Polymer-Based Topical Drug Delivery: Advances in Skin Penetration and Targeted Therapy

Hydrogel

Three-dimensional, cross-linked networks of water-soluble polymers make up hydrogels (7). Hydrogels can be made from nearly any water-soluble polymer with a wide variety of bulk physical properties and chemical contents. Additionally, hydrogels can be produced in various physical forms, including films, coatings, microparticles, and nanoparticles, as depicted in Figure 2. Hydrogels degrade and gradually release drugs once absorbed by the body. Because the polymers used to create hydrogels are nontoxic, nonreactive, and suitable for use in pharmaceutical preparations, hydrogels have a long history of good safety. Excellent outcomes were obtained from the fabrication, characterization, and in vitro and in vivo safety profiles of carboxymethyl chitosan and polyvinyl alcohol hydrogels for the delivery of oxaliplatin. Hydrogel-based patches are becoming increasingly popular due to their unique features. Hydrogels, which are primarily composed of hydrophilic polymers, have a significant water-holding capacity of 10-20% of their dry weight and can reach thousands of times their dry weight, making them ideal candidates for controlled drug delivery systems. Hydrogels are an appropriate dosage form for topical usage because of their significant water content, which contributes to skin flexibility and moisturization (8). As a result, hydrogels are widely used in both clinical and experimental medicine for a range of applications, including cellular immobilization, tissue engineering and regenerative medicine, diagnostics, biomolecule or cell separation, and barrier materials to regulate biological adhesions (9).

Several polymers frequently used in hydrogel compositions include cellulose, hemicellulose, starch, agar, alginates, psyllium, chitin, vulcanized rubber, Nylon (synthetic fiber), PVA, polyethylene, and synthetic rubber (10). Hydrogels are three-dimensional networks of hydrophilic polymers that can hold and absorb a lot of water without losing their structural integrity. Because of their superior biocompatibility, high water content, non-greasy nature, ease of application, and ability to provide controlled drug release, they have gained prominence as topical drug delivery methods (11). Drugs can be administered through the skin with ease, and hydrogels are an ideal vehicle for delivering medications directly to the site of action. Their high-water content enhances patient comfort, keeps skin hydrated, and provides a cooling, calming effect. This moist environment is especially helpful for dermatological problems and wound healing (12). Compared to ointments and creams, hydrogels have superior spreadability, are non-staining, and are simple to remove from the skin. Additionally, they have bioadhesive properties that enhance therapeutic efficacy by prolonging residence time at the site of application. The ability of hydrogels to regulate and sustain drug release is another significant benefit. The medicine is integrated into the porous polymeric network, which serves as a reservoir, allowing for a long-term, progressive release. This improves patient compliance, reduces dosing frequency, and decreases side effects. Hydrogels can also encapsulate a variety of medicinal substances and are biocompatible and biodegradable. They are flexible carriers for topical and transdermal drug delivery because their swelling behavior, porosity, and drug-release properties can be altered by varying the polymer composition and degree of cross-linking (13).

Emulgels

Emulsions of the water-in-oil or oil-in-water types that are gelled by combining with a gelling agent (8) are known as emulgels. The emulsion also serves as a controlled-release medication-delivery device, allowing drug particles trapped in the internal phase to pass through the external phase and gradually permeate the skin. Through the interior layers, which serve as a drug reservoir, the medication is carefully delivered to the skin's outer layer. Thanks to a cross-linked network, the gel can trap tiny drug particles and release them in a controlled manner. Due to its mucoadhesive nature (9). It extends the duration of pharmaceutical contact with the skin. Because it has the characteristics of both gel and emulsions, it serves as a dual control (10). Therapeutic efficacy in emulgels depends on various factors, such as polymeric gelling agents (types), stability of the emulsion, size & distribution of the droplets, and drug and polymer interactions. Recent advances focus on using bioadhesive and stimuli-responsive polymers to increase skin adherence and control drug delivery rates (14).

They are greaseless, readily spreadable, easily removable, emollient, non-staining, water-soluble, have a prolonged shelf life, are bio-friendly, and have translucent, aesthetically pleasing qualities, making them an excellent choice for dermatological applications. There are essentially three ways that molecules can enter the skin: via sebaceous follicles, sweat ducts, or intact stratum corneum. They also have several advantages, such as enhanced patient compliance, site-specific drug administration, avoidance of first-pass metabolism and gastrointestinal incompatibility, and suitability for self-medication. They enable controlled drug release, facilitate simple cessation of therapy, and are useful for medications with short biological half-lives and narrow therapeutic windows (15).

