Advanced oral drug delivery systems: Current challenges and emerging technologies

Oral drug administration is the most widely used route for drug delivery in both traditional and modern medicine due to its convenience, non-invasiveness, and high patient compliance1, 2. The absorption of a drug can be classified into mainly two processes, dissolution and permeation. In the dissolution process, an oral formulation is disintegrated in the stomach, followed by its dispersion and dissolution in the gastrointestinal (GI) tract. Various physiological conditions in the GI tract, such as pH levels, gastric fluid volume, gastric emptying rate, intestinal transit time, and food intake, can theoretically influence drug dissolution3. These parameters could be intra- or inter-individually variable depending on many endogenous or exogenous factors2. The endogenous factors could be influenced by several physiological changes4, 5. For example, aging changes several GI conditions to influence the dissolution and intestinal permeation of a drug, and some diseases could also alter the physiology in the GI tract endogenously. In addition to the impact of physiological changes on the absorption of drugs, a number of new drugs and drug candidates have been found to be hydrophobic compounds, mostly classified into biopharmaceutics classification system (BCS) class II drugs with low GI solubility and high permeability6. The dissolution behavior and oral absorption profile of these drugs tend to be affected by physiology in the GI tract, more than hydrophilic drugs. To ensure consistent oral absorption, solubilization technologies aimed at improving the dissolution behavior of hydrophobic drugs have been explored and continue to be investigated in both academic and industrial research.

Various pharmaceutical technologies have been developed to enhance the dissolution behavior of BCS class II (low solubility, high permeability) and class IV (low solubility, low permeability) drugs, aiming for more stable pharmacokinetic profiles and improved clinical outcomes7. These strategies include the use of micro- and nanoparticles, microenvironmental pH-modifiers, solid dispersion (SD), micelles, emulsions, and cyclodextrin complexation7. Particle size reduction is the simplest way to improve the dissolution rate of drugs, and especially nano-sized particles lead to accelerated dissolution of poorly soluble drugs8. Destruction of the crystalline lattice of a drug is needed for its dissolution, and the solubility of metastable forms or amorphous states of drugs could be higher than that of most thermodynamically stable states9. A promising strategy for achieving amorphization is amorphous solid dispersion (ASD) technology, where active pharmaceutical ingredients are dispersed in molecular and amorphous states within inert carriers10. Many marketed formulations have adopted this SD technology to enhance oral absorption of poorly soluble drugs, and SD of such drugs could improve their oral bioavailability in humans, compared with their crystalline forms11.

These formulation technologies would not always be applicable to all BCS class II and IV drugs, as their effectiveness depends on the specific physicochemical properties of each drug. Leveraging accumulated knowledge and experience from previous biopharmaceutical investigations can facilitate the formulation design and development of oral dosage forms with consistent pharmacokinetic behavior. This article highlights various formulation strategies aimed at enhancing and stabilizing oral drug absorption and, thereby, better clinical outcomes. In this review, we discuss key factors influencing the pharmacokinetic behavior of drugs, explore various drug delivery strategies aimed at enhancing dissolution, and present examples of their practical applications.

4. Advanced oral drug delivery systems

To overcome the inherent limitations of conventional oral formulations, a variety of advanced oral drug delivery systems have been developed by strategically addressing key physicochemical and biopharmaceutical barriers. Critical factors such as poor aqueous solubility, limited intestinal permeability, degradation in the GI tract, and extensive first-pass hepatic metabolism can significantly impair the oral absorption and bioavailability of many therapeutic agents. Therefore, innovative formulation strategies, such as pH-independent drug release systems, solid dispersions, polymeric nanoparticles, lipid-based carriers (e.g., self-emulsifying drug delivery systems), and mucosal drug delivery platforms, have been engineered to improve drug solubility, permeability, stability, and other key biopharmaceutical profiles (Table 2 19, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 7, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 8, 80, 81, 82, 83). These advanced systems not only improve systemic drug exposure but also contribute to more consistent pharmacokinetic profiles and enhanced therapeutic outcomes.

