Advanced Drug Delivery Strategies to Overcome Solubility and Permeability Challenges: Driving Biopharmaceutical Advancements Toward Commercial Success

Abstract

Oral drug administration is the safest and most convenient route for drug delivery. Nevertheless, solubility and permeability are two major issues regarding drug design; these issues must be addressed to overcome the biopharmaceutical challenges associated with them. Drugs are classified into four groups according to the biopharmaceutical classification system. Furthermore, drugs from BCS class II demonstrate poor solubility; meanwhile, drugs related to BCS class IV show poor solubility along with poor permeability. However, some drugs of BCS class IV are also substrates for p-glycoprotein and CYP3A4. These features lead to issues of bioavailability and reduced patient compliance. Moreover, the anatomical and physiological behavior of the body and physicochemical features of the drug are also associated with compromised bioavailability. All these concerns make it difficult for any formulator to manufacture drugs, and hurdles related to these drugs make it difficult to deliver them to the actual market. Hence, this review aims to summarize the advanced innovative methodologies to get suitable solutions to overcome the limitations associated with solubility and permeability and accordingly improve the drug’s bioavailability. Traditional approaches like physical modifications of drugs, i.e., micronization, solid dispersion in carriers, complexation, cryogenic techniques, and supercritical fluid technology; moreover, chemical modifications of drugs, i.e., salt formation, cosolvency, hydrotropy, and prodrug formation, contribute to treating solubility problems. Meanwhile, a few advanced drug delivery strategies, including lipid-based drug delivery systems, polymeric nanocarriers, pharmaceutically engineered crystals, and p-gp efflux pump inhibitors, have been mentioned that aid in improving the drug’s stability in diverse bodily environment, enhance solubility along with permeability, and increasing bioavailability, which directly leads to enhanced patient compliance. Incorporating these methods is essential to address solubility and permeability challenges, lower treatment costs, and enhance patient outcomes. Nanobased delivery systems offer significant potential for improving therapeutic effectiveness and patient compliance.

1. Introduction

The route of drug administration has a greater impact on the therapeutic efficacy of drugs. A variety of drug delivery methods have been used nowadays for the efficient delivery of drugs, including ocular drug delivery, intramuscular, subcutaneous, topical or transdermal, intravenous, intradermal, intranasal, and oral drug delivery systems (ODDS). Among all these routes, most attention is given to ODDS because of its various beneficial attributes, i.e., ease of administration, ease of designing solid formulations, patient preference, cost-effectiveness, sustained and controlled delivery of drugs, and targeted drug delivery to a specific region.

Chemical entities are classified into the BCS classification system. This system classifies the drugs into 4 major groups in terms of solubility and permeability. Drugs belonging to BCS class IV demonstrate low solubility and low permeability to biological membranes. Subsequently, these drugs seem problematic and are not optimal candidates for oral drug delivery due to their insufficient solubility and permeability, which leads to the development of low oral bioavailability. As a result, the drug’s performance is compromised because these two are prime factors that control the rate and extent of gastrointestinal drug absorption. Moreover, some drugs of BCS class IV are also substrates for CYP3A4 and P-glycoprotein (P-gp), which further enhances their poor therapeutic performance. However, high inter- and intravariability of these drugs is also problematic. Despite this, some other biopharmaceutical challenges also affect the drug’s absorption; for instance, physiological factors, physicochemical factors, and characteristics associated with the dosage form. ,

Although BCS class IV members are not optimized for oral delivery, they are still gaining importance, and many researchers are evaluating different approaches to design optimized delivery strategies to make it possible; otherwise, these drugs are administered via the intravenous route, which causes inconvenience, pain, and unwanted side effects to patients.

For conquering the development of drug delivery, it is important to address these drawbacks to potentiate the drug’s efficacy and therapeutic responses; as a result, different approaches have been developed to encounter the issues of low solubility, low permeability, and consequently poor absorption of drugs. To improve the solubility of hydrophobic drugs and then enhance their bioavailability, some traditional approaches are useful, i.e., physical modification of drug molecules via micronization, solid dispersion in carriers, complexation, cryogenic techniques, and supercritical fluid technology; a drug’s chemical modification via salt formulation, cosolvency, hydrotropy, and the formation of prodrugs.

Nowadays, recent studies have exhibited a number of emerging strategies that include modern approaches; for instance, lipid-based drug delivery systems, including multiple formulations like self-emulsifying drug delivery systems (self-microemulsifying drug delivery systemsSMEDDS and self-nanoemulsifying drug delivery systemsSNEDDS), liposomes, emulsions, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid nanocapsules. Additionally, another approach involves polymer-based nanocarriers, including dendrimers, polymeric micelles and polymeric nanoparticles. Pharmaceutically engineered crystals like nanocrystals and cocrystal technology are also contributing well to modern approaches. Permeability-glycoprotein inhibitors (P-gp inhibitors) can also be used to contribute to enhancing the oral bioavailability of BCS class IV drugs. All of the traditional and modern strategies are summarized in Figure .

1.

Demonstrated the various traditional and modern emerging strategies that help to overcome biopharmaceutical challenges .

The main intent of writing this review is to address various approaches that are useful for effective delivery of drugs having poor solubility and permeability. These two are the primary biopharmaceutical challenges in BCS class IV drugs, consequently leading to the development of poor oral bioavailability and decreased therapeutic effectiveness. The aforementioned strategies are playing a key role in the development of such formulations that contribute to conquering the challenges in oral drug delivery systems and promote patient effectively.

2. Challenges Associated with Reduced Bioavailability of Orally Administered Drugs

Definitely, oral administration of drugs is safe and convenient for patients, but some limitations minimize the advantages of conventional oral drug delivery. Biological barriers are a major challenge that contribute in different ways to reduce the solubility and permeability of orally administered drugs, specifically in BCS class IV drugs. Because these two factors are responsible for controlling the rate and extent of drug absorption, they directly influence the drug’s bioavailability immensely. Biological barriers majorly include anatomical factors, metabolic or biochemical factors, and physiological factors; all challenges are summarized in Figure .

2.

Different biopharmaceutical challenges include: (1) enzymatic degradation, where a variety of digestive enzymes in the intestinal lumen contribute to drug metabolism prior to its absorption; (2) the stomach’s acidic medium disturbs protein-natured drugs and also influences drug degradation and pH fluctuation; (3) anatomical aspects, where despite the large surface area of the small intestine, drug molecules have to tolerate the presence of bile salts, pancreatic enzymes, and drug efflux via P-gp; and (4) the mucosal barrier, where mucus acts as a semipermeable barrier that prevents direct interaction of substances with the surface of enterocytes, and various physicochemical factors are associated with the reduced bioavailability of orally administered drugs.

