Alqahtani 2021

REVIEW
published: 19 February 2021

doi: 10.3389/fphar.2021.618411
Advances in Oral Drug Delivery

Mohammed S. Alqahtani 1,2*, Mohsin Kazi 1, Mohammad A. Alsenaidy 1,2 and
Muhammad Z. Ahmad 3
1
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, 2Nanobiotechnology Unit,
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, 3Department of
Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
The oral route is the most common route for drug administration. It is the most preferred
route, due to its advantages, such as non-invasiveness, patient compliance and
convenience of drug administration. Various factors govern oral drug absorption
including drug solubility, mucosal permeability, and stability in the gastrointestinal tract
environment. Attempts to overcome these factors have focused on understanding the
physicochemical, biochemical, metabolic and biological barriers which limit the overall drug
bioavailability. Different pharmaceutical technologies and drug delivery systems including
nanocarriers, micelles, cyclodextrins and lipid-based carriers have been explored to
enhance oral drug absorption. To this end, this review will discuss the physiological,
and pharmaceutical barriers influencing drug bioavailability for the oral route of
administration, as well as the conventional and novel drug delivery strategies. The
challenges and development aspects of pediatric formulations will also be addressed.
Keywords: nanoparticles, lipophilic, stomach, oral drug delivery, biodegradable, solubility
Edited by:
Weien Yuan,
Shanghai Jiao Tong University, China ORAL DRUG DELIVERY
Reviewed by:
Oral medication is the most common form of drug administration because of advantages such as
Urjita Sheth,
Uka Tarsadia University, India
convenience of drug administration via the oral route, patient preference, cost-effectiveness, and ease
Amit Kumar Nayak, of large-scale manufacturing of oral dosage forms. Around 60% of established small-molecule drug
Seemanta Institute of Pharmaceutical products available commercially are administered via the oral route. Current estimates indicate that
Sciences (SIPS), India oral formulations represent about 90% of the global market share of all pharmaceutical formulations
*Correspondence: intended for human use. Around 84% of the best-selling pharmaceutical products are orally
Mohammed S. Alqahtani administered and are currently valued at $35 billion, with an annual growth rate of 10% (Prasad
msaalqahtani@ksu.edu.sa et al., 2017).
The compliance of patients to oral formulations is generally higher than that to other parenteral
Specialty section: routes such as intravenous, subcutaneous, and intramuscular injections, as well as to inhalation for
This article was submitted to asthma medications (Ingersoll and Cohen, 2008). Furthermore, orally administered drugs can be
Translational Pharmacology, targeted to particular regions within the gastrointestinal (GI) tract for localized treatment of
a section of the journal
pathological conditions such as stomach and colorectal cancers, infections, inflammations, bowel
Frontiers in Pharmacology
diseases, gastro-duodenal ulcers, and gastroesophageal reflux disorders (Figure 1).
Received: 16 October 2020
Despite these advantages, the development of oral formulations presents several challenges, which
Accepted: 11 January 2021
are mainly attributed to the physicochemical properties of drugs, including poor water solubility and
Published: 19 February 2021
membrane permeability. In addition, the absorption of drugs can be limited by their poor chemical
Citation:
and biological stability, as well as by physiological barriers, including pH, efflux transporters, and
Alqahtani MS, Kazi M, Alsenaidy MA
and Ahmad MZ (2021) Advances in
metabolic enzymes. Further, some drugs can cause local irritation and nausea (Rubbens et al., 2018).
Oral Drug Delivery. Over the last four decades, numerous studies have focused on understanding the mechanism of drug
Front. Pharmacol. 12:618411. absorption and transport, intestinal transit, microenvironment of the GI tract, and drug stability in
doi: 10.3389/fphar.2021.618411 the GI fluids (Daugherty and Mrsny, 1999; Reix et al., 2012). Thus, the elaboration of oral drug
Frontiers in Pharmacology | www.frontiersin.org 1 February 2021 | Volume 12 | Article 618411

Alqahtani et al. Advances in Oral Drug Delivery
are intercalated with enterocytes and joined by zonula occludens