Table 2. Advanced oral drug delivery systems.

4.1. Microenvironmental pH-modifier

Microenvironmental pH modulation is a commonly used strategy to enhance the solubility and dissolution rate of poorly soluble drugs with pH-dependent solubility53. A weak acid or base as a microenvironmental pH-modifier is commonly used to modify the microenvironmental pH inside matrices surrounding API particles/domains that favor drug dissolution, and electrostatic interaction and/or ion-pairing between drugs with counter-ions might result in long-term supersaturation (Fig. 4). In theory, the degree and duration of microenvironmental pH modulation are critical factors in enhancing the biopharmaceutical properties of drugs. Additionally, stabilizing the supersaturated state in bulk solution can be a key strategy for improving drug exposure following oral administration through pH modification. This approach employs limited amount of a microenvironmental pH-modifier that does not alter the pH of the bulk dissolution media; however, it could enhance the in vivo dissolution and bioavailability of drug substances with pH-dependent solubility (Table 2)54. The microenvironment refers to a microscopic layer enveloping a solid particle, where the particle creates a saturated solution of adsorbed water. Careful consideration should be made before selecting and optimizing counter-ions in formulation designs with the microenvironmental pH-modification approach, since the microenvironmental pH can influence the physicochemical properties of solid dosage forms, including the hygroscopicity and chemical stability, as well as dissolution and supersaturation profiles55. Organic acids, such as citric, fumaric, succinic, and tartaric acids, are commonly employed as acidifiers for weakly basic drugs. In our earlier study, a granule formulation of dipyridamole, a weakly basic drug, was developed, in which fumaric acid was added as a microenvironmental pH-modifier53. In a rat model of hypochlorhydria, oral administration of dipyridamole resulted in limited and inconsistent systemic exposure. In contrast, a novel dipyridamole formulation with fumaric acid showed rapid and potent oral absorption even under hypochlorhydria, the pharmacokinetic behavior of which was found to be almost identical to that of dipyridamole in normal rats. Considering the enhanced systemic exposure observed shortly after oral administration in hypochlorhydric rats, the novel dipyridamole formulation utilizing the pH-modification strategy could potentially lead to improved clinical outcomes in patients with hypochlorhydria.

4.2. Solid dispersions

4.2.1. Amorphous solid dispersion

An amorphous solid dispersion (ASD) refers to the distribution of active pharmaceutical ingredients in molecular and amorphous states, encapsulated within inert carriers (Fig. 5A)56. The ASD approach can be used to modify the crystalline lattice of drugs to generate a higher energy state of the amorphous form, leading to higher saturated solubility and significant improvement of oral bioavailability (Table 2)7, 57. The use of hydrophilic polymers as excipients for ASD can attenuate the nucleation of drug molecules, and they should be biologically inactive and less absorbed in the GI tract. Commonly used excipients are cellulose derivatives such as hydroxypropyl cellulose (HPC), HPMC, and hypromellose acetate succinate (HPMCAS), chitosan, poloxamers, PVP, polymethacrylates, polyvinylpyrrolidone-vinyl acetate copolymer (PVP/VA 64), and polyethylene glycol (PEG) derivatives58. There are various strategies for the preparation of ASD, including solvent-based methods (e.g., freeze-drying, spray-drying, and supercritical fluid technology), melt-based methods (e.g., hot-melt extrusion and KinetiSol® dispersing), wet granulation, and co-precipitation59. Numerous studies have shown that ASD technology can provide rapid dissolution and supersaturation of various poorly soluble drugs and chemicals, including itraconazole, nobiletin, and tacrolimus60. Also, the ASD formulation approach can provide more stable and improved pharmacokinetic behavior of orally taken drugs, including NSAIDs and carvedilol60, 61. However, amorphous drugs are generally less chemically and physically stable than crystalline form. Over long-term storage, ASD formulations may undergo transformation from the amorphous to the crystalline state, which can reduce oral bioavailability. The use of suitable polymers can be effective for stabilization of ASD and potential prevention of crystallization; therefore, careful consideration should be made to select suitable polymers.