2.1. Anatomical Aspects

The mouth, esophagus, stomach, small intestine, and large intestine are the major organs of the gastrointestinal tract. However, the small intestine is the prime site for the absorption of drugs due to its extensive network of villi and microvilli, which provide a gigantic surface area to interact with the dosage form. Enterocytes are interconnected via tight junctions; these junctions provide a pathway for hydrophilic drug’s absorption paracellularly, and lipophilic drugs absorb transcellularly because of the phospholipid bilayer nature of enterocytes. Aside from these features, the existence of various enzymes, pancreatic secretions, bile salts, and mucosal covering makes it difficult to absorb drugs. Any macromolecule that tries to penetrate into the enterocyte epithelium via endocytosis will undergo degradation and hydrolysis intracellularly, due to the existence of multiple enzymes there. Subsequently, the bioavailability of orally administered drugs declines.

2.2. Metabolic or Biochemical Barrier

After oral administration, drugs have to bear the harsh biochemical environment, particularly around enterocytes. Numerous digestive enzymes, i.e., trypsin, chymotrypsin, pancreatic amylase, lipases, and peptidases, which are responsible for intestinal metabolism, are frequently present in the intestinal lumen. Additionally, enterocytes also contribute to metabolism inside brush border cells; participating enzymes include alkaline phosphatase, isomaltase, and other peptidases. As a result, the enterocytes serve as a site for metabolism prior to the absorption into the bloodstream and significantly impact the drug’s bioavailability.

Molecules taken up by the enterocytes also have a probability of being metabolized quickly by intracellular enzymes, including phase-I (cytochrome P450) and phase-II metabolizing enzymes, and then becoming deactivated.

Typically, permeability glycoprotein (P-gp) is present at the surface of enterocyte brush border cells, where it acts as an efflux transporter. Besides its defensive feature, it contributes to pulling out the exogenous substance actively back to the lumen. Moreover, in mature enterocytes, CYP3A4 is also present along with P-gp, which means drugs that are actively pumped out from cells might be metabolized prior to their reabsorption. In conclusion, it can be easily summarized that these aspects also lead to the development of low oral bioavailability.

2.3. Physiological Considerations

2.3.1. Fluctuation in GIT pH

pH fluctuates at different regions of the GIT; it gradually increases from the stomach to the large intestine within the range of 1–8. Alteration from an acidic to an alkaline medium affects the drug’s absorption process and bioavailability as well. During fasting, the average pH of stomach content is approximately .at 2 pepsin is activated at this pH, so protein-natured drugs and drugs that are sensitive in acidic mediums will require protection from that pH; otherwise, the therapeutic response will be diminished. Drugs that are pH-dependent are chiefly manipulated by the simultaneous food administration. However, the pH in the small intestine is suitable for the absorption of drugs, but drug molecules should bypass the drastic effects of stomach content initially.

2.3.2. Gastric Residence Time

Gastric transit or residence time also influences the drug’s bioavailability. In BCS class IV drugs, where both solubility and permeability are low, dissolution is considered a rate-limiting step and is precisely associated with aspects inevitable in gastric emptying time. Gastric emptying rate is self-reliant on the physical features of the drugs but might increase or decrease due to the presence of food. Moreover, food also influences the physicochemical characteristics of the drugs, i.e., rate of dissolution, solubility, and permeability. Consequently, it will affect the oral bioavailability and therapeutic efficacy of the active ingredients.

2.3.3. Mucosal Barrier

The mucosal layer is formed due to the generation of mucus, which is composed of water, antimicrobial peptides, electrolytes, and proteins. The mucosal layer can be divided into two parts: loose mucus and firm mucus. A firm mucus layer is attached tightly to the epithelial surface. Mucin is the major component of the mucus; its molecules attach firmly via disulfide bonds. In recent studies, it was demonstrated that the drug molecules have to cross the mucosal layer in order to enter epithelial cells and the bloodstream. Moreover, the mucus layer acts as a filter and prevents the entry of macromolecules, but molecules having a size of around 200 nm easily enter, as in the case of nanoparticles. Mucus is a semipermeable barrier, so it is not easy to come in direct contact with the epithelial surface. As a result, the drug’s interaction with mucus influences the absorption and bioavailability of drugs.

2.4. Physicochemical Aspects

In order to analyze the bioavailability of orally administered compounds, it is mandatory to evaluate the physicochemical characteristics of the compounds because these factors might affect the oral bioavailability. Essentially, drug release and its dissolution are both crucial factors to evaluate the absorption and oral bioavailability of the drugs. Here, we consider those physicochemical aspects that influence the drug’s dissolution because it directly influences the bioavailability. Primarily, physicochemical characteristics classify according to the physical shape and chemical structure of the drug molecules.

2.4.1. Surface Area/Particle Size

Surface area, or we can say particle size, is a significant feature that influences the drug’s dissolution rate. Surface area is inversely related to particle size and directly proportional to the dissolution rate. Various factors influence the dissolution rate other than surface area, in accordance with the Noyes–Whitney equation.

$$\mathrm{DR}=\frac{\mathit{A}·\mathit{D}}{\mathit{h}}(C_{\mathrm{s}}-\mathit{C})$$ 1

In eq , DR is the dissolution rate, A is the surface area, D is the diffusion coefficient, h is the thickness of the diffusion layer, and C _s – C is the difference between the concentration at the diffusion layer and in the bulk solution, respectively.

So, a particle having less size is mandatory to enable absorption and to get bioavailable. Because for larger particles, it is not possible to cross the well-adjusted and tightly packed phospholipid bilayer. , Moreover, according to Lipinski’s rule of five, a drug molecule having a molecular weight <500 indicates good oral absorption.

2.4.2. Nature of Drug Molecule

2.4.2.1. Lipophilicity

In terms of absorption and bioavailability, lipophilicity is a valuable factor. Considering the absorption, the drug’s molecule has to cross the lipid bilayer of enterocytes from the apical surface and then to the basement membrane to enter into the bloodstream. So, lipophilicity supports the absorption, but it should not be too high because if the molecule adheres tightly to the lipid bilayer membrane, then it would be difficult to cross the biological membrane. So, the estimated lipophilicity value (cLog P) for appropriate absorption should be <5, as stated by the Lipinski’s rule of five.

2.4.2.2. Polymorphisms

Different crystalline forms also impact the solubility and, accordingly, the rate of dissolution and bioavailability of drug molecules. Polymorphism is the phenomenon in which a drug exists in more than one crystalline form and directly reflects the physicochemical behavior of drugs. In between amorphous and crystalline polymorphs of drugs, compelling differences exist. Predominantly, the amorphous form of the drug demonstrates better solubility and dissolution rate compared to its crystalline form; subsequently, the rate and extent of oral absorption might be increased. Although the amorphous form of a drug molecule is usually less chemically stable. ,

2.4.3. Salt Form of the Drug Molecule

Weak acids or bases are two classified groups of drug molecules that contribute to developing healthy ionic interactions with oppositely charged counterions to form charged drug molecules. Active pharmaceutical ingredients in salt forms have been studied extensively. By altering the pH at the diffusion layer of the dissolving solid, the salt form of the molecule occasionally modifies the dissolution rate. Slight modification in microenvironmental pH accelerated the dissolution rate. For instance, salts of acidic or basic drugs contribute to enhancing the acidic or basic drug dissolution rate because the segregation of ions increases the microenvironmental pH, as in the case of sodium and hydrochloride salts for acidic and basic drugs, respectively. Although, it cannot be summarized that these salts have enough potential because acetic acid and organic acids are occasionally used for better dissolution rate. However, the appropriate form of salt should be evaluated via a screening process.

