprises a hydrophilic composition and a hydrophobic composition in admixture. The hydrophobic composition includes a NO-releasing compound such as a diazeniumdiolate functionalized co-condensed silica particle while the hydrophilic composition can include hydrophilic polymers such as chitosan [134]. Patent US 8324356 B2 discloses novel polysaccharide derivatives including chitosan-containing residues of glucosamine or galactosamine with lipoic acid. This invention was found to be useful as topical compositions with moisturizing, elasticizing, toning, anti-aging, or anti-acne action or as adjuvants for the treatment of skin lesions such as inflammations, ulcers, wounds, dermatitis, and skin hyperthermia caused by radiation [135]. Another invention by Igor and Liudmila provided a method comprising the step of incubating chitosan in an aqueous solution of an organic carboxylic acid for use in human and veterinary medicine for skin diseases complicated by allergies, in particular allergic atopic eczema (EP 3429600 B1) [136]. Another invention (US 10443033 B2) involves the heat-killed (at a temperature range of 60–100 °C) Lactobacillus rhamnosus conjugated to a polysaccharide polymer binder such as chitosan which showed that is has an excellent therapeutic effect for AD and the patent also claims the formulation has a similar treating effect as steroid-based drugs [137]. A formula with patent number EP 2968209 B1 is a topical administered aqueous gel developed by French researchers intended for inflammatory and hyper-proliferative dermatological illnesses such as AD. The gel is claimed to have substantial water-barrier properties and it is composed of a water-soluble polymer such as chitosan; policosanol nanoparticles in a therapeutically effective concentration; and water [138]. Interestingly, non-aqueous topical compositions are developed for the treatment or prevention of skin infections such as acne, AD and impetigo. It can also be useful for topical bacterial decolonization, e.g., applied prior to surgical procedures. This formulation consists of a halogenated salicylanilide, PEG 600 and a gel-forming agent such as chitosan (EP 3429691 B1) [139].

Conclusions and future perspective

AD is a chronic, relapsing inflammatory skin disease with a considerable social and economic burden. AD is primarily characterized by its chronic pattern along with important modifications in the quality of life of patients and caretakers. Chitosan has attracted attention as a functional biopolymer for diverse applications, especially in pharmaceutics and medicine, due to its antimicrobial, antioxidative, and inflammatory response modulation properties. Owing to properties such as the biodegradability and biocompatibility, the chitosan is also generally considered to be safe for therapeutic use. The physicochemical and biological properties of chitosan have been presented to be robust biomaterials in formulating delivery systems for AD.

Chitosan composites prepared along with natural or synthetic polymers indicated remarkable applications in AD formulations. As hydrogel, film, and nanofibers’ composites, chitosan is exploited as a polymeric matrix, alone or blended with other polymers for the loading of actives due to its ability to form a polymeric network with or without cross-linkers and show remarkable benefits to dermal applications such as AD.

Topical CSNPs can be used to improve the skin drug bioavailability by prolonging the residence time of drugs applied topically or by enhancing the passing of drugs through the epithelial cells by opening the tight junctions between epithelial cells as well as reduced adverse reactions. In particular, the steroids’ compound-associated side effects have been shown to reduce tremendously using CSNPs as carrier. Many experimental studies have demonstrated that CSNPs are safe and effective for the use as AD treatment [36, 104, 106, 111]. However, despite the aforementioned desirable traits of CSNPs, their clinical applicability is not widely explored, and especially for topical application CSNPs pertaining to AD, no reports were made of their clinical applicability till current date. Human study is an important milestone on the use of chitosan-based nanoparticles for AD, proving its safety and tolerability in the long-term use.

The textile delivery systems were sufficiently validated with robust feasibility evaluation after incorporation in fabrics. Moving forward, efficacy study on AD is warranted. To date, only one randomized controlled clinical study was carried pertaining to AD on chitosan-coated cotton [37]. The chitosan-based coated garment was studied in human clinical settings using Scoring Atopic Dermatitis Index (SCORAD) score or quality of life assessment as primary outcome measurements [37]. The chitosan group has shown to elevate SCORAD from baseline by 43.8% in AD patients. The study inferred that significant improvement on quality of life with chitosan treatment was related to reduction in AD severity [37].

Patent data is imperative for recognizing technical development trends, assessing technological competitiveness in the industry, determining the rivals’ technological strengths and weaknesses, and analyzing the possible market structures. Through the patent survey for the period of 2012–2022, it is interesting to underline that significant work is still directed towards the development of formulation for the treatment and prevention of skin inflammation utilizing chitosan biopolymers as well as its derivatives. There is a rapidly expanding demand in this field for academic researchers and companies to both publish their research in peer-reviewed journals and to patent their chitosan-based formulations in various countries with regard to chitosan formulation in AD. From the perspective of the number of publications, many researchers have reported the diverse chitosan drug delivery applications in AD but only a few of them are reported for intellectual protection and patent approvals. It is possible that the lack of more evidential data on in vivo safety has hindered the commercial interest of chitosan products pertaining to AD. In addition, more comprehensive characterization studies are warranted to rule out any adverse effects of chitosan when derived from different sources. Most studies included in the present review have been conducted in vitro or in vivo, but with few randomized controlled clinical trials. More evidence supporting in vivo safety will facilitate full-scale commercial exploitation as well as progression to clinical trials. Further clinical investigations involving AD patients are encouraged in order to enable scholars as well as clinicians to achieve a more robust finding and evidence on chitosan-based drug delivery systems. Given the rapid growing researches involving chitosan-based drug delivery system today, we hypothesized that chitosan-based formulations will become the mainstay for AD treatment in the coming decades.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

A. actinomycetemcomitans

Aggregatibacter actinomycetemcomitans

AD

Atopic dermatitis

AMP

Antimicrobial peptides

BMV

Betamethasone

C. albican

Candida albican

CSA

Chitosan-sodium alginate

CSNPs

Chitosan nanoparticles

DNCB

1-Chloro-2, 4-dinitrobenzene

EP

Europe

H&E

Hematoxylin and eosin

HC

Hydrocortisone

HT

Hydroxytyrosol

IgE

Immunoglobulin E

IL

Interleukin

iNOS

Inducible nitric oxide synthase

ISAAC

International Study of Asthma and Allergies in Childhood

kD

Kilodalton

MY

Malaysia

NIC

Nicotinamide

NMF

Natural moisturizing factor

NO

Nitric oxide

NOAEL

No-observed adverse-effect level

P. gingivalis

Porphyromonas gingivalis

PEG- HA

Polyethylene-glycolated hyaluronic acid

PF127

Poly(ethylene oxide)-b-poly (propylene oxide)-b-poly(ethylene oxide)

PLGA

Poly(lactic-co-glycolic acid)

PVA

Polyvinyl alcohol

RNA

Ribonucleic acid

ROS

Reactive oxygen species

S. aureus

Staphylococcus aureus

SC

Stratum corneum

SCORAD

Scoring Atopic Dermatitis Index

SEM

Scanning electron microscopy

SLN

Solid lipid nanoparticles

SMEDDS

Self-microemulsifying drug delivery system

TEWL

Transepidermal water loss

Th2

T-helper 2

TMC

N,N,N-trimethyl chitosan

TNF-α

Tumor necrosis factor-alpha

TSLP

Thymic stromal lymphopoietin

UK

United Kingdom

US

United States

Author contribution

All authors contributed to this review article. The first draft of the manuscript was compiled by Shiow-Fern Ng and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data availability

N/A.

Declarations

Ethics approval and consent to participate

N/A.

Consent for publication

N/A.

Competing interests

The authors declare no competing interests.