Conventional topical preparations such as ointments, creams, and lotions have various drawbacks, including stickiness, greasiness, poor spreadability, the need for rubbing during application, and instability. Gels are favored because they are non-greasy, transparent, easy to spread, and have higher patient acceptance. The inability of gels to efficiently integrate hydrophobic (water-insoluble) medications is a significant drawback.

To solve this issue, the emulgel system was created. An emulgel is a mixture of an emulsion and a gel in which the medicine is added to an emulsion before being combined with a gel base. This makes it possible to administer medications through the skin that are both hydrophilic and hydrophobic. Emulgels, which offer better drug loading, increased stability, higher skin penetration, controlled drug release, simplicity of application, and increased patient compliance, thereby combine the benefits of emulsions with gels. Emulgels are therefore regarded as an efficient topical drug delivery system for a variety of pharmaceutical and cosmetic products (16,17).

Polymers used in emulgels include Carbopol (Carbomer 934, 940, 941), Sodium Carboxymethyl Cellulose (NaCMC), and Poloxamer 407 (Pluronic F127). As gelling agents, these polymers impart the emulgel formulation with viscosity, stability, spreadability, and controlled drug release (18).

Nanoparticles and Nanogels

Gels containing nanoparticles primarily serve as transport scaffolds for drug delivery, but they can be modified to include different ligands that enable targeted drug delivery and release (19). Nanogels are highly crosslinked scaffolds of nano-hydrogels made of either copolymerized or nonionic or ionic monomers (20). Nanoparticles made from polymers (or "polymeric nanoparticles") and nanogels are emerging as advanced systems for topical drug delivery. Polymeric nanoparticles and nanogels have superior characteristics because of their small particle size, high surface area, and ability to enhance drug penetration through the outermost layer of skin (the stratum corneum). Nanogels are polymeric networks crosslinked in three dimensions, allowing them to hold large amounts of water while encapsulating therapeutic agents. In contrast to conventional hydrogels, nanogels offer improved skin permeation, greater stability, and greater control over drug-release kinetics. Examples of the polymers that have been studied most extensively include chitosan, PLGA, PEG, polyacrylic acid, and hyaluronic acid (21). Recent studies have shown that nanogels have great promise for wound healing, antimicrobial therapy, inflammation treatment, and targeted delivery of dermatological products. In addition to these benefits, polymeric nanocarriers present challenges, including large-scale manufacturing, batch-to-batch consistency, regulatory approval, and long-term safety concerns. Additionally, many polymers used in nanoparticle formulations are not biodegradable and, as such, their excessive accumulation can cause chronic toxicity, thereby requiring careful consideration of which polymer to use and extensive toxicological testing before final product development (22).

Lipid-Polymer Hybrid Nanoparticles (LNPs)

Lipid-Polymer Hybrid Nanoparticles (LPNPs) combine the advantages of both polymer and lipid-based nanoparticles regarding structural, biocompatibility, and loading efficiency of drugs. Usually, LPNPs consist of a polymeric core surrounded by a lipid shell, which can enhance encapsulation efficiency, control drug release, and improve penetration through the skin. LPNPs have been studied for topical delivery of antifungal agents, anti-inflammatory medications, corticosteroids, and anticancer drugs. Compared with traditional nanoparticles, LPNPs exhibit greater ability to retain drugs within the layers of the skin, thereby reducing the risk of systemic exposure. However, the manufacturing complexity, scalability issues, and regulatory hurdles are preventing their widespread commercialization.

Microparticles and Microspheres

Common components of multi-particulate drug delivery systems, microparticles, microspheres, and microcapsules offer several benefits based on their structural and functional capabilities, and their use is appropriate for convenient and tolerable drug administration via multiple routes (23). They can be added to a variety of pharmaceutical dosage forms, including liquids (solutions, suspensions, and even parenteral), semisolids (gels, creams, and pastes), and solids (capsules, tablets, and sachets), depending on the formulation. Microcarriers have an advantage over nanoparticles in that they act locally, since they cannot pass through the interstitium beyond the 100 nm size limit that the lymph transports. Liquids can be treated as solids in the form of dried microparticles, and potentially hazardous materials can be transported in capsules (24). From a technological perspective, microencapsulation offers several benefits: microparticles are designed to shield the core from the environment; they can also mask an unpleasant taste; they can preserve volatiles or cell viability; they can separate incompatible substances; they can shield the body from side effects; and they can optimize, prolong, or target a drug's effect. The polymer excipient shields the active pharmaceutical ingredient (API) from the body's irritative or mucosa-damaging effects or from the environment (oxidation, temperature, pH) given in Table 1.

Polymeric Films

Forming systems (FFS) are appealing, alternative topical formulations in dermatology and common components of multiparticulate drug delivery systems, microparticles, microspheres, and microcapsules offer several benefits based on their structural and functional capabilities, and their use is appropriate for convenient and tolerable drug administration via multiple routes (25, 26). When the solvent evaporates, FFS that have been applied directly to the skin form thin, translucent films. In order to control the release of the drug substance, the substance is dissolved in the film-forming vehicle and incorporated into the film that forms on the skin of the drug substance to the skin reservoir It is crucial to maintain full skin contact throughout the application process (27).

A. Trans follicular route

The fastest route for a medication to enter the systemic circulation is the transfollicular pathway, which provides a large surface area for drug diffusion. Ducts that open to the skin's surface are found in hair follicles, oil glands, sweat glands, and pores. These ducts provide a continuous conduit for the transport of pharmaceuticals across the stratum corneum; however, a variety of factors, including the quantity and composition of gland secretions shown in Figure 2, influence drug movement along this pathway. However, because it only accounts for 0.1% of the skin's total surface area, the trans appendageal route contributes very little (38).

B. Intercellular route

In the intercellular pathway, the medication diffuses across the continuous lipid matrix that separates the cells. To cross the alternating lipid and aqueous domains, the drug must partition into the lipid bilayer and diffuse to the inner side. The convoluted nature of the corneocytes is responsible for this route's barrier feature. This method is primarily appropriate for uncharged lipophilic medicines because it has been discovered that water must travel 50 times further (39).

C. Transcellular route

It is the most popular route for many different kinds of medications. The medicine travels through the cell's matrix, or cytoplasm, along the transcellular route. This method works well for hydrophilic medicines. The medication travels via the stratum corneum's corneocytes. Highly hydrated keratin provides hydrophilic medications with an aqueous route of administration. To get the medication through the cell matrix, several partitioning and diffusion processes are required (40). It is generally acknowledged that the transepidermal pathway is the most common route of skin penetration and that, under sink conditions, the rate-limiting phase that determines the total permeant flow is diffusion across the stratum corneum. The permeant moves from the epidermis to the dermis and hypodermis via the intracellular and/or extracellular spaces via the transepidermal route. The chemical may act intercellularly or transcellularly (41).

These pathways' proportional contributions will change based on the formulation and the permeant's physicochemical characteristics. Numerous investigations have demonstrated that, at steady state, the trans-epidermal pathway surpasses the appendageal system, which quickly but briefly dominates (42).

Drug solubility

The stratum corneum (SC), viable epidermis (VE), dermis (DE), and hypodermis are the sequential functional layers that make up the structure of the skin. The main part of the skin barrier is the SC layer, which is made up of corneocytes embedded in a lipid-rich extracellular matrix. The SC layer stops all but a few molecules with a perfect partition coefficient—usually between 1 and 3— from penetrating in the absence of physical action. Therefore, to improve the penetration of transdermal medications. By making lipophilic compounds more soluble in water, dendritic polymers improve skin penetration (53).

Drug thermodynamic activity

The drug's thermodynamic activity in the formulation can be increased or optimised by using PEs to cause a thermodynamically active reaction. It is possible to maximise the drug's penetration and deposition into the skin while it is at its maximum thermodynamic activity (54). The medicine can more easily penetrate the skin when the skin barrier's integrity is reduced. The highly ordered organisation of intercellular lipid bilayers is disrupted by PEs' interaction with lipid alkyl chains, which lowers SC's diffusion resistance to medicinal molecules shown in Figure 4.

PEs can be applied topically, added to formulations, bind keratin filaments, and kill keratinocytes. Nonionic surfactants have the potential to lower the SC lipid matrix's barrier function to active substances, improve the fluidity of barrier lipids, and define the intercellular domains of the SC lipid matrix (55, 56).

Certain PEs may interact with polar head groups when the agent penetrates the skin via the intercellular route, altering ionic forces and hydrogen bonding. As a result, the polar head-group packing order in the aqueous region can be affected. This disruption increases the volume of water between lipid layers and fluidizes the lipid region, allowing polar PEs to diffuse into the aqueous region (57).

When cationic polymers are employed as PEs, the medicine can enter the skin deeply because the positively charged cationic polymer's surface interacts with the negatively charged skin surface through electrostatic attraction, creating large skin pores (58). Polymer designs sometimes necessitate sophisticated synthesis strategies, complex characterization, and ineffective drug loading, necessitating additional research into their handling and complex modes of action (59).