2.4.4. Solubility

Particularly, the solubility influences the drug’s concentration at the absorption site and, accordingly, influences the drug’s absorption. Moreover, the prime determinant for the dissolution rate of the drug molecule is its solubility. The drugs having poor solubility demonstrate a slower dissolution rate and lead to reduced oral bioavailability. This mainly occurs when the aqueous solubility of the molecule is <100 μg/mL. In order to differentiate the poorly soluble drugs, drug dose and solubility ratio are other parameters. In detail, this ratio indicates the volume of GIT fluid needed to dissolve the administered amount of drug. If the volume of GIT fluid is less than the desired volume required to dissolve the administered drug, then it might be forecasted that the bioavailability declines.

3. Strategies to Overcome Biopharmaceutical Challenges and Improve Oral Drug Bioavailability

Traditional approaches have been used to overcome limitations and improve the bioavailability of administered drugs. Nowadays, modern strategies are emerging and contributing effectively to improving and overcoming the impactful biopharmaceutical challenges. Here, we will discuss both of these aforementioned approaches to summarize the solutions that effectively improve the bioavailability of orally administered drugs.

3.1. Traditional Approaches

Usually, physical and chemical modification protocols are considered traditional approaches that aid in overcoming challenges affiliated with reduced oral bioavailability of drugs.

3.1.1. Approaches Based on Physical Modifications

Based on the physical modification of drugs, different approaches or strategies have been utilized, as mentioned in Table .

1. Enlist Physical Modification Approaches of Drugs to Overcome the Solubility Issues of Poorly Water-Soluble Drugs .

Approach/Strategy		Method Involve	Refs
Particle size minimization		(HPH)	,
		Jet milling	,
		Ball milling	,
Solid dispersion in carriers		Hot melt method	,
		Solvent evaporation method (SE)	,
		(HME) or Spray drying	,
		Melting solvent method (MS)	,
		Solid solutions
Complexation	Metal complexes
	Molecular complexes
	Inclusion complexes	Kneading method	,
		Freeze-drying/lyophilization	,
		Microwave irradiation (MI)
Cryogenic techniques		Spray freeze-drying (SFD)
		Spray freezing into liquid (SFL)
		Thin film freezing (TFF)
Supercritical Fluid Technology (SCF)		RESS	,
		RESOLV
		SAS
		ASES

^aHPH: high pressure homogenization, RESS: rapid expansion of supercritical solution, RESOLV: rapid expansion of a supercritical solution into a liquid solvent, SAS: supercritical anti-solvent, ASES: aerosol solvent extraction system, HME: hot melt extrusion.

3.1.1.1. Particle Size Minimization

Solubility directly correlates with the surface area of the drugs. Particles larger in size exhibit less surface area and, accordingly, reduced solubility. Reduction of particle size is a convenient way to enhance the surface area, which afterward improves the dissolution. Increased surface area also provides increased chances of interaction between solvent and drug molecules. The most advanced technique for the reduction of particle size is micronization, which aids in developing the particles of micron size via physical processes.

Liang et al. conducted a study on Panax notoginseng (PN), a compound that is a traditional Chinese medicine known for aiding in maintaining blood sugar levels and providing anti-inflammatory, antioxidative, and antitumor effects. The objective of the study is to analyze the effect of size reduction via micronization on a given compound and monitor its potential to promote bioavailability. The results demonstrated that the particle size reduction within the range of 60–214 μm improves the in vitro dissolution and in vivo pharmacokinetic features of the PN. It was concluded that the appropriate reduction in particle size of PN gives the highest bioavailability.

Techniques like spray drying, crystallization, and freeze-drying are used for the micronization process, but these techniques cause nonuniform distribution of particle size and their degradation because of excessive force. After that, modern micronization technologies that adequately increase the surface area via particle size reduction includes high-pressure homogenization (HPH), jet milling and ball milling. A schematic demonstration of HPH is illustrated in Figure .

3.

High-pressure homogenization is a general scheme indicating the reduction of the particle size to increase the surface area of the particles.

3.1.1.2. Solid Dispersion in Carriers

Micronization serves to reduce particle size and accordingly enhance surface area because this feature is correlated with dissolution rate, which directly influences oral bioavailability. Aside from this technique, dispersion of solids (SD) in a suitable carrier (polymer) also serves to enhance particle size for improved dissolution. This technique is one of the promising approaches that ensures the improved oral bioavailability of poorly soluble drugs. In detail, this technique involves two major components: the dispersion of a hydrophobic drug into a suitable inert hydrophilic matrix (polymer), as illustrated in Figure . Both the drug and polymer change to the molten state and then solidify by cooling. The dispersed drug can either be crystalline or amorphous in nature, depending on the molecular arrangements.

4.

General demonstration of the dispersion of a hydrophobic drug into a suitable and inert hydrophilic carrier (polymer).

Pharmaceutical techniques that can be engaged for dispersion of solids into an inert carrier include the hot melt method, solvent evaporation method (SE), hot melt extrusion (HME), spray drying, melting solvent method (MS), and solid solutions. Polymers like poly­(vinyl alcohol), crospovidone, polyethylene glycol (PEG), polyvinylpyrrolidone, and hydroxypropyl methylcellulose (HPMC) are commonly employed for these techniques .

A study was conducted to improve the aqueous solubility of ritonavir; a lyophilized milk-based solid dispersion was prepared. In order to evaluate the physicochemical behavior and robustness of the designed formulation, characterization was done via scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), photomicroscopy, differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). Results truly demonstrated the improved solubility and rate of dissolution of ritonavir SD by 30-fold and 10-fold, respectively. By using eight different hydrophilic polymers, eight different SD formulations of amorphous cyclosporine A (CsA) were designed to improve the oral bioavailability of the drug. Among all those formulations, products with polymer hydroxyl propyl cellulose (HPC) have been shown to enhance C _max and AUC up to 5-fold, which justifies the improved bioavailability of the drug.

3.1.1.3. Complexation

In general, a complex is the association between different molecules developed due to the interactions among substrates and ligands. Accordingly, the phenomenon of complexation between drug molecules and other substances may also exist. Interactions between drugs and other molecules depend on the forces, i.e., hydrogen bonding (H-bonding), London forces, and hydrophobic interactions. By inducing modifications in the physicochemical features of drugs, complexation may improve the solubility, rate of dissolution, and, accordingly, oral bioavailability of BCS class IV drugs. This technique majorly includes metal, molecular and inclusion complexes. To enhance the solubility, dissolution rate, and oral bioavailability of poorly soluble drugs, inclusion complexes gain very much value and are truly designed. In detail, a hydrophobic drug molecule (termed as guest) is infused into the cavity of a different molecule (termed as host i.e., cyclodextrin) whose inner surface is hydrophobic and outer walls are hydrophilic in nature, as illustrated in Figure . The host must have enough space for the accommodation of the drug molecule and should be small enough to reduce the interaction of water between the inner hydrophobic region of the host and the hydrophobic drug. For inclusion complexes, major pharmaceutical techniques are the kneading method, freeze-drying/lyophilization, and microwave irradiation (MI) method.