4.2.2. Self-micellizing solid dispersion

Thus, several polymers used for ASD have been found to be effective crystallization inhibitors, stabilizing supersaturated solutions; however, they sometimes showed slow but steady nucleation and crystal growth in some drug molecules57, possibly leading to poor pharmacokinetic behavior and a shorter duration of action. To address these limitations on ASD formulations, the concept of self-micellizing solid dispersion (SMSD) was established as a new solubilizing technology (Table 2)62, 63, 64. SMSD is an SD system that utilizes amphiphilic polymers, including poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) [poly(MPC-co-BMA)] and Soluplus®. Unlike conventional SD systems, SMSD system offers enhanced and prolonged solubilization of poorly soluble drugs due to its self-micellization property. This occurs through hydrophobic interactions between the amphiphilic polymer and the lipophilic drug, leading to drug encapsulation (Fig. 5B). When the SMSD system was applied to tranilast64 and cyclosporine A63 with the use of poly(MPC-co-BMA), SMSD formulations demonstrated significantly improved dissolution behavior compared to their crystalline and amorphous counterparts. Then, the formation of micelle-like nanoparticles was observed in aqueous media, and NMR spectroscopy indicated molecular interactions between the drug and poly(MPC-co-BMA). Compared to crystalline or amorphous powders, SMSD formulations increased oral bioavailability by approximately 40–50-fold and significantly reduced inter-individual variability. Additionally, an SMSD formulation of celecoxib exhibited rapid micellization in aqueous media, forming nanoparticles with a mean diameter of 153 nm and demonstrating rapid dissolution even under acidic conditions62. In a rat model with impaired gastric motility induced by propantheline, orally administered crystalline celecoxib showed a prolonged mean absorption time (MAT) and a significant reduction in AUC0–4, reaching only 12% of the value observed in normal rats. However, the SMSD formulation of celecoxib mitigated both the delay and reduction in oral absorption under these conditions. These findings suggest that the SMSD approach employing amphiphilic polymers may serve as an effective dosage strategy for poorly soluble drugs, offering improved and stable oral absorption.

4.3. Drug nanocrystals

The particle size reduction approach is widely utilized to enhance drug dissolution rates, as smaller drug particles result in a larger surface area, thereby accelerating dissolution (Table 2)7. According to the Prandtl boundary layer equation, reducing the diffusion layer thickness, particularly by decreasing particle size to less than 5 μm, can significantly enhance dissolution rates8. Marked attention has been focused on nanodrug approaches, particularly drug nanocrystal technology, in the pharmaceutical field. With this strategy, nanosuspensions of drugs can be produced by nanofabrication processes, such as the so-called ‘bottom-up’ (controlled precipitation, inclusion complexation, coacervation, electrospraying, and supercritical fluid technique) and ‘top-down’ (wet-milling with beads, ultrasonication, and high-pressure homogenization) approaches65, 66, 67. While the bottom-up method forms nanoparticles from molecular or atomic units, the top-down technique reduces larger crystalline drug particles into nanosized particles. In both approaches, hydrophilic polymers and/or surfactants are commonly used to enhance colloidal stability.

The top-down method offers advantages such as consistency in particle size, shape, and geometry, along with a monodisperse particle population, high yield, and excellent encapsulation efficiency68. This approach converts large crystalline drug particles into nanosized particles through mechanical forces, allowing for industrial-scale production with high reproducibility. However, the top-down approach also has several drawbacks, including high equipment costs, requirement of an intensive amount of energy, uncontrolled particle growth, and the risk of product contamination. In a previous investigation, a conventional wet-milling system as a top-down method was applied to coenzyme Q10 (CoQ10) to obtain a nanosuspension; however, due to the heat generated during the nano-pulverization process, partial melting of the particles led to large aggregate formation70. Generation of high energy and friction heat in the nano-pulverization process might be part of reasons for amorphization and aggregation of CoQ10 because of its low melting point (ca. 48 °C). To mitigate this issue, a cold wet-milling system with temperature control was developed, successfully producing a CoQ10 nanosuspension with a mean particle diameter of approximately 129 nm. In comparison with crystalline CoQ10, marked improvements in aqueous dissolution and oral absorption were noted for the nanosuspension of CoQ10 prepared with the cold wet-milling system. Herein, the cold wet-milling system would be a promising top-down technology to improve the efficacy of poorly soluble drugs with a low melting point69, 70.

The bottom-up method for nanoparticle preparation offers several advantages, particularly for pharmaceutical and biomedical applications66. As well as precise control over particle size, shape, and composition, the bottom-up method typically involves milder processing conditions, making it suitable for heat-sensitive drugs, and often results in higher purity and crystallinity. Additionally, bottom-up techniques can enhance the solubility and bioavailability of poorly water-soluble drugs and offer flexibility for surface functionalization, making them ideal for targeted and controlled drug delivery systems. As one bottom-up approach, flash nano precipitation (FNP) has been widely explored for nanoparticle preparation using a wide variety of drug molecules71. FNP employs a rapid mixing process based on kinetically controlled nanoprecipitation, allowing precise control over nanoparticle size and surface properties through the formulation of unique compositions with stabilizers84. This method involves two key kinetic processes: micromixing and stabilizer adsorption. Micromixing in confined jet mixers facilitates antisolvent mixing, generating supersaturation levels as high as 10,000 within 1.5 milliseconds, leading to extremely high nucleation rates and the rapid formation of nanoparticles at high solution concentrations85. The rapid and diffusion-limited aggregation is then controlled by stabilizer adsorption, ensuring precise size regulation. There are two main types of confined impinging jet mixers used in FNP: two-jet mixers and multi-inlet vortex mixers (MIVM), which provide more precise control over inlet stream concentrations86. The FNP approach with use of MIVM has been applied to produce nanoparticles from various poorly soluble drugs and nutraceuticals, including cyclosporine A71, astaxanthin87, fuzapladib88, ibuprofen89, and curcumin90.

Numerous studies have demonstrated that nanotechnology-based formulations significantly improved the biopharmaceutical properties of pharmaceuticals and nutraceuticals8. In theory, upon oral administration, these nanocrystals would undergo a series of complex in vivo processes that ultimately determine their therapeutic outcomes91. These include dispersion in gastrointestinal fluids, interaction with mucus and intestinal membranes, dissolution into molecular form, and absorption into systemic circulation. The in vivo fate of drug nanocrystals can be influenced by various factors such as particle size, surface properties, stabilizers, and gastrointestinal physiology. In the nano-sized formulation approach, Cmax and bioavailability have been shown to increase by several folds compared to conventional formulations with micrometer-sized particles.

4.4. Emulsions

Emulsions have been extensively studied to enhance the biopharmaceutical properties and/or therapeutic index of drugs8. In recent years, self-emulsifying drug delivery systems (SEDDS) have emerged as a promising strategy to improve the oral bioavailability of poorly soluble drugs, particularly highly lipophilic drugs7. Self-emulsifying formulations are isotropic mixtures of oil, surfactant, co-solvent, and a solubilized drug, and the SEDDS approach would require effective dissolution and chemical stability of the drug in the oil phase. These formulations rapidly form oil-in-water (O/W) fine emulsions upon dispersion in GI fluid, making them a valuable solution for the poor oral absorption of lipophilic drugs (Table 2), especially those classified as BCS class II and IV7.

SEDDS can be classified into (i) self-microemulsification drug delivery systems (SMEDDS) and (ii) self-nanoemulsification drug delivery systems (SNEDDS) based on the size of their oil droplets7. SMEDDS produce microemulsions with droplet sizes ranging from 100 to 250 nm, while SNEDDS generate nanoemulsions with droplet sizes below 100 nm. The rapid emulsification of these formulations in the GI tract contributes to improved oral absorption and more consistent plasma concentration profiles7. It has been well-established that the droplet size of an emulsion can influence the biopharmaceutical properties of orally taken drugs. For example, there are two SEDDS formulations of cyclosporine A on the market: (i) Sandimmune®, a coarse SMEDDS formulation, and (ii) Neoral®, a fine SNEDDS formulation. The aqueous solubility of Sandimmune® is not high enough, and this SMEDDS formulation requires the presence of bile and pancreatic enzymes for its absorption72. Also, marked intra- and inter-individual variability was noted regarding its pharmacokinetic profiles, and oral absorption was affected by the concomitant intake of food. In contrast, Neoral® forms nanoemulsions in GI fluids, enabling more rapid and consistent absorption. Clinical studies in adults demonstrated that Neoral® could increase systemic exposure and achieve higher peak concentrations compared with similar doses of Sandimmune®.

The enhanced oral absorption of drugs delivered via SEDDS occurs through multiple complementary mechanisms73, 74. Firstly, the increase in surface area and solubilization can improve dissolution kinetics, allowing for a higher concentration gradient across the intestinal epithelium, a key determinant for membrane permeability. Secondly, the presence of lipids facilitates the stimulation of bile secretion and the formation of mixed micelles, which can assist in the solubilization and transport of lipophilic drugs across the unstirred water layer of the intestine. Thirdly, certain components of SEDDS, such as long-chain triglycerides, might promote lymphatic transport by facilitating chylomicron formation in enterocytes, enabling the drug to bypass hepatic first-pass metabolism and directly enter systemic circulation75. Moreover, surfactants and co-solvents within SEDDS can alter membrane fluidity, and open tight junctions, further enhancing intestinal permeability and drug uptake. Some SEDDS formulations might also reduce enzymatic degradation in the GI tract, increasing drug stability during transit. Herein, these mechanisms can contribute to the improved oral absorption of lipophilic and poorly soluble drugs upon SEDDS a highly effective and versatile platform in oral drug delivery.

Despite their biopharmaceutical advantages, SEDDS formulations still face several challenges, including physical and chemical instability, potential leakage during storage, and restricted use in solid-dosage forms. These factors can impact patient adherence and large-scale production feasibility. To overcome these limitations, solidification of SEDDS has gained marked attention, and several approaches have been established for the preparation of solid SEDDS (S-SEDDS)77, 78. S-SEDDS can primarily be developed through several methods such as solid carrier adsorption, melt extrusion, spray-drying, dry emulsion, and solid dispersion. These formulations can then be conveniently transformed into pellets, tablets, and capsules76. The S-SEDDS approach combines the advantages of SEDDS in liquid form and solid dosage form with greater stability, portability, ease of manufacturing, dosage form variety, and patient compliance (Table 2). Additionally, these formulations offer improved drug-loading capacity, controlled-release characteristics, and are well-suited to contemporary manufacturing methods, presenting a strong alternative to traditional liquid SEDDS.

4.5. Mucosal drug delivery systems

In the GI tract, the mucosal layer functions as a lubricating barrier, and mucus is present either as a gel layer adherent to the mucosal surface or as a luminal soluble or suspended form. This mucus is primarily composed of water (approximately 95%), while the remaining portion consists of glycoproteins, soluble proteins, enzymes, lipids, and immune factors79. Serving as the first line of defense, the mucus layer protects against microorganisms, digestive enzymes and acids, digested food particles, and food-related toxins. However, this protective function also acts as a “barrier” that restricts the diffusion of orally administered drugs toward the epithelium, making drug delivery challenging. In this context, overcoming this barrier has become a critical aspect of achieving effective oral drug absorption. For more effective and sufficient oral absorption of drugs, avoiding protective mechanisms and/or even turning barrier mechanisms has been a key consideration. As one of the viable formulation approaches, the mucosal drug delivery system (mDDS) has drawn significant attention, since it could offer strategic control of diffusive properties of drug molecules within the mucus layer (Table 2)81, 82. Three types of mDDS offer new possibilities for more efficient mucosal drug delivery: (i) mucopenetrating delivery systems, (ii) mucoadhesive delivery systems, and (iii) mucoadhesive-to-mucopenetrating delivery systems79, 80. The mDDS approach with mucoadhesive and mucopenetrating potentials can be developed by changing the interactions between the mucin layer and surface of nanoparticles. Mucoadhesive-to-mucopenetrating delivery systems can be simply defined as the integration of mucoadhesive delivery systems and mucus-penetrating delivery systems into one entity.

Mucopenetrating nanoparticles are designed to effectively spread across the mucosal layer and penetrate deeper mucus regions, eventually reaching the underlying epithelium (Fig. 6A)79, 83. This property can be achieved using PEG coatings, which reduce interactions between the drug and mucus, thereby enhancing translocation across the mucus layer. Additionally, a zwitterionic micelle platform can mimic viral surface properties, facilitating efficient mucus penetration and transporter-mediated epithelial absorption without the need to open tight junctions. Another interesting approach involves conjugating nanoparticles with mucolytic or mucus-clearing agents to disrupt the mucus layer, allowing for easier access to the epithelial membrane. Moreover, self-propelled micro-/nano-motors have attracted interest due to their ability to move autonomously92. In drug delivery applications, they have demonstrated significantly improved tissue penetration and high drug-loading capacity, resulting in superior therapeutic outcomes compared to passive-targeted nanoparticles.

In contrast to mucopenetrating nanoparticles, upon suitable surface modification and/or particle design, mDDS with mucoadhesive properties are designed to show prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcomes. Possible mechanisms for mucoadhesion are complicated, and involve various types of adhesion, such as physical entanglement, electrostatic interactions, dehydration, covalent bonding between thiol groups in mucin, and weaker forces like hydrogen bonding and van der Waals forces (Fig. 6B)79. Mucoadhesion occurs in two stages: contact and consolidation. Initially, nanoparticles must be in close contact with the mucus layer surface, and then the adhered particles may easily be removed by GI motions and physiological turnover of the mucus layer if the attractive forces between nanoparticles and the mucus layer are weaker than repulsive forces. There is still a need for consolidation to achieve long-lasting adherence of nanoparticles to the mucus layer. This process can strengthen mucoadhesive joints through mechanical and/or chemical interactions, possibly leading to resistance to mechanisms clearing nanoparticles from the mucus layer.

Herein, mDDS with mucoadhesive properties can extend the absorption process, possibly resulting in long-lasting systemic exposure to orally taken drugs, and mDDS with mucopenetrating properties can achieve faster and higher rates of absorption. In a previous investigation, two mDDS formulations of cyclosporine A with different surface charges were prepared, and they exhibited mucopenetrating and mucoadhesive properties81. Based on outcomes of a fluorescent imaging study, orally taken mucopenetrating nanoparticles were observed to reach the vicinity of the GI epithelium, while mucoadhesive nanoparticles were localized on the luminal side of the GI mucus layer. Also, after oral administration in rats, mucopenetrating nanoparticles exhibited markedly enhanced oral bioavailability and the shortest Tmax. In contrast, mucoadhesive nanoparticles showed delayed Tmax, suggesting longer retention in the GI tract. These observations were in agreement with the concept and theory of the mDDS strategy. A better understanding of the mechanisms of diffusion and/or adhesion in the mucus layer would enable formulators in both academia and industries to identify, select, and develop materials for the design of mDDS formulations with potent biopharmaceutical properties.