or tight junctions, are present at their apical surface. The tight
junctions are mainly accountable for the passage of hydrophilic
molecules via paracellular route. The epithelium on the apical
surface projects with the lamina propria to form villi that contain
microvilli. About 3,000–7,000 microvilli per cell in the small
intestine provide a large surface area for drug interaction and
absorption (Zhuu et al., 2017). Although the structures of the
microvilli remarkably increase the surface area for absorption in
the small intestine, they additionally provide an enzymatic barrier
since their brush border is concentrated with digestive enzymes
(Zupančič and Bernkop-Schnürch, 2017).
Absorption of drugs from the lumen of the GI tract requires
their passage through multiple layers including gastric juice,
pericellular matrix, and mucous rich layer, to reach the
epithelium, mucosa, and blood or lymph capillary walls.
Therefore, bioadhesive drug delivery systems often exhibit
improved performance compared to matrix tablets.
Bioadhesive microspheres can diffuse into the mucous gel
layer because of the small size of the nanocarriers and show a
FIGURE 1 | Schematic diagram of the gastrointestinal tract showing the prolonged gastric residence time (Vasir et al., 2003). The
major regions for drug absorption denoted in red color. GI tract diagram by maintenance of a bioadhesive system in the stomach for an
Olek Remesz (https://commons.wikimedia.org/wiki/File:GISystem.svg),
extended time facilitates the treatment of both local diseases as
under a Creative Commons license.
well as prolonged drug absorption for systemic delivery.
Another factor that influences drug absorption is the pH of
the GI fluid. In the fasting state, the stomach pH varies, and the
delivery systems necessitates a thorough understanding of the median basal pH for adult males is 2.18 ± 0.18 (Goldschmiedt
physicochemical properties, GI permeability, biological barriers, et al., 1991). Thus, drugs with poor stability under acidic pH
pharmacokinetics, and pharmacodynamics of drugs. need to be protected in the stomach. Pepsin, which plays an
important role in digesting most of the ingested proteins, is
Biological Barriers active at acidic pH, but is promptly inactivated above pH 4
Most orally administered medications are primarily absorbed by (Rouge et al., 1996). Thus, a sufficient amount of pH-
the duodenum and jejunum in the upper parts of the GI tract. The increasing buffer that raises the local stomach pH to values
drug absorption ability of the stomach is less than that of the above 4 can deactivate pepsin. Enteric polymer coatings such
intestine because of the smaller surface area and thicker mucus as acetate phthalate and methacrylate-based polymers can be
layer (thickness, 1.5 mm) of the former (Table 1) (Mudie et al., used to protect drugs that are unstable under acidic pH
2010). The epithelial lining of the intestines is one of the major conditions of the stomach (Chen et al., 2000). Unlike the
barriers to drug absorption in the GI tract. Epithelial cells are stomach, the duodenum is a highly permeable region of the
arranged in a single-column layer, and the building blocks, which intestine with neutral pH (Zhu et al., 2017).
TABLE 1 | Physiological features of the human gastrointestinal tract.
GI tract Approx. Approx. pH Epithelial type Approx. Major enzymatic activities

region length surface residence
(m) area (m2) time
Oral cavity – 0.01 6.5 Stratified – Polysaccharidase

Squamous
Esophagus 0.2–0.25 0.02 – Stratified 4–8 s –
Squamous
Stomach 0.25 3.5 1.0–3.0 Secretory 1–3 h Proteases, lipases
Columnar
Duodenum 0.35 1.9 4.0–5.5 Simple columnar 30–40 min Polysaccharidase, oligosaccharidases, proteases, peptidases,
lipases
Jejunum 2.8 184 5.5–7.0 Simple columnar 1.5–2.0 h Oligosaccharidases, peptidases, lipases
Ileum 4.2 276 7.0–7.5 Simple columnar 5–7 h
Colon 1.5 1.3 7.5–8.0 Columnar 16–35 h Broad spectrum of bacterial enzymes
dominated
Rectum 0.12 – 7.0 Columnar –
dominated