5.

Schematic presentation of complexation (inclusion complex) shows a hydrophobic drug complexed with a hydrophilic host.

Artemisinin inclusion complexes have been developed with β- and δ- cyclodextrin in order to improve its oral bioavailability. Three parameters, i.e., AUC, C _max, and T _max were monitored to evaluate the oral bioavailability of the given drug inclusion complexes. An indicative difference has been found between the oral bioavailability of artemisinin and that of the artemisinin inclusion complex. Overall, the oral bioavailability of the drug inclusion complex improved. Acyclovir, a drug used to treat herpes virus, has poor solubility and permeability as a result of having low oral bioavailability. To improve its oral bioavailability, its inclusion complex with hydroxylpropyl-b-cyclodextrin was prepared via a kneading method. The formulation was characterized via FTIR, DSC, and NMR, and dissolution studies were also performed. To analyze in vivo bioavailability, a rat model was selected. After that, comparing the physical mixture of the drug with its inclusion complex, it was found that the bioavailability of the given drug improved.

3.1.1.4. Cryogenic Techniques

To enhance the solubility and dissolution rate of the drug, cryogenic technologies were designed for this purpose. Generally, in this process, the nanostructured amorphous highly porous drug particles are created at low-temperature settings, showing intensely magnified surface area, followed by increased dissolution rates and accordingly improved bioavailability. This method employs a rapid change in the solubility of the drugs, followed by the generation of solid particles, and, accordingly, this technique can be categorized as a microparticle or nanoparticle precipitation technique. Methods that are usually employed for drying the particles include vacuum drying, lyophilization, and spray drying. Composition of cryogenic solution, kind of injection equipment, and location of nozzle are basic parameters for defining the cryogenic method, as shown in Figure . Commonly employed cryogenic methods include spray freeze-drying (SFD), spray freezing into liquid (SFL), and thin film freezing (TFF).

6.

Illustrating the schematic pattern of spray freezing into liquid (SFL)  a cryogenic technique  the feed solution contains active pharmaceutical ingredient (API) and pharmaceutical excipients, which are sprayed via nozzle into liquid nitrogen in order to solidify the feed solution droplets.

Rogers et al. conducted a study to improve the rate of dissolution of carbamazepine and danazol, poorly water-soluble drugs, via spray freezing into liquid (SFL), one of the cryogenic methods. In results, it was concluded that the SFL might be used to improve the dissolution of poorly soluble drugs along with their bioavailability.

3.1.1.5. Supercritical Fluid Technology (SCF)

Supercritical fluid technology is another nanosizing procedure used to reduce particle size via engaging the supercritical fluids and accordingly enhancing the bioavailability of drugs. These fluids have a rare feature to behave like gases as well as liquids because the pressure and temperature for such fluids are above their critical point (critical pressure and critical temperature). Most commonly, carbon dioxide is used as a supercritical fluid, with a temperature and pressure of 31.3 °C and 72.9 atm, respectively. Various methodologies have been employed in SCF, including rapid expansion of supercritical solution (RESS) process, illustrated in Figure , rapid expansion of a supercritical solution into a liquid solvent (RESOLV), supercritical antisolvent (SAS), and aerosol solvent extraction system (ASES). Over conventional processes, SCF offers benefits such as low agglomeration and more spherical-shaped particles.

7.

Demonstration of schematic presentation of rapid expansion of the supercritical solution (RESS) process, a promising supercritical fluid technology.

Yang et al. conducted a study with the aim of preparing bile salt-containing liposomes via supercritical fluid technology in order to enhance the solubility and bioavailability of silymarin (SM). After that, liposomes obtained by this method showed increased encapsulation efficiency (EE) and drug loading capacity (DL). Moreover, particles of the smallest size were obtained along with an improved in vitro drug release profile. There was a 4.8-fold increase in the in vivo AUC observed. On behalf of these findings, it was concluded that the preparation of liposomes via supercritical fluid technology is effective in enhancing the oral bioavailability of poorly water-soluble drugs.

3.1.2. Approaches Based on Chemical Modifications

Based on chemical modification of drugs, different approaches or strategies have been utilized.

3.1.2.1. Salt Formation

Formation of salts of acidic and basic drugs is a suitable way for enhancing the solubility, dissolution rate and bioavailability of poorly soluble drugs. Specifically, salt forms of drugs show higher solubility as compared to their acidic or basic nature. For enhancing the solubility and oral uptake of poorly water-soluble drugs, salt selection is a crucial factor. In between, the drug and counterion charged group attract each other due to the existence of intermolecular forces to crystallize the salt shape under suitable circumstances, as shown in Figure . It was recorded that delavirdine mesylate showed 2000-fold higher solubility, 320 mg/mL, in its salt form, whereas the free base only showed 143 μg/mL at pH 6.0.

8.

Basic principle indicates the salt formation process in a schematic manner.

BM635 is a small chemical substance identified for its exceptional antimycobacterial activity. However, this compound shows poor solubility and low in vivo bioavailability. So, a study was designed to prepare the salt forms of this compound to support its solubility profile. Five different salts of BM635 were prepared via hydrochloric (HCl), methanesulfonic (Mes), phosphoric, tartaric (TA), and citric acids (CA). Besides BM635-HCl, all salts surprisingly showed improved solubility and an extraordinary effect on bioavailability. BM635-Mes exhibited the maximum bioavailability enhancement.

Chi et al. conducted a study to improve the oral bioavailability of candesartan, an antihypertensive drug with poor solubility. Three different salts of candesartan were designed via the solvent-assisted grinding technique. DSC, FTIR, NMR, X-ray diffraction, thermogravimetry, and powder X-ray diffraction techniques were used for the characterization of prepared salts. A rat model was used to monitor the plasma-drug concentration. The oral bioavailability of salts 1–3 is improved by 1.3, 2.5 and 3.1-fold, respectively, as compared to the active pharmaceutical ingredient (API).

3.1.2.2. Co-Solvency

The most prevailing and earliest method to enhance the solubility of poorly soluble drugs is cosolvency because it is easy to incorporate. The principle on which this process relies is the addition of poorly soluble drugs into a suitable organic water-miscible solvent, wherein the API dissolves easily. This method is termed as cosolvency due to the involvement of cosolvents. Cosolvents are a combination of one or more organic water-miscible solvents and water; subsequently, a solution is formed, as presented in Figure . That solution is used to enhance the solubility of poorly water-soluble drugs. This technique works via reducing the interfacial tension between the poorly soluble drug and water. Propylene glycol, glycerin, ethanol, sorbitol, and polyethylene glycols (PEG-300) are frequently employed cosolvents because of their minimal toxicity in the formulation. Dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP) are organic solvents that may also be utilized.

