Emerging Strategies in Innovative Topical Delivery Systems for Treating Atopic Dermatitis
Swati Raysing*, Vaibhav Mote
Department of Industrial Pharmacy and Quality Assurance, R.C. Patel Institute of Pharmaceutical Education and Research, Near Karwand Naka, Shirpur 425405, Dist. Dhule.
*Corresponding Author E-mail: swatiraysing123@gmail.com
ABSTRACT:
Atopic dermatitis (AD) is an inflammatory condition characterized by T helper 2 (Th2) immunological responses and loss of epidermal barrier function. Chronic inflammatory dermatosis called atopic dermatitis (AD) can flare up and go into remission at different times. Intense, ongoing itching, as well as the severity and variety of clinical symptoms, are characteristics of AD. The methods of delivering topical medications, commonly employed for addressing various skin conditions, have evolved significantly from their primitive forms. Progress in percutaneous absorption, the refinement of product designs driven by a deeper comprehension of how drugs, formulations, and skin interact, along with associated research endeavors, and the implementation of quality-centric design principles have collectively propelled their advancement. Topical drug delivery entails drug transportation from a skin-based product to a local target location, followed by drug clearance by diffusion, metabolism, and excretion. and the deeper tissues and the remainder of the body's dermal circulation.
INTRODUCTION:
Atopic dermatitis (AD) is a common inflammatory skin condition that affects roughly 10% of adults and up to 25% of children1. This autoimmune skin disorder is characterized by recurring eczematous lesions, increased trans-epidermal water loss, and psychological distress, resulting in a significant psychosocial burden for those living with it. In addition to its impact on appearance, AD also imposes functional limitations on individuals affected by it. Furthermore, AD increases the risk of developing various health conditions, including asthma, arthritis, allergic rhinitis, food allergies, and other immune-mediated inflammatory disorders.
The clinical presentation of AD typically begins with symptoms such as itching (pruritus), redness (erythema), and the development of dermatitic plaques, which can vary in severity, possibly oozing, forming crusts, or scaling, depending on the duration of the lesions2. AD often manifests prominently on the face, neck, and the extensor surfaces of limbs. In older children and adults, the lesions frequently become lichenified and tend to appear on the flexural surfaces of the extremities3. The primary objectives of AD management involve addressing the deficiency in the skin barrier, reducing inflammation, and restoring the skin's microbiome to extend periods of remission. Achieving these goals heavily relies on the use of topical treatments, which offer localized anti-inflammatory effects, improvement in skin pathology, and are considered safer and more cost-effective when compared to systemic treatments.
The benefits of administering drugs topically include their ease of use, improved patient adherence, increased compliance, and the avoidance of first-pass metabolism. Nevertheless, there are some disadvantages to consider, such as the potential for limited or reduced absorption rates and cosmetic concerns. These insights have paved the way for the development of new delivery approaches that can enhance the effectiveness, tolerability, and aesthetic appeal of topical formulations4–6.
SKIN ANATOMY AND PHYSIOLOGY
The skin stands as the body's largest organ, uniquely specialized to bridge the divide between the internal body and the external world. It carries out a multitude of functions, including shielding against injury, safeguarding against pathogens and allergic reactions, regulating body temperature, preventing excessive water loss, and facilitating excretion10
Our skin, the body's largest organ, spans approximately 2 square meters. Comprising three distinct layers, each layer has a unique role in upholding the integrity and function of the skin.
Fig. 1: Anatomy of Skin
Epidermis:
The whole outer surface of the body is covered by the squamous epithelium known as the epidermis, The stratum corneum is additional classification as:
· Stratum Basale (Basal Layer)
· Stratum Spinosum (Prickly Layer)
· Stratum Granulosum (Granular Layer)
· Stratum Lucidum (Clear Layer, in thick skin)
· Stratum Corneum (Horny Layer)
Dermis:
The dermis, located approximately 3–5 mm beneath the epidermis, is primarily composed of a connective tissue matrix that accommodates nerves, lymph nodes, and blood vessels. One crucial aspect of regulating body temperature involves the circulation of blood within the skin. Additionally, it plays a role in purifying the skin by removing impurities and waste products while simultaneously delivering vital nutrients and oxygen.