The GI transit time is also important for developing an oral inhibition of cytochrome P450 3A4 (CYP3A4) enzyme has
dosage form. In humans, the transit time of drug dosage forms been associated with the drug transport and metabolism
through the small intestine is constant with a universally accepted inhibition effect of these juices. Further, some components
value of 3 h and is independent of the physical characteristics of such as flavonoids and furanocoumarins in some of these
the dosage forms, such as density and size, as well as of food juices inhibit P-glycoprotein (P-gp) and organic anion
(Dressman and Reppas, 2016). However, the gastric transit time is transporters (Guo et al., 2000).
known to vary and so does the drug bioavailability. This As drugs travel throughout the GI tract, they have the potential
variability might eventually lead to unpredictable levels of to cross the mucous membranes of the GI organs including the
drug plasma and can severely limit the clinical efficacy. mouth, esophagus, stomach, duodenum, jejunum, ileum, and
Gastrointestinal movements are of two types: propulsive and colon. If they are not able to cross the membranes by the time they
mixing; they are mainly affected by the fed or fasted state as well reach the colon, they end up eliminated in the feces and will not
as the sleep cycle. The peristalsis motilities primarily determine be completely absorbed by the intestine. Following oral
the passage rate and thus, the residence time of a drug after oral administration, the dissolution of a drug starts when it comes
administration (Rouge et al., 1996). In humans, the intestinal in contact with the GI fluids, followed by the penetration of the
content has been shown to pass through the intestinal tract at a aqueous medium into the dosage form, which generally
rate of 3 cm/min (Said and Mohammed, 2006). The passage rate contributes in the disintegration of the solid dosage into fine
is higher in the upper parts of the intestinal tract and declines particles. The next step includes the mixing of the drug molecule
toward the ileum. A drug capsule requires 3–4 h to pass through into the dissolution medium. The dissolution process has been
the entire small intestine. However, the transit time is studied by Wagner (1970). Drug molecules in solution can cross
considerably greater in the large intestine and depends on the the mucosal membrane of the GI tract via several mechanisms
volume of fiber in the intake. In healthy humans, the route time that include passive diffusion or active drug transport. Passive
through the large intestine is estimated to be around 2 to 4 days diffusion involves two distinguished routes: the paracellular
(Read et al., 1980). The residence time in the intestine also route, in which drugs diffuse through the small pores at the
imitates the absorption of drugs that are poorly soluble or that tight junctions between the mucosal enterocytes; the transcellular
dissolve slowly in the intestinal fluids, as well as of the route, which involves lipophilic drug diffusion across the cell
pharmaceutical formulations that sustain the release of the membrane phospholipid of intestinal enterocytes. Active drug
drug. Furthermore, the transit or residence time is essential for transport is facilitated by cell membrane transporters and is
small drug molecules that are absorbed by transport carriers, as divided into active influx of drug and efflux pump. The
these drugs are favorably absorbed in the location with the highest significance of each mechanism is determined by the physico-
carrier density (Dressman and Reppas, 2016). For instance, chemical characteristics of drug molecules and their affinity for
vitamin B2 is absorbed mostly in the proximal small intestine different transporter proteins (Mannhold et al., 2009; Dahlgren
via sodium-dependent, carrier-mediated transport (Said and and Lennernäs, 2019).
Mohammed, 2006). Hence, influences that effect intestinal The transcellular route is the main pathway of absorption for
motility can impact the bioavailability of vitamin B2. Thus, the the smallest drug molecules. Overall, the absorption via the
extent of drug absorption after oral administration is directly transcellular route is basically due to diffusion down a
affected by the GI residence time (Sakr, 1999). concentration gradient, and the rate of absorption is primarily
Food can influence the absorption of drugs: it can decrease, determined by the rate of drug transport across the intestinal
increase, delay, or accelerate drug absorption (Custodio et al., membrane, which is dictated by the physico-chemical properties
2008). Food affects the GI functions such as gastric emptying, of a drug. However, in the paracellular pathway, nonionized
intestinal transit time, bile acid secretion, stomach pH change, lipophilic drugs with molecular weight of more than 300 g/mol
and liver blood flow increase. Further, it can alter the are absorbed via the transcellular pathway. In addition, the
physiochemical characteristics of drugs, such as solubility, hydrogen-bonding capability of the drugs dictated by the
intestinal permeability, size, and dissolution profile. In general, number of hydrogen bond donors and acceptors should be
hydrophobic drugs or drugs with solubility that is pH-dependent less than 10 and 5, respectively (Lipinski, 2000; Avdeef, 2001).
are mainly manipulated by the co-administered food (Cheng and In paracellular transport, drug molecules are absorbed by
Wong, 2020). It is known that, high-fat meals increase the diffusion and convective volume flow through aqueous
concentrations of the pancreozymin (cholecystokinin), which intercellular spaces (Hayashi et al., 1997). In common, drugs
stimulates gallbladder secretion of bile within the GI tract. that are absorbed via this route are small hydrophilic molecules
This leads to the formation of solubilizing micellar carriers, with molecular weight less than 200 g/mol. Moreover, since the
which can assist in the solubilization of drugs and their junctional complex of the intestinal epithelium has an overall
absorption from the lumen of the GI tract (Shneider, 2001). negative charge, cationic molecules pass through more freely
Certain fruit juices are known to either affect the transport and (DiMarco et al., 2017). Nevertheless, absorption via this pathway
metabolism of drugs or enhance the extent of drug absorption is mostly low as the tight junctions between cells with a pore
(Ameer and Weintraub, 1997). The effects of grapefruit juice have diameter of 4–8 Å limit free trans-epithelial passage of most drug
been extensively studied, although studies on other juices, molecules across the intestinal membrane. In addition, the
including orange, tangerine, lime, and apple, have been paracellular transport represents around 0.1–0.01% of the total
performed. From the perception of drug metabolism, the surface area of the intestinal membrane and becomes less