9.

Schematic overview of the cosolvency process, demonstrating the addition of a hydrophobic or poorly water-soluble drug in cosolvent to enhance its solubility.

A study was conducted by Shi et al.; the objective of the study is to enhance the solubility and bioavailability of pazopanib, an anticancer agent. Two cosolvents are employed, including (ethyl acetate +2-propanol) and (ethyl acetate + ethanol). It was concluded at the end that the overall solubility and bioavailability of the drug improved.

3.1.2.3. Hydrotropy

Another solubilization technique that facilitates improving the solubility and dissolution of poorly water-soluble drugs is hydrotropy. It is a molecular phenomenon that aids in enhancing the solubility of hydrophobic drugs via amphiphilic solutes or hydrotropes, as illustrated in Figure . At a minimum hydrotrope concentration (MHC), hydrotropes have sufficient ability to self-assemble into micelles. This ability of hydrotropes to assemble is the basic principle for enhancing the solubility of poorly soluble or hydrophobic drugs. Hydrotropes are ionic organic salts; commonly employed agents include sodium acetate, sodium benzoate, sodium alginate, sodium salicylate, urea, benzenesulfonate, and cumene sulfonate. These agents have significant potential to increase the solubility of poorly soluble drugs by several times.

10.

Hydrotropic agent demonstrating the phenomenon of self-aggregation, a hypothesis involved in the solubility-enhancing feature of hydrotropes.

In the study, three hydrotropic agents, i.e., cholinium vanillate, cholinium gallate, and cholinium salicylate, were employed to analyze their effect on the solubility of ibuprofen and naproxen. In the case of naproxen, all three agents increased the solubility by up to 600 times. On the contrary, cholinium salicylate surprisingly enhanced the solubility of ibuprofen by up to 6000 times. Meanwhile, cholinium vanillate and cholinium gallate improved the solubility of ibuprofen by up to 500 times.

3.1.2.4. Formation of Prodrugs

Prodrugs are the chemically designed inactive variants of a parent drug that require enzymatic or biochemical modifications for activation and accordingly show their pharmacological response. , Major objectives to design the prodrugs are to improve the physicochemical, biochemical, chemical stability, and oral bioavailability features of pharmacological substances. Moreover, prodrug formation is a recognized strategy that aids in enhancing the oral drug bioavailability of poorly soluble drugs. Bioprecursors and carrier-linked prodrugs are two major divisions of prodrugs. Bioprecursors are activated after chemical modification, whereas carrier-linked prodrugs are temporarily linked to a carrier molecule and become detached after biotransformation, , as shown in Figure . In detail, prodrugs are further classified into classic, mixed, mutual, and targeted prodrugs. Esters, amides, phosphates, and N-Mannich bases are commonly employed to design prodrugs.

11.

Schematic illustration of prodrug permeability: a drug linked with a chemical moiety or carrier to form a prodrug, and after permeation, it undergoes chemical modification and releases the drug for a pharmacological response.

The oseltamivir carboxylate (GOC), having reduced intestinal permeability, Incecayir et al. tried to design a prodrug via a carrier-mediated prodrug strategy in order to improve its permeability. (GOC-ISP-Val), the valyl amino acid prodrug of oseltamivir carboxylate with an isopropylmethylene-dioxy linker, was designed and evaluated for its permeability via Coca-2 cells and mice. It was analyzed that the permeability of GOC-ISP-Val was significantly improved.

Paclitaxel (PTX), a BCS class IV drug, shows poor oral bioavailability; to improve its bioavailability, PTX was linked with cholic acid-functionalized PEG (CPP) via a polymeric prodrug strategy. It was analyzed that the solubility of the compound surprisingly increased >30,000-fold, a permeability study on Coca-2 cells indicated a 4-fold improvement, and bioavailability was enhanced by about 10-fold.

3.2. Emerging Strategies

Divergent emerging drug delivery strategies are listed in Table . Moreover, we are going to discuss all those strategies below.

2. List of Drugs Engaged in Various Studies to Overcome Their Bioavailability Issue via Emerging Drug Delivery Strategies .

Strategy Utilized	Drugs	BCS Class	Conclusion	Refs
SEDDS	Atorvastatin	BCS II	Bioavailability Improved
SMEDDS	Vinpocetine	BCS II	Increased drug release rate, 1.72-fold hike in oral bioavailability
	Nilotinib	BCS IV	2.11- fold improved relative oral bioavailability
S-SMEDDS	RTV	BCS IV	2-fold increased C max
Liposomes	Curcumin	BCS IV	Oral bioavailability enhanced
	DXT	BCS IV	3-fold hike in AUC
	Furosemide	BCS IV	Enhance solubility and drug dissolution
Nanoemulsion	Nitrendipine	BCS II	Better therapeutic efficacy and bioavailability
Microemulsion	Amp B	BCS IV	2-folf improved permeation
SLNs	Lopinavir	BCS IV	Bioavailability Improved
	PXT	BCS IV	T 1/2 of drug improved
	DXT	BCS IV	Improved intestinal and oral bioavailability
NLCs	Oxaprozin	BCS II	Enhanced drug uptake
	PXT	BCS IV	6.36-fold enhanced AUC
	Entacapone	BCS IV	T 1/2 and AUC increased
LNCs	PXT	BCS IV	2-fold hike in oral bioavailability
Dendrimers	Nifedipine	BCS II	Solubility increased
	Bortezomib	BCS IV	Improved solubility
	Amp B	BCS IV	Improved therapeutic activity
Polymeric micelles	PXT	BCS IV	Increased oral bioavailability of p-gp substrate drugs
	Ticagrelor	BCS IV	2.2-fold better oral bioavailability
	Amp B	BCS IV	Targeted drug delivery
Polymeric NPs	Amp B	BCS IV	Improved oral bioavailability ∼ 800
	PXT	BCS IV	Enhanced oral bioavailability
	Resveratrol	BCS II	Improved the solubility, permeability and anti-inflammatory activity of resveratrol-loaded NPs
Nanocrystals	PXT	BCS IV	10.0-fold improved in C max, 14.9-fold hike in AUC0–12
	Nimodipine	BCS II	2.18-fold improved in C max, 2.61-fold hike in AUC0–12
	Cinacalcet	BCS IV	1.9-fold improved in C max, Enhanced oral bioavailability
Co-crystals	Hydrochlorothiazide	BCS IV	2-fold hike in permeability
	Furosemide	BCS IV	Improved solubility
P-gp inhibitors	PXT	BCS IV	Improved permeation and oral bioavailability

^aBCS: Biopharmaceutical Classification System, SEDDS: Self-emulsifying drug delivery systems, SMEDDS: Self-microemulsifying drug delivery system, S-SMEDDS: Solid self-microemulsifying drug delivery system, Cmax: Maximum plasma drug concentration, AUC: Area under the curve, T _1/2: Half-life, NPs: Nanoparticles, P-gp: Permeability-glycoprotein, PXT: Paclitaxel, Amp B: Amphotericin B, DXT: Docetaxel, RTV: Ritonavir

3.2.1. Lipid-Based Drug Delivery Systems

Drugs that demonstrate poor bioavailability are challenging; however, lipid-based drug delivery systems are perfect to overcome this drawback. Different emerging lipid-based strategies are used for this purpose and are discussed below.

3.2.1.1. Self-Emulsifying Drug Delivery Systems

Over a decade, self-emulsifying drug delivery systems (SEDDS) have been broadly used to improve the bioavailability of hydrophobic drugs, particularly because of enhanced drug solubility. This system is composed of oil, surfactant, and cosurfactants, making it possible for hydrophobic drugs to solubilize in the oil phase and stabilize with the cosurfactants. Upon exposure to water after slight agitation, it becomes an emulsion, as illustrated in Figure . Based on size, SEDDS are categorized into self-microemulsifying drug delivery systems (SMEDDS) and self-nanoemulsifying drug delivery systems (SNEDDS). Along with improved bioavailability, SEDDS also aid to reduced daily dose and improve plasma drug profile.

12.

Diagrammatic presentation of self-emulsifying drug delivery system (SEDDS) formation.

To increase the oral bioavailability of paclitaxel, a supersaturable self-emulsifying drug delivery system (S-SEDDS) was designed. The drug-loaded formulation showed a 5-fold improved oral bioavailability, and approximately a 10-fold increase in plasma drug concentration (C _max) was observed. Solid self-microemulsifying drug delivery systems (S-SMEDDS) were designed to enhance the oral bioavailability of ritonavir (RTV). The designed formulation upgraded the area under the curve (AUC_0–24 h) and plasma drug concentration (C _max), which were 2-fold better than the suspension of ritonavir.

3.2.1.2. Liposomes

Liposomes are phospholipid bilayer vesicular structures. Because of their unique formation, they accommodate both hydrophilic and lipophilic drugs, as demonstrated in Figure . Liposomes have significantly contributed to enhancing the bioavailability of various drugs. Along with their biocompatibility and solubilizing capacity, liposomes demonstrate structural and compositional similarity to the biological membranes, and these features ensure the oral delivery of poorly permeable drugs. However, liposomes have poor intestinal permeability because of their large size. Moreover, liposomes are also susceptible to gastric digestion, so they are not preferred for oral use.

13.

Illustration of liposomes presenting the accommodation of both hydrophobic and hydrophilic drugs.

Furosemide, a BCS class IV drug, was loaded into the chitosan-coated nanoliposomes in order to enhance its solubility and dissolution rate. As a result , improved solubility and dissolution rate of furosemide were determined. Amphotericin B-loaded mannosylated liposomes were designed to treat visceral leishmaniasis effectively. The designed formulation efficiently reduced the parasitic load. Moreover, a biodistribution study clearly showed improved uptake of mannosylated liposomes and targeting to the infectious site via the reticuloendothelial system.

3.2.1.3. Emulsion

One of the most ancient methods for the delivery of hydrophobic drugs is an emulsion-based approach. Nowadays, micro- and nanoemulsions are used for supporting the oral bioavailability of BCS class IV drugs. These two versions of emulsions provide small droplet sizes with improved thermodynamic and kinetic stability. Emulsions are usually composed of oil, surfactant, cosurfactant, and an aqueous vehicle. On the basis of size, they are categorized into micro- and nanoemulsions. These two groups depend on their sizes for categorization and are also classified as oil-in-water (O/W) and water-in-oil (W/O) emulsions, as shown in Figure .

14.

Schematic presentation of emulsion formation according to the nature of the dispersed phase: (A) oil is the dispersed phase, and the hydrophobic tail of the surfactant encloses it inside to produce an (O/W) emulsion. (B) water acts as the dispersed phase after emulsification, hydrophilic ends of the surfactant are inverted to form a (W/O) emulsion.

To improve the solubilization and oral bioavailability of docetaxel, we prepared an oil-in-water (o/w) microemulsion system. In conclusion, it was summarized that the docetaxel microemulsion is suitable for oral drug delivery because it has shown improved solubility and enhanced oral bioavailability of hydrophobic drugs. Moreover, improved oral bioavailability is a synergistic result of increased solubility and permeability, along with P-gp efflux inhibition. For the treatment of invasive fungal diseases, amphotericin B-loaded microemulsion has been designed by Butani et al. The optimized formulation exhibited the size, polydispersity index, and pH of 84.20 ± 2.13 nm, 0.164 ± 0.031, and 7.36 ± 0.02, respectively. Moreover, rat skin was employed, and 2-fold higher drug permeation was observed in contrast to the plain drug.

3.2.1.4. Solid Lipid Nanoparticles (SLNs)

SLNs are considered the first generation of lipid nanoparticles and serve as a surrogate for conventional colloidal systems like liposomes, emulsions, and polymer nanoparticles. SLNs are accomplished only by blending solid lipids; for their production, high-pressure homogenization and microemulsion processes are commonly employed. They are quite efficient at enhancing the oral bioavailability of poorly soluble drugs (see Figure ).

15.

Diagrammatic presentation of solid lipid nanoparticles (SLNs).

Lopinavir is a protease inhibitor for HIV infection but shows poor permeability into the central nervous system (CNS) due to the blood–brain barrier. A study was conducted by Alex et al. to design drug-loaded SLNs and improve the drug’s bioavailability. To compare bioavailability, a drug suspension and a rat model were employed; the formulation exhibited improved bioavailability along with a 632.86 ± 81.61 ng/mL C _max and 25 ± 7.75 min T _max. The noticeable drug concentration was monitored in cerebrospinal fluid by the given formulation.

Paclitaxel (Taxol) is an anticancer drug, and due to its compromised solubility, there is a need to deliver it with polyethoxylated castor oil (Cremophor EL), which induces severe side effects. To overcome this drawback, a study was conducted by Chen et al . in which paclitaxel-loaded SLNs were designed to improve the drug’s efficacy and eradicate the utilization of cremophor EL. Two long-circulating SLNs were prepared via drug carriers, i.e., F68 and Brij78; the half-life of the drug was improved compared to its injection, with 10.06 h for F68-SLNs and 4.88 h for Brij78-SLNs. Consequently, the drug would remain in the blood for a long period of time to provide better results.

Cho et al. presented a study to enhance the oral bioavailability of docetaxel via SLNs modified with D-alpha-tocopheryl poly­(ethylene glycol 1000) succinate (TPGS 1000) and Tween 80. The solvent diffusion method was used to design the formulation. In the results, it was evaluated that the SLNs modified with Tween 80 showed improved intestinal absorption and oral bioavailability. Meanwhile, TPGS 1000-modified SLNs demonstrated greater performance, primarily due to P-gp efflux inhibition and lymphatic transport.

3.2.1.5. Nanostructured Lipid Carriers (NLCs)

NLCs are considered a second generation of lipid nanocarriers, a modified form of SLNs but more compatible due to their imperfect crystal lattice structure developed via the existence of both solid and liquid lipids, , as shown in Figure . NLCs aid to provide enhanced drug loading capacity, targeted drug delivery, enhanced permeation and increased bioavailability of orally administered drugs.

16.

Diagrammatic presentation of nanostructured lipid carriers (NLCs), composed of both solid and liquid lipids.

To enhance the oral bioavailability of aprepitant (APT), a BCS class IV drug with poor solubility and permeability, mucoadhesive APT-loaded NLCs were designed. In this study, NLCs were prepared via the nanotemplate engineering technique and thiolated to achieve surface modification and enhance mucoadhesion. It was concluded that the designed formulation exhibited a 6.7 ± 0.8% drug loading capacity, along with 86 ± 3% entrapment efficiency. Moreover, mucoadhesive APT-loaded NLCs exhibited 24.8% relative bioavailability and a 2.56-fold increase in C _max. Based on these findings, it was concluded that the NLCs are suitable nanocarriers for oral drug delivery. In another study, entacapone-loaded NLCs were designed to overcome limited dissolution and first-pass effect. It was analyzed that the area under the curve (AUC) and t _1/2 increased. Accordingly, the drug was available for a prolonged time, and therapeutic effectiveness increased. It can be summarized that the NLCs are compatible nanocarriers for oral drug delivery.

3.2.1.6. Lipid Nanocapsules (LNCs)

Lipid nanocapsules are another emerging approach to overcoming biopharmaceutical challenges. They are primarily composed of three main constituents: nonionic surfactant, oily phase, and aqueous phase, , as mentioned in Figure . Several beneficial effects make LNCs impactful for drug delivery, including sustained release of drugs, biocompatibility, effective drug payloads, targeted delivery, and improved oral bioavailability. Most commonly, LNCs are prepared via the phase inversion technique.

17.

Demonstrating schematic preparation of lipid nanocapsules (LNCs) via a phase inversion temperature technique.

In contrast to the paclitaxel (PX) formulation, the paclitaxel-loaded LNCs provided enhanced antitumor activity. Lacoeuille et al. conducted a study to perform in vivo evaluation of PX-loaded LNCs. Hepatocellular carcinoma was chemically induced in Wistar rats, likely to monitor the antitumor activity of the designed formulation. ¹⁴C-trimyristin (¹⁴C-TM) and ¹⁴C-phosphatidylcholine (¹⁴C-PC) were utilized for biodistribution studies. Plasma drug concentration profiles showed that both ¹⁴C-TM-LNCs and ¹⁴C-PC-LNCs demonstrated longer blood circulation and slower elimination. Compared to the control, animals treated with PX-loaded LNCs showed better survival, and accordingly, LNCs were considered optimized for drug delivery. In another study, the oral bioavailability of paclitaxel was monitored via PX-loaded LNCs. After preparation and suitable characterization, the formulation was tested for its oral bioavailability. In the results, it was analyzed that the oral bioavailability of PX-loaded LNCs was enhanced by 3-fold.

3.2.2. Polymer-Based Nanocarriers

Polymer-based nanocarriers usually include dendrimers, polymeric micelles, and polymeric nanoparticles, as illustrated in Figure .

18.

Diagrammatic illustration of polymer-based nanocarriers: (A) polymeric nanoparticles, (B) polymeric micelles, and (C) dendrimers.

3.2.2.1. Dendrimers

“Dendran” is the Greek word from which the word “dendrimer” originated, an innovative polymeric carriers attracting attention due to its particular characteristics, such as having a small size range between 1 and 100 nm, a controlled molecular structure, uniformity in particle size distribution, multiple binding sites, and a three-dimensional structure consisting of (i) a core present at the center containing an atom or molecule, (ii) branching polymers, and (iii) peripheral functional groups present at the surface, by which the properties of the dendrimers are determined. Dendrimer types are determined on the basis of different polymers such as poly­(aryl ethers), polyamidoamines (PAMAMs), polyamides (polypeptides), polyamines, DNA, polyesters, and carbohydrates. , Dendrimers have desirability in oral drug delivery by assisting in modulating the integrity and tight junctions of cell membranes and having the ability to be involved in surface modification. By directly conjugating the drug with the dendrimer either by complexation or by encapsulation, the drug bioavailability can be improved. Moreover, dendrimers increase drug absorption by having the potential to penetrate the intestinal membrane and increase the residence time of the drug within the intestine by having the characteristic of mucoadhesion. ,,

Many studies have been conducted to prove that dendrimers improve the therapeutic efficacy of BCS class IV drugs. According to Devarakonda et al., dendrimers improve the solubility and dissolution of furosemide. According to another study, dendrimers improve the targeted drug delivery of amphotericin B to macrophages, helping to reduce toxicity and enhance therapeutic activity. Teow et al. proved that when paclitaxel was conjugated with a polyamidoamine (PAMAM) dendrimer-based carrier, the permeability of paclitaxel with this formulation increased 12 times compared to paclitaxel alone. ,

3.2.2.2. Polymeric Micelles

Polymeric micelles are considered auspicious drug delivery vehicles because of their characteristics of reduced toxicity, small size (10–100 nm), targeting capability, increased solubilization, and higher blood circulation time. They also exhibit side effects due to their stability in the physiological environment, but this property makes them ideal for the safer transport of the drug and increasing its bioavailability. ,

To improve the bioavailability of the poorly water-soluble drugs, these polymeric micelles are formed by amphiphilic copolymers consisting of a hydrophilic shell, which surrounds the hydrophobic core. This hydrophobic core acts as a reservoir for the drug encapsulated by them. Commonly employed polymeric micelles, e.g., carboxypolymethylene, cross-linked polyacrylic acids (PAA), alginate, carboxymethyl cellulose, chitosan, and their derivatives, enhance their mucoadhesive properties.

The studies prove the concept that polymeric micelles play a vital role in enhancing the target delivery of BCS class IV drugs. In one of the studies, 1, 2-distearoyl-sn-glycero-3- phosphoethanolamine-N- [methoxy (polyethylene glycol)-2000] (PE–PEG)-based micelles carried Amphotericin B, designed by Shao et al., in which angiopep-2 was used as a surface modifier. This unique formulation not only increases the targeted delivery of amphotericin B into the brain but also decreases toxicity and hemolysis in vitro. In two of the studies, polymeric micelles were prepared for paclitaxel. The aqueous solubility of the formulation prepared by Dabholkar et al. increased 5000 times, with a concentration of 5 mg/mL, while the other formulation of paclitaxel showed enhanced solubility with a concentration of 38.9 mg/mL. ,

3.2.2.3. Polymeric Nanoparticles

These are the nanocolloidal vehicles made up of the natural, synthetic, and biodegradable polymers with a size range of 10–1000 nm⁸. The most common natural polymers employed for their composition are albumin, gelatin, and alginate, and the synthetic polymers are polylactic acid, poly­(d,l-lactide-coglycolide), poly­(d,l-lactide), and polycaprolactones. , Further, polymeric nanoparticles can be divided into two classes, i.e., nanocapsules and nanospheres. The former are used for the oral delivery of enzymes, proteins, peptides, oils, and organic or inorganic catalysts, due to their micron size. The major barrier in their use is their degradation by digestive enzymes. While the latter protect the drug from enzymatic degradation, they exist in crystalline or amorphous forms. The drug and polymeric link can be described by the encapsulation, drug adsorption on the surface of the polymer, or chemical linkage of the drug with polymer. Their multiple advantages, such as targeted drug delivery, improved bioavailability, higher solubilization, and reduced toxicity, make them ideal for improving the efficacy of BCS class IV drugs. , One of the studies shows that drug-loaded polymeric nanoparticles can increase the anticancer activity and bioavailability of the chemotherapeutic drugs. The bioavailability and anticancer efficacy of curcumin were studied by preparing their nanoparticles with Eudragit E 100. Their efficacy was studied in colon-26 tumor-bearing mice and Wister rats. In another study, the oral bioavailability of paclitaxel was shown to be improved when it was complexed with cyclodextrin in nanoparticles. The reason behind the increased bioavailability of the paclitaxel was due to the inhibitory effect of the cyclodextrin on the cytochrome P450 and P-glycoprotein, and the bioadhesive property of the nanoparticles in which the drug was encapsulated.

3.2.3. Pharmaceutically Engineered Crystals

3.2.3.1. Nanocrystal Technology

As they have the ability to load an increased amount of the drug with a little amount of carrier molecules, the nanocrystals are presented as a viable technique for increasing the solubility and bioavailability of poorly soluble drugs, such as BCS class IV drugs. , These are the small-sized solid particles of pure drugs, usually stabilized by the stabilizers or surfactants. They are considered ideal candidates for BCS class IV drugs due to their multiple benefits, such as an enhanced dissolution rate, ease of preparation, and stabilized absorption rate under both well-fed and fasting conditions, as illustrated in Figure .

19.

Diagrammatic presentation of the nanocrystal formation.

Multiple studies have been conducted in which the nanocrystals were prepared for the BCS class IV drugs such as aprepitant, rebamipide, saquinavir, paclitaxel, coenzyme Q10, berberine, cinacalcet and etoposide, resulting in increased area under the curve (AUC), C _max, and bioavailability of these poorly soluble drugs. −

3.2.3.2. Co-Crystal Technology

Co-crystal is an innovative technique formed as a result of intermolecular interactions, such as the van der Waals forces and hydrogen bonding, between the active ingredient and excipient. Various examples of coformers include caffeine, carboxylic acids, nicotinamide, and saccharin. These are mostly water-soluble, as presented in Figure . They change the physicochemical properties of the drug rather than altering the pharmacological properties of the drugs, such as having an impact on the permeability, solubility, and bioavailability. , When nanocrystals of the furosemide and hydrochlorothiazide, which belong to poorly soluble BCS class IV drugs, were prepared using the liquid-assisted grinding technique, both formulations showed a change in the physicochemical properties of the drugs, resulting in the higher solubility of these formulations. ,

20.

Due to the cocrystallization process, a cocrystal and lipophilic drug are attached to form a suitable product.

3.2.4. Permeability-Glycoprotein Inhibitors (P-gp Inhibitors)

P-glycoprotein is an ATP-driven transmembrane efflux pump on the apical surface of intestinal epithelial cells that pumps out the unrelated hydrophobic compounds from cells back to the lumen. Although P-gp also has a great impact on cellular uptake from the blood to the brain. P-gp is linked with the absorption and bioavailability of substances. Drugs that are substrates of this transporter can bear bioavailability issues. HIV protease inhibitor drugs, which belong to the BCS class IV drugs, are substrates of the P-gp transporter. Subsequently, these drugs face complications regarding bioavailability. Different strategies can be employed to overcome this drawback. Primarily, coadministration of a specific inhibitor or another P-gp substrate along with the desired drug, as illustrated in Figure , lipidic or polymeric excipient administration with the drug tends to block the efflux pump receptor, and a novel peptide prodrug strategy.

21.

Demonstrating the performance of efflux pump inhibitor aids in enhancing the bioavailability of p-gp substrates while inhibiting the activity of the p-gp efflux pump.

Simultaneous administration of a lipidic or polymeric excipient with a drug influences the drug’s absorption to verify this concept. A study was conducted by V.S. Varma et al.; the aim of the study is to monitor the impact of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) on the solubility and permeability of paclitaxel, a BCS class IV drug. TPGS was found to provide the efflux pump inhibition of P-gp at a minimum conc. of 0.1 mg/mL and is likely to increase the apical to basolateral permeability (A-B). Moreover, the solubility of the given drug was also enhanced. This conc. of TPGS has shown the concentration-dependent response on the drug’s permeability, as the highest permeability of the drug was observed at this concentration. The plasma drug concentration in rats was enhanced by coadministration of TPGS at an oral dose of 50 mg/kg. Furthermore, a 6.3-fold bioavailability was enhanced with simultaneous administration of TPGS with paclitaxel. It was concluded that the coadministration of TPGS is suitable to improve the oral bioavailability of poorly soluble and permeable drugs.

In another study, two drugs, paclitaxel (PXT) and docetaxel (DXT), which are termed as taxanes, were loaded into a self-microemulsifying drug delivery system (SMEDDS) and concurrently used with the P-gp inhibitor elacridar (GF120918). To evaluate the permeability, an in vitro model of intestinal epithelia was designed. In Coca-2 cell studies, it was analyzed that the PXT-loaded SMEDDS with the P-gp inhibitor showed a 4-fold increase in permeability, while DXT with the same aforementioned combination exhibited a 9-fold improvement permeability.

4. Conclusion

Different drug formulations have been designed to enhance patient compliance, reduce dose frequency and toxicity, and improve therapeutic effectiveness. To attain these benefits, formulators used various techniques to resolve the issues regarding stability, solubility, permeability, and reduced bioavailability. In traditional approaches, solubility-related issues have been mentioned along with their solutions, which indicates that solubility has a great impact on product development. Moreover, emerging strategies mentioned the nanodrug delivery system. Nowadays, nanodrug delivery systems are considered as a promising approach to overcome biopharmaceutical challenges, as mentioned in various techniques. It is now possible to resolve bioavailability-related issues in a more appropriate manner and commercialize the product effectively to promote patient compliance.

In terms of future perspectives, further research should be conducted to correlate the in vitro and ex-vivo studies data to the appropriate in vivo model. So, the formulators could analyze the strength of emerging delivery strategies in a more relevant way. Moreover, commercialization of these strategies is important to overcome the limitations and also to improve the treatment costs, as any agent with poor solubility and permeability faces problems getting into the actual market. Emerging nanodrug delivery designs give some promising concepts toward better patient health and compliance.

The authors declare no competing financial interest.