Fig. 2: Layer of epidermis
The majority of molecules can traverse the capillaries and penetrate the skin barrier to reach a depth of approximately 0.2mm beneath the skin's surface. Furthermore, the dermis is home to various hematopoietic cells, including dendritic cells (DC), mast cells, macrophages, and lymphocytes.
Hypodermis:
The dermis and epidermis are layers of the skin, with the dermis situated beneath the epidermis. The dermis provides structural support to the skin and contains subcutaneous fatty tissue, serving as a reservoir for fat storage. Additionally, it plays a crucial role in mechanical protection, nutrient supply, and thermal regulation. Blood vessels, nerves, and sensory receptors are also housed within the dermis, contributing to its functionality in maintaining skin health and sensation. A medicine must permeate all three layers of skin in order to reach the circulatory system during skin delivery 11.
MANAGEMENT OF AD:
Therapeutic choices for atopic dermatitis (AD) are somewhat restricted, but several therapeutic approaches have been employed and investigated to effectively handle this condition. Successful management of AD primarily hinges on the avoidance of triggering factors and the practice of proper skincare. The pharmacological treatment for AD predominantly involves the use of topical remedies that aim to restore the skin's barrier function, reduce inflammation, and modulate the immune response12
Emollient Foam:
Emollient foam is a type of foam designed to soothe and moisturize the skin upon application. These foams are emulsions comprising water and oil, making them comparable to traditional cream-based vehicles in terms of their vehicle properties. Their mechanism of action involves replenishing the skin's lipid content, thereby reducing moisture loss. Additionally, they enhance skin hydration by acting as humectants, increasing the stratum corneum's ability to retain water. Emollients are commonly employed to alleviate dryness and provide symptomatic relief for conditions characterized by skin scaling and wrinkles, such as xerotic skin conditions including ichthyoses, xeroderma, keratinization disorders, and atopic dermatitis 13,14.
Emulsions, especially foam emulsions, constitute complex systems that do not consistently take shape. Even minor alterations to the formulation of emulsion foam, triggered by the introduction of active ingredients, can induce instability. Moreover, numerous emulsions fail to exhibit significant foam capacity, foam stability, or rapid response to pressure in topical foam formulations, or they may not perform as expected at the desired temperature.
Emollient foam composition:
Emollient foams consist of water and oil as their fundamental constituents, which are blended together in an emulsion during the formulation process. The oil component can vary and includes options such as mineral oil, triglycerides like plant oils and capric/caprylic triglyceride, fatty acid esters (e.g., isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate), and even essential oils. In specific cases, the choice of oil is influenced by its therapeutic properties. For instance, omega-3 and omega-6 polyunsaturated oils, known for their therapeutic effects on inflammatory skin conditions, can be integrated into the oil phase. Additionally, silicon oils are a preferred choice due to their skin-protective attributes.15
The gelling compound plays a crucial role in stabilizing the emulsion, a particularly important function considering the low viscosity of the composition, as previously mentioned. This gelling component also enhances the smoothness of the foam when it is applied to the skin.
A pharmaceutical emollient foam product may comprise a single pharmaceutical drug or a combination thereof, which can be dissolved in either the hydrophilic or hydrophobic phases of the carrier composition. In certain instances, the drug may be dispersed within the emulsion even if it exhibits limited solubility in the water or oil phase of the formulation. The composition may include both large macromolecules and small molecules. Various drugs have been successfully integrated into emollient foam formulations, such as antibiotics, antifungals, antivirals, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), retinoids, keratolytic agents, immunomodulators, anesthetics, antiallergic agents, and antiproliferative medications. Upon application to an affected area, the therapeutic effect of the drug can be influenced by its concentration.15
Emollient foam properties
Pharmaceutical emollient foams should offer a high degree of user-friendliness. They ought to emerge in a foam state upon release from the aerosol canister, enabling easy and mess-free application. Furthermore, when applied lightly to the skin, they should effortlessly spread and be rapidly absorbed.15
It is imperative that the emulsion mixture maintains its chemical integrity and shelf life over an extended period. Achieving physical stability is essential in this context. It's worth noting that the presence of oils and propellants can compromise emulsion stability and interfere with the emulsion's formation. Nevertheless, when foam is discharged from a pressurized container, it should remain stable.15
Janus Kinase Inhibitors:
Emollients, corticosteroids, calcineurin inhibitors, and crisaborole represent a selection of the topical therapies available for AD management at present. These treatments aim to restore the skin's barrier function and alleviate inflammation16–18. Despite the fact that itch is frequently the most troublesome symptom experienced by AD patients, these topical medications often exhibit limited tolerability and efficacy, sometimes proving ineffective in addressing this particular symptom19,20. To address these challenges, topical Jakinibs present a promising treatment option. Among the topical Jakinibs, examples include Tofacitinib, delgocitinib (JTE-052), and ruxolitinib.
Delgocitinib:
Delgocitinib suppresses the activity of tyrosine kinase 2, JAK1, JAK2, and JAK321. In preclinical studies, topical application of delgocitinib demonstrated effectiveness in reducing skin inflammation22 enhancing skin barrier function23, and alleviating IL-31-induced itching24. These findings indicate that topical delgocitinib holds promise as an advanced treatment option for atopic dermatitis.
Ruxolitinib
Ruxolitinib (RUX) is a potent selective JAK1 and JAK2 inhibitor that, when applied topically, allows for the direct targeting of multiple pathogenic pathways that cause AD.25,26
Phosphodiesterase-4 Inhibitors:
PDE4 inhibitors have been recognized as prospective therapeutic drugs for the treatment of AD throughout the past several years27,28. PDE4 activity in circulating leukocytes plays a part in the pathophysiology of AD by degrading cyclic adenosine monophosphate (cAMP). Increased levels of cAMP, which are involved in regulating the synthesis of important inflammatory cytokines such prostaglandin E2 and IL-4, are brought on by the inhibition of PDE429. By regulating the nuclear factor-kB and nuclear factor of activated T-cell signaling pathways downstream, PDE4 inhibition in monocytes promotes the cellular control of inflammation30.
Crisaborole:
The intracellular enzyme phosphodiesterase 4 (PDE4) has been shown to play a role in promoting the synthesis of IL-4, IL-5, and TNF-. Crisaborole is a small molecule inhibitor designed to target PDE4. In patients with atopic dermatitis (AD), the presence of IL-13 and IFN-c can exacerbate skin immunodeficiency31. The approval of crisaborole is primarily supported by two pivotal clinical trials conducted in the United States, namely AD-301 and AD-302, which were multicenter randomized controlled trials (RCTs)32. However, there have been debates about the selection of primary endpoints and the interpretation of results in these trials33. Nevertheless, these trials remain a central focus of numerous research articles supporting the use of crisaborole as a therapeutic option for AD.
Topical Calcineurin Inhibitors:
Two macrolactams possessing immunosuppressive properties are tacrolimus and pimecrolimus. According to current theories, both of these Topical Calcineurin Inhibitors (TCIs) function by suppressing the immune system's response. They achieve this by inhibiting the release of various proinflammatory cytokines that are involved in T lymphocyte activation34. In contrast to topical corticosteroids, TCIs do not affect Langerhans' cells and do not reduce the quantity of T cells in healthy skin34. Both TCIs exhibit significantly lower transepidermal penetration compared to topical corticosteroids, with tacrolimus in ointment form having a 70- to 100-fold reduction, and pimecrolimus in cream form displaying nearly five times lower flux34. Furthermore, these agents have been investigated for their potential applications in various other inflammatory skin disorders35. Notably, tacrolimus is also approved for oral and intravenous36.
Topical corticosteroids:
The utilization of topical corticosteroids stands as the primary or initial pharmacotherapeutic approach for treating AD. This treatment method has an extensive history, dating back to the discovery of hydrocortisone in the early 1950s, followed by the identification of fluorinated corticosteroids in the 1960s. Over time, topical corticosteroids have established themselves as the benchmark against which all other treatment options are evaluated. Their effectiveness in AD can be attributed to their anti-inflammatory, anti-proliferative, immunosuppressive, and vasoconstrictive properties37
Corticosteroids come in various potencies, which are categorized into seven groups (designated as classes 1 through 7) based on their vasoconstrictor assay results, with efficacy decreasing as the class number increases. These medications exert their effects by interacting with corticosteroid-responsive genes in the cell nucleus, controlling transcription and protein synthesis. Their mechanism of action is centered around inhibiting the transcription of proinflammatory cytokine genes such as Interleukin-1, IL-2, IL-4, IL-6, IL-13, IFN-g, and TNF-. Simultaneously, they stimulate the expression of genes responsible for anti-inflammatory cytokines like TGF- and IL-10 within lymphocytic cells. Additionally, corticosteroids have demonstrated the ability to halt the proliferation of specific cell types.38,39
DRUG DELIVERY APPROACHES IN AD:
In addressing the evolving requirements for effective AD therapy, the pharmacotherapeutic management of AD has relied on variations in treatment approaches. Immunomodulatory drugs come with their own set of risks and potential side effects. Consequently, there is a continuous pursuit of improved drug delivery methods to optimize benefits while minimizing pharmaceutical-related hazards. Colloidal drug carriers have also found application in topical drug delivery. Topically applied colloids influence transdermal drug diffusion by affecting drug activity at the skin's surface and drug partitioning within and through the skin. The primary mechanism through which colloidal carriers impact drug deposition is by facilitating hydrophilic pore opening and enhancing drug partitioning within the stratum corneum. Various nanocarriers have been investigated in the context of AD treatment.40
Fig. 3: Various carriers used in atopic dermatitis with a reference to their size.
Liposomes:
Liposomes, which are artificially crafted lipid bilayer-based vesicles, find extensive applications in pharmaceuticals and cosmetics for precisely delivering drugs to specific skin layers or regions. These spherical vesicles comprise an amphiphilic lipid membrane, featuring one lipophilic side and another polar side, resembling the bilayer membranes present in living cells. Owing to their amphiphilic characteristics, liposomes can encapsulate hydrophilic compounds within their lipid bilayer and also accommodate aqueous core materials. This adaptability makes liposomes efficient carriers for a diverse array of substances 40,41
Microemulsion:
Extensive research has been conducted on the utilization of microemulsions for cutaneous drug delivery. They offer several advantages, including ease of manufacturing, thermodynamic stability, a high surface area, and the ability to solubilize both hydrophilic and lipophilic drugs, resulting in enhanced drug delivery42,43. Microemulsions can improve dermal or transdermal drug transport through various mechanisms, such as denaturation of intracellular keratin or alteration of its conformation, perturbation/fluidization of lipid bilayers, formation of liquid pools, extraction of stratum corneum (SC) lipids, increased drug partitioning and solubility in the SC, elevated thermodynamic activity of the drug, a steeper concentration gradient, and appendageal transport44–48. Depending on the formulation, the water-in-oil (w/o) method predominantly delivers the drug to deeper skin layers, while the oil-in-water (o/w) formulation is designed to target drug accumulation in the SC and epidermis.
Nanoemulsion:
Nanoemulsions are a distinct type of emulsion, capable of existing in either water-in-oil or oil-in-water configurations. Their defining characteristic is the presence of extremely minute droplets upon formation. Achieving nanoemulsions necessitates specific thermodynamic conditions, specialized manufacturing procedures, and the use of particular surfactants to ensure the stabilization of these nano-sized droplets. This unique composition enables nanoemulsions to efficiently transport lipophilic compounds into the skin, making them an ideal vehicle for enhancing the penetration of active ingredients within the lipophilic environment of the pilosebaceous unit, especially in the treatment of acne. Furthermore, nanoemulsion particles exhibit non-pore-blocking properties and can offer additional therapeutic advantages such as improved skin hydration and viscoelasticity49
Solid lipid nanoparticles:
Solid lipid nanoparticles (SLN) have displayed promising potential as a vehicle for delivering drugs topically. However, their performance on the skin has not been thoroughly explored due to the intricate nature of their composition and structure.
SLNs have proven effective for drug administration through the dermis, offering several advantages. These colloidal particles provide controlled drug release and are composed of biodegradable lipids with excellent tolerability, low toxicity, and minimal cytotoxicity. Their small size allows for close and prolonged contact with the stratum corneum (SC), facilitating enhanced drug penetration into the skin. Moreover, SLNs' increased occlusivity contributes to improved skin hydration, thereby potentially improving the balance between the benefits and risks of topical drug treatments. Additionally, SLNs can enhance the stability of compounds susceptible to light, oxidation, and hydrolysis50–52
Ethosomes:
Ethosomes are specialized phospholipid vesicles containing ethanol in addition to phospholipids and water. They are known for enhancing drug absorption primarily by fluidizing the skin's lipid layer, a phenomenon often referred to as the 'ethanol effect.' Ethanol content makes these vesicles flexible and aids in more efficient fluidization of the stratum corneum (SC), which contributes to improved drug absorption53–55.
Typically, ethosomes consist of various phospholipids with different chemical structures, including phosphatidic acid (PA), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidylglycerol (PPG), phosphatidylinositol (PI), hydrogenated PC, alcohol (ethanol or isopropyl alcohol), water, and propylene glycol (or other glycols). This combination allows for the delivery of high concentrations of active substances through the skin. Adjusting the ratio of alcohol to water or alcohol-polyol to water can control drug delivery. Soybean phospholipid, such as Phospholipon 90(PL-90), is a commonly used phospholipid, typically in the range of 0.5-10% weight per weight. Cholesterol may also be added in amounts ranging from 0.1% to 0.10%. Examples of alcohols that can be used include ethanol and isopropyl alcohol56.
Researchers investigated Tacrolimus ethosomes in a mouse dermatitis model caused by haptens. These vesicles exhibited higher encapsulation efficiency and smaller vesicles compared to liposomes. When compared to Protopic®, a commercial tacrolimus ointment, the proposed formulation demonstrated significant improvement in suppressing allergic reactions57
Polymer-Based formulation:
Hydrophilic polymers have found applications in enhancing drug delivery through various means. They can be utilized in hydrogel formulations or in the development of nanoparticles to aid in the cutaneous distribution of medications. Studies on size reduction and efficacy have indicated that increased surface area can also facilitate drug penetration into the skin58,59. Furthermore, polymers can be employed within the lesion area to provide an occlusive dressing. Occlusion, as achieved with hydrocolloid dressings, can significantly impact transepidermal water loss (TEWL) and influence the transdermal diffusion of drugs60,61
Microsponges:
It is an innovative method for the controlled release of topical medications, involving microporous beads containing an active ingredient, typically measuring 10-25 microns in diameter. These biologically inert particles are composed of synthetic polymers capable of retaining an amount of active substance equivalent to their own weight. Microsponge technology finds application in various formulations, although it is frequently used in gel formulations. When applied to the skin, microsponges enable the gradual release of active substances.62
Transferosomes:
Transferosomes have been shown to improve therapeutic effectiveness and lengthen the duration of action. Topically administered doses can distinguish the region of pharmacological targeting. Low dosages encourage drug retention in the skin, but greater doses result in systemic drug intrusion. As a result, using transferosome formulations in suitable concentrations can help with local medication targeting62 When compared to ointment and liposome-loaded gel, transferosome-loaded gel demonstrated more in vitro drug release and skin penetration63.
CONCLUSION:
In conclusion, recent research activities are increasingly focusing on innovative and alternative drug delivery systems. The transdermal route of drug delivery has seen significant advancements in recent years, making it a rapidly growing field due to its practical benefits. However, many device-based transdermal drug delivery techniques are still in the early stages of commercialization, aiming to optimize the delivery of high-quality products to the market.
CONFLICT OF INTEREST:
The authors have no conflicts of interest regarding this investigation.
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Received on 22.05.2024 Revised on 20.09.2024 Accepted on 02.12.2024 Published on 03.05.2025 Available online from May 05, 2025 Asian J. Pharm. Res. 2025; 15(2):215-222. DOI: 10.52711/2231-5691.2025.00035 ©Asian Pharma Press All Right Reserved
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