accessible from the jejunum toward the colon, thereby providing TABLE 2 | The biopharmaceutics classification system.
only a limited window for drug absorption (Sugano et al., 2002). Class I Class II
Unlike passive diffusion of drug, carrier-mediated transport
requires the interaction of drug molecules with a protein carrier, High solubility Low solubility
High permeability High permeability
usually in the apical membrane of the enterocyte cells. Several
Class III Class IV
transporters belonging to the adenosine triphosphate (ATP) High solubility Low solubility
binding cassette transporters (ABC transporters) superfamily Low permeability Low permeability
and solute carrier (SLC) transporters are expressed in the
apical and basolateral membranes of the GI tract for the influx
or efflux of endogenous substances and xenobiotics. The cytosol and depends on drug properties such as polarity, charge,
absorption via this pathway is an energy-consuming process and lipophilicity (Lennernäs, 2007). A drug is known to be highly
requiring ATP hydrolysis and can occur against a permeable if the percentage of absorption is ≥90% of the
concentration gradient, that is, from a region of lower drug administered dose. BCS Class I drugs have high solubility and
concentration to that of higher concentration. Although permeability and are good candidates for oral delivery.
diverse transporters are exhibited in the enterocytes, only a Conversely, other BCS classes are challenging candidates for
limited number of transporters are known to play an oral delivery owing to their low solubility (BCS Class II), low
important role in the intestinal absorption of drugs (Müller permeability (BCS Class III), or both (BCS Class IV). The oral
et al., 2017). For instance, ABC transporters superfamily absorption ability of BCS Class II drugs can be improved by
utilizes ATP to initiate the transport and are called primary increasing their dissolution rate.
active transporters. For example, methotrexate, a folic acid In addition to solubility and permeability, drug metabolism can
antagonist, was found to be absorbed via the ABC-dependent, also influence their oral bioavailability. Hence, Wu and Benet
proton-coupled folate transporter/heme carrier protein 1 in the proposed the Biopharmaceutics Drug Disposition Classification
proximal small intestine (Yokooji et al., 2009). Conversely, SLC System (BDDCS) (Wu and Benet, 2005). The BDDCS provides
transporters mainly use the ion gradients (hydrogen, calcium, understandings into the effects of diet on drug absorption and
and sodium ion gradients) created within the cellular membrane information on the interplay between drug absorption,
by primary active carriers (Na+/K+-ATPase and Na+/H+-ATPase) elimination, and transport. According to the BDDCS, drug
(Tsuji and Tamai, 1996). ABC transporters distributed and permeability is influenced by the major route of elimination.
expressed in the intestinal epithelium include permeability Class 1 BDDCS drugs, which have high solubility and are
glycoprotein (P-gp), breast cancer resistance protein (BCRP), considerably metabolized, are not expected to display significant
and multidrug resistance (MDR) proteins. P-glycoprotein 1, transporter drug interactions. Thus, high-fat meals should have no
BCRP, MDRP2, and MDRP4 are expressed on the apical side significant effect on the extent of the bioavailability of such drugs.
of the membrane, whereas specific MDRPs are localized on the However, high-fat meals delay stomach emptying and reduce
basolateral membrane of the absorptive epithelial cells. These absorption and thus increase the Tmax (Custodio et al., 2008).
membrane transporters functionally minimize the cellular levels Class 2 BDDCS drugs, which are poorly soluble and highly
of their substrates by decreasing uptake and enabling the efflux metabolized, might be subjected to significant transporter
pump. By contrast, the facilitated drug absorption involves a effects, mainly efflux transporter effects, due to their insolubility.
protein carrier but does not involve energy. The drug Therefore, high-fat diets might increase their bioavailability owing
concentration gradient, as in passive diffusion, is the main to the inhibition of efflux pump such as P-gp transporters in the
driving energy for this absorption pathway. The common intestine. Dosage form changes that significantly increase the
examples of facilitated absorption are the intestinal uptake of solubility of BDDCS class 2 drugs might decrease or eliminate
glucose, folate, and vitamin B12 (Steffansen et al., 2004). the effect of high-fat meals and mostly minimize other drug
transporter interactions. Class 3 BDDCS drugs are known to be
Physicochemical Barriers more vulnerable to the effect of uptake transporters owing to their
The absorption of drugs in the GI tract require their release from low permeability. Fatty diets can reduce the bioavailability of these
the dosage form; the released drug dose need to be in a solution drugs owing to the inhibition of intestinal uptake transporters.
form or should have the ability to dissolve in the GI fluid. Further, However, if a drug is a substrate for transporters (influx or efflux),
the dissolved drug must be permeable through the intestinal the main effect will depend on the degree of transporter inhibition,
membrane. Therefore, the aqueous solubility and intestinal as well as on the substrate’s relative affinity for the transporters.
epithelial membrane permeability of drugs are the critical This can result in either an unpredicted increase in the drug
determinants of GI absorption; these criteria form the basis bioavailability or no effect (Dressman and Reppas, 2016). For
for the classification of drugs into four categories by the class 4 BDDCS drugs, predicting the effect of a high-fat meal
Biopharmaceutical Classification System (BCS; Table 2) on drug absorption is difficult, as a combination of interactions of
(Amidon et al., 1995). In the BCS, the solubility criteria are both class 2 and 3 compounds is possible. Conversely, when fatty
based on the highest dose strength that can dissolve in a glass of diet effects appear, they are mostly exhibited by an increase in the
water (250 ml; volume) or less of aqueous media over a pH range drug bioavailability, resulting from the combination of enhanced
of 2–7.5. (Yu et al., 2002). Permeability is often referred to as the solubilization of a drug in the GI, as well as the inhibition of efflux
diffusion across the apical membrane of enterocytes into the transporters.

TABLE 3 | Factors that affect drug absorption from the gastrointestinal tract.
Physiological factors Physicochemical factors Formulation factors Miscellaneous
I. Physiology of GIT i. Drug stability in the GI fluid i. Solutions i. Age

a. pH of various segments ii. Ionization constant ii. Suspensions ii. Gender
b. Esophageal transit time iii. Lipophilicity of the drug iii. Capsules iii. Smoking and Alcohol abuse
c. Esophageal motility iv. Drug solubility iv. Tablets iv. Other drug use
d. Presence or absence of food v. Crystal properties v. Coated tablets
II. Mode of transport across the GI tract vi. Dissolution rate
a. Passive diffusion vii. Salt form
b. Active transport viii. Protein binding
III. Metabolism ix. Complex formation
x. Adsorption
Metabolic and Biochemical Barriers This mechanism limits the bioavailability of many drugs (Gibson
Intestinal metabolism is normally triggered by digestive enzymes and Skett, 2001). Moreover, it can lead to drug-drug interactions,
secreted by the pancreas, such as lipases; amylase; and peptidases, especially when drugs are made to inhibit P-gp or CYP3A4
including chymotrypsin and trypsin, as well as those that are (Thummel, 2007). The main factors that affect drug
originated from the intestinal flora of the colon found mainly absorption after oral administration are summarized in Table 3.
within the lower part of the GI tract. In addition, the first-pass
metabolism, which includes intracellular and brush-border Strategies to Improve Oral Drug Delivery
metabolism, occurs on the enterocyte surface by enzymes Development of oral formulations for drugs with poor aqueous
present within the membrane of the brush border. Brush- solubility requires the understanding of barriers. Drug solubility
border metabolism occurs mainly in the small intestine. is a key element of the low oral bioavailability of hydrophobic
Isomaltase, alkaline phosphatase, sucrose, and other peptidases drugs (Boyd et al., 2019). Other factors related to low
contribute to the brush border metabolism (Barthe et al., 1999). bioavailability of hydrophobic drugs are food effect, gastric
First-pass metabolism might limit oral absorption. irritation, slow onset of action, lack of dose proportionality,
Intracellular metabolism occurs in the enterocytes and mainly and high intra- and inter-subject variability (Singh and Kim,
involves phase-I metabolizing enzymes, including cytochrome 2002). Therefore, many approaches are utilized to improve the
P450 enzymes such as CYP3A4; several phase-II conjugating aqueous solubility of drugs (Table 4). Formulation
enzymes associated with reactions such as sulfation and considerations such as surfactant selection, particle size
glucuronidation; and other enzymes such as esterases (Gibson reduction, and salt selection need to be carefully screened to
and Skett, 2001). Although the intestinal epithelium is a site for develop formulations of poorly soluble drugs. Traditionally, a
pre-absorptive metabolism, it can act as a major site for the combination of surfactants has been utilized for improving the
delivery of ester-type pro-drugs such as aspirin (Thummel et al., oral absorption of drugs (Wong et al., 2006). Surfactants contain a
1997). In addition to the intestinal epithelium, hepatic first-pass hydrophilic head and hydrophobic tail, in which both the
metabolism represents the major metabolic barrier. hydrophilic and lipophilic groups help the drug molecules in
Membrane transporters can be categorized into two types: localizing at the interface, thereby diminishing the interfacial
uptake and efflux transporters; they facilitate the transport of tension. Surfactants improve the bioavailability of drugs via
drugs and endogenous compounds out or into the cells. Thus, several mechanisms, which include enhancing the solubility
membrane transporters are important determinants for oral drug and permeability of drugs by momentarily opening tight
absorption, disposition, and bioavailability (Shugarts and Benet, intracellular junctions. However, the use of surfactants at
2009). The main uptake transporters that enable xenobiotic higher concentrations can become a safety concern and
transport of drugs into the cells belong to the solute carrier requires careful consideration (Lawrence, 1994). Other
(SLC) superfamily, whereas the efflux transporters belong to the techniques such as micro/nanonization can also improve the
ABC superfamily (Giacomini et al., 2010). In the liver and bioavailability of drugs to a remarkable extent (De Villiers et al.,
intestine, efflux transporters, including bile salt export pump 2008; Liu, 2018). In these techniques, the particle size of
(BSEP), Pgp, MRP1-6, and BCRP, are highly expressed. Most of pharmaceuticals is reduced considerably, which in turn
these membrane transporters utilize ATP to pump substrates increases their surface area and subsequently the dissolution
against a concentration gradient. In the small intestine and largely rate. A brief summary of the formulation approaches for
in the colon, P-gp is mainly located in the brush border surface of various BCS class drugs is shown in Table 5.
enterocytes where it acts as a defense barrier against exogenous
compounds. Furthermore, CYP3A4 is co-localized with P-gp in Salt Formation
mature enterocytes and has overlapping substrate specificity Salt formation is the common conventional method for
(Watkins, 1997). Thus, most of substrate drugs might be enhancing the oral absorption of weakly acidic and basic
metabolized by pumping them out of the enterocytes into the drugs (Serajuddin, 2007). In general, salts of weakly acidic and
lumen via P-gp before they can be reabsorbed again into the cells, basic drugs have higher solubility than their corresponding pure
thereby prolonging their exposure to CYP3A4 (Watkins, 1997). forms. Among the salt forms approved by the Food and Drug

TABLE 4 | Different strategies to enhance the aqueous solubility of drugs.
Frontiers in Pharmacology | www.frontiersin.org
Alqahtani et al.
Type Advantages Limitations References
Crystal Metastable polymorphs Minimal amounts of surfactants and polymers are required for Challenges in drug/polymer miscibility, excipients compatibility (Blagden et al., 2007; Varshosaz et al., 2018)
engineering Co-crystal formation stabilization. High drug loading and high energy systems that are for a chosen drug. Physical instability upon storage
beneficial in drug dissolution
Chemical Pro-drug formation Improved drug solubility, lipophilicity, transporter-mediated Limitations in prodrug screening and development. (Mueller, 2009; Sanches and Ferreira, 2019)
modification absorption. The potential to achieve site-specific delivery Associated with a higher possibility for the formation of
degradation by-products and lack of chemical stability.
Disruption of solid-state crystallinity and polymorphism
Salt formation The most commonly applied technique to increase solubility and Restricted to weakly acidic or weakly basic drugs and is not (Serajuddin, 2007; Vioglio et al., 2017)
the preferred approach for the development of liquid suitable for neutral drug compounds. Conversion of the drug
formulations. Enhanced the dissolution rate by increasing the salt back into its respective free acid or base forms in the GI
apparent intrinsic solubility of the drug. Ease of synthesis and fluid after oral administration. Limitations in salt screening and
low cost of raw material the selection of optimal salt forms
Particle size Micronization and nanosized Easy to scale up and time efficient. Reduced drug degradation Physicochemical-related stability issues such as aggregation (Miiller et al., 2002; Kesisoglou et al., 2007;
reduction drugs, e.g., NanoCrystal, because the drug is in the crystallin solid-state. Feasibility of or a change in the solid state of the drug. The excess use of Williams et al., 2013)
DissoCubes formulating a drug under different pharmaceutical dosage forms excipients as stabilizers which may change the drug
bioavailability and pharmacological activity. Bulking care is
essential particularly during handling and transport
Amorphization Solid dispersion Provided extra stability and protection of the drug during The high-energy amorphous drug tends to convert and (Leuner and Dressman, 2000; Savjani et al.,
formulation. Enhanced solubility and dissolution rate compared recrystallize to a low energy crystalline form. The miscibility 2012; Baghel et al., 2016)
with traditional crystal habit modification; it also retarded between the selected drug and polymeric matrices is required.
agglomeration/crystallization of drug molecules due to its Limited stability is a known drawback
molecular level dispersion and steric hindrance interactions
within the polymeric matrices
Solvent pH adjustment The simple and powerful strategy for solubility adjustment of The long-term effect on the drug stability. The distortion of (Strickley, 2004; Jouyban, 2008; Vemula et al.,
composition ionizable drugs. The drug candidate is ionized to a degree that physiological pH. The precipitation tendencies and 2010)
6
allows complete solvation of the target drug dose. This incompatibility upon dilution
approach applies equally to drug salts or the corresponding free
acid or free base drugs
Co-solvent Provided the optimum solubility for nonpolar drugs by reducing The use of co-solvents is limited to relatively few solvents. The
solvent polarity. The presence of a cosolvent can provide risk of precipitation upon dilution. It may alter the pH and
additional solubilization for drug solutions where pH strength of the buffers that are contained in a drug formulation
manipulation is insufficient
Drug carrier Micelles Its hydrophobic core acts as a reservoir for lipophilic drugs. Ease Disintegration of micelles due to their dilution after oral (Yano et al., 2010; Keskin and Tezcaner, 2017;
systems of chemical modification and can be stimuli-responsive administration, in vivo instability below the critical micelle Zhang et al., 2017)
concentration. Low drug loading
Nanoparticles Increased solubility of lipophilic drugs, enhanced drugs stability, Challenges in biocompatibility and safety of polymeric carriers. (Merisko-Liversidge et al., 2003; Hu et al., 2004;
sustained drug delivery, shielding of the drug cargo from Toxicity as a result from high tissue accumulation of non- Merisko-Liversidge and Liversidge, 2008)
enzymatic activity, prolonged retention in the gastrointestinal biodegradable NPs. Difficulties in optimizing the process
February 2021 | Volume 12 | Article 618411
tract, improved mucoadhesiveness, overcoming multidrug parameters and to scale up the production into a
resistance, the potential for targeting specific cells and uptake pharmaceutical product
via M cells
Cyclodextrins Generally recognized as safe (GRAS) excipient. Suitable for the The requirement for a large amount of cyclodextrin compared (Hirayama and Uekama, 1999; Brewster and
generation of supersaturated drug solutions. Enhance both the to the drug to solubilize the drug. The weak binding and Loftsson, 2007; Kim et al., 2020)

physical and chemical stability of drugs and their shelf-life dissociation of complexes upon dilution in the GIT. The intact
drug/CD complexes are unable to permeate the lipophilic
epithelium membranes which may result in low bioavailability
especially for BCS class III drugs
Lipid-based formulations (SLN, Non-immunogenic, biocompatible, can stimulate the secretion Poor stability and short shelf life (Pouton, 2000; Ahn and Park, 2016; Menzel
liposomes, SEDDS) of bile salts, phospholipids and cholesterol, which form vesicles et al., 2018)
and micelles that then facilitate drug absorption, scalable and
easily manufacturable
TABLE 5 | Formulation approaches for various BCS class drugs.
Solubility Permeability BCS % of marketed Formulation approaches

class drugs
High High I 35 Conventional capsule or tablet

Low High II 30 Nanotechnologies, micronization, self-emulsifying and microemulsifying systems, solid dispersions,
surfactant-based formulations, complexation with β-cyclodextrins, and adsorption onto hydrophilic inert
carriers or ion-exchange resins
High Low III 25 Absorption and permeability enhancers, lipid-based formulations, and ion-pairing approach
Low Low IV 10 Combination of approaches for classes II and III
Administration (FDA), hydrochloride and methanesulfonate microflora to achieve site-specific drug delivery (Schacht et al.,
(mesylate) are the most common ions for basic drugs, whereas 1996). Approximately 7% of the marketed drugs are estimated to
sodium and calcium are the most common ions used for acidic be prodrugs (Rautio et al., 2008). Lipophilic esters are the most
drugs (Lam et al., 2010). The pH solubility profile can be used to commonly used for oral prodrugs; they can enhance drug
increase the aqueous solubility of a drug by adjusting the pH. absorption by improving membrane permeability and
Furthermore, the capability of a salt to alter the overall medium absorption via the lymphatic route (Charman and Porter,
pH is especially important because the micro-environmental 1996). Some representative examples of oral prodrugs are
conditions in the diffusion layer have been shown to represent listed in Table 6.
a critical role in enhancing the dissolution rate of drug molecules
(Yang et al., 2014). A basic drug with a higher pKa, maximum Solid Dispersions
intrinsic solubility, and lower salt solubility has been shown to Solid dispersion indicates the dispersion of one or more drugs in
favor salt formation under increased pH; in contrast, for an acidic an inert excipient or matrix, in the solid form. It is usually
compound, lower pKa and increased intrinsic solubility yield a prepared using the melting (fusion), solvent evaporation, co-
lower pH, thereby increasing the possibility for salt formation. precipitation, melting–extrusion, or spray drying method
Nevertheless, an error and trial process is required to identify and (Serajuddin, 2018). Solid dispersions are generally formulated
select the most suitable salt form for drugs. using a hydrophilic polymer and a poor water-soluble drug. In
solid dispersions, the physical state of the active pharmaceutical
Chemical Modification ingredient is notably transformed from the crystalline to
A prodrug is a chemical derivative of a main drug; it needs to amorphous state (Serajuddin, 1999). Solid dispersions of
undergo enzymatic biotransformation in the body to convert to drugs in an amorphous state are rarely eutectic and thus
an active drug. The prodrug approach is a common chemical remain metastable and thermodynamically active, leading to
modification to improve drug properties, including aqueous their supersaturation in the GI fluid. This leads to a greater
solubility, lipophilicity, stability, mucosal membrane concentration gradient and thus increased dynamic force for
permeability, and therapeutic index. The most common drug transport across the cellular membrane. Moreover, the
prodrug types include ester, amide, carbonate, carbamate, azo, dissolution rate and bioavailability of solid dispersions of poorly
glucuronidic, and glycosidic bonds. In addition, polar moieties water-soluble drugs are considerably higher because of the
such as polyethylene glycol (PEG) are commonly included in increased surface area and wettability owing to the reduced
drug molecules (Greenwald et al., 2000; Basit et al., 2001). particle size. This approach can be used for BCS class II drugs
Paclitaxel is BCS class IV drug with insolubility and poor that have dissolution rate-limited absorption. The melting
permeability; is absorption following oral administration was method is commonly used for developing scalable quantities
increased by PEGylation. The improvement of the oral of pharmaceutical formulations, but it is not applicable to
absorption of a PEGylated prodrug is partially attributed to thermolabile compounds (Serajuddin, 2018). Common
the bypass of P-gp efflux pump and cytochromes P450 pharmaceutical excipients suitable for solid dispersions
metabolism (Choi and Jo, 2004; Hussain et al., 2019). In include cellulosic compounds such as hydroxypropyl cellulose
addition, the inhibitory activity of efflux pump by several (HPC) or hydroxypropyl-methylcellulose, PEG,
conjugates such as PEG-based detergents have been reported polyvinylpyrrolidone, polyvinyl alcohol, and crospovidone
(Veronese and Pasut, 2005). Among these detergents, polysorbate (Serajuddin, 1999; Newman, 2015). The bioavailability of
(Tweens) and tocopheryl poly(ethylene glycol) succinate 1,000 orally administered cyclosporine A (CsA), a BCS class II
(TPEGS 1000) are the most commonly used in oral drug delivery. drug, was improved by preparing its solid dispersion
The prodrugs should be inert, nontoxic, and metabolizable. The formulation using the wet-milling method and HPC
prodrug design can improve the oral bioavailability of drugs by hydrophilic polymers. The amorphous solid dispersion of
enhancing their water solubility and gastrointestinal permeability CsA showed significant increase in the Cmax and AUC to
and overcoming first-pass metabolism. Prodrugs can improve the about 5-fold, leading to enhanced therapeutic efficacy in
carrier-mediated absorption of charged or polar drugs with inflammatory disease treatment and organ transplantation
negligible passive absorption (Shah et al., 2020). Further, they (Onoue et al., 2010) A representative list of commercially
can target specific bioactivation mechanisms or colon bacterial available oral solid dispersions is shown in Table 7.

TABLE 6 | Representative examples of prodrugs used for oral drug delivery.
Prodrug type Oral application Commercial examples

®
Esters Enhancing aqueous solubility Etoposide phosphate (Vepesid )
®
Oxides Sulindac (Clinoril )
® ® ®
Esters Improving lipophilicity and intestinal permeability Enalapril maleate (Vasotec ), Ramipril (Altace ), olmesartan medoxomil (Benicar )
®
Ester salts Carrier-mediated absorption Valacyclovir (Valtrex )
®
Amides Midodrine (Amatine )
®
Carbamates Gabapentin enacarbil (Horizant )
®
Azo prodrugs Colon-specific targeting Sulfasalazine (Azulfidine )
Drug Complexation pairing can compete with endogenous compounds such as sialic
Inclusion complex formation with drug molecules is another acid, bile acids, and phosphoglycerides (Varshosaz et al., 2018). In
approach to improve their aqueous solubility; it allows to control addition, most counter ions are not safe, which could cause
the release rates of lipophilic drugs; mask the taste of bitter drugs; membrane irritation and toxicity, particularly at higher doses.
and maximize the tolerance of oral drug formulations by Ion pairing by using naphthoic acid as a counter ion has been
minimizing the irritation of the drugs after oral administration used to deliver highly polar antiviral drugs (Miller et al., 2010). A
(Loftsson and Brewster, 1996). Moreover, it has the added study showed that itraconazole cocrystals with succinate, maleate,
advantage of improving the stability of drugs, especially esters, and tartrate behaved in a identical manner to the amorphous
by shielding chemically labile substances from potentially harsh form, however its solubility improved from fourth to twentieth
environmental conditions and reducing their enzymatic fold in comparison to that of the crystalline form of the drug
degradation, hydrolysis, or oxidation. Generally, cyclodextrins (Remenar et al., 2003).
are considered as potential carriers to improve oral delivery of
drugs, although other types of complexing agents for instance Absorption Enhancers
sodium benzoate, niacin, caffeinate, and salicylate can be used Various absorption enhancers are known to increase drug
(Loftsson and Duchêne, 2007). Cyclodextrins are chains of cyclic permeability in the intestine, especially for BCS class III drugs.
oligomers enclosing 6, 7, and 8 D-glucopyranose structures Compounds such as surfactants, cholesterol, glycerides,
named alpha, beta, and gamma-cyclodextrins, respectively. salicylates, bile salts,, and chelating agents are used as
Hydroxy-propyl chemical derivatives of β-cyclodextrin have absorption enhancers (Aungst, 2012). Most absorption
considerable higher aqueous solubility than the native enhancers increase the transport of hydrophilic drugs by
cyclodextrins. β-cyclodextrins are one of the potential altering their paracellular permeability (LeCluyse and Sutton,
complexing agents; their central hydrophobic cavity can be 1997). However, some absorption enhancers might cause
utilized to form inclusion complexes with nonpolar molecules. mucosal damage and systemic toxicity. Ethylene diamine
Thus, they increase the aqueous solubility of drugs that are tetraacetic acid (EDTA) is commonly used as a paracellular
slightly soluble or water-insoluble to boost their oral permeation enhancer to deplete calcium and magnesium in
bioavailability. At present, more than 85 different oral drug the tight junctions (Lemmer and Hamman, 2013). However,
formulations based on complexation are available in the strategies involving the modulation of the permeability of tight
market (Choudhury et al., 2018). junctions have safety concerns. Once tight junctions are opened,
not only drugs but also other toxic molecules can be transported
Ion Pairing (Co-Crystals) across the intestinal membrane. Conversely, transcellular
Co-crystals can be described as crystalline solids consisting of two promoters can increase the oral absorption of drugs primarily
or more molecular and ionic compounds held together by non- by fluidizing, solubilizing, or reorganizing the intracellular
covalent forces (Blagden et al., 2007). They might be considered phospholipids, causing the disruption of membrane integrity.
as the crystalline counterpart of solid dispersions. The formation Examples of such enhancers include tartaric acid, sodium
and sustenance of co-crystals in a supersaturated solution can salicylate, sodium caprate, and sodium caprylate.
enhance drug absorption and oral bioavailability (Kwei et al.,
1995). Orally consumed co-crystals act similar to a single unit and Metabolism and Efflux Pump Inhibitors
partition into the intestinal membrane as a hydrophobic unit. The co-administration of metabolism and efflux pump inhibitors
This approach involves the co-administration of an additional has been shown to overcome multidrug resistance and increase
concentration of a counter ion. The ionic compounds dissociate the oral bioavailability of drugs that are substrates of efflux
when diluted after administration in the GI medium. In principle, transporters such as P-glycoprotein, MRP2, and BCRP (Pang,
this strategy is simple and eliminates the need for chemical 2003). Recently, many excipients have been shown to modulate
modification or prodrug design. Ion pairs need to have desired the function of efflux transporters, such as polyethoxylated castor
characteristics such as high lipophilicity, sufficient aqueous oil (Cremophor EL), polysorbates (Tweens), poloxamers
solubility, biocompatibility, and physiological stability. The (pluronic P85), tocopherol polyethylene glycol 1,000 succinate
most commonly used counter ions are phthalic acid, succinic (TPGS 1000), and polyethylene glycol (PEG) (Murakami and
acid, and benzoic acid. However, these counter ions used for ion Takano, 2008). Recent studies on oral delivery have been focusing

TABLE 7 | Representative examples of solid dispersion formulations.
Technology Drug molecule BCS class Trade name Formulation Therapeutic use
Nanocrystal (wet media milling) Rapamycin II Rapamune Tablets Immuno-suppressant

Aprepitant IV Emend Capsules Antiemetic
Fenofibrate II Tricor Tablets Antilipidemic
Megestrol acetate II Megace ES Oral suspension Hormonal therapy
High-pressure homogenization Fenofibrate II Triglide Tablets Antilipidemic
Melt extrusion Verapamil HCL I Isoptin SRE Tablets Antihypertensive
Nifedipine II Adalat SL Capsules Antihypertensive
Troglitazone II Rezulin Tablets Antidiabetic
Melt adsorption Nifedipine II Afeditab Tablets Antihypertensive
®
Melt granulation (MeltDose technology) Fenofibrate II Fenoglide Tablets Antilipidemic
Tacrolimus II LCP-Tacro Tablets Immuno-suppressant
Spray drying Intelence IV Etravirine Tablets Antiviral
Itraconazole II Sporanox Capsules Antifungal
Nilvadipine II Nivadil Capsules Antihypertensive
Tacrolimus II Prograf Capsules Immuno-suppressant
Lyophilization Olanzapine II Zyprexa Tablets Antipsychotic
Ondansetron II Zofran ODT Tablets Antiemetic
Piroxicam II Proxalyoc Tablets Anti-inflammatory
on exploring the ability of pharmaceutical polymers to inhibit the Second generation P-gp inhibitors such as biricodar (VX-710) are
efflux pump activity (Werle, 2008; Dahlgren and Lennernäs, potent and selective, but have adverse pharmacokinetic
2019). Although the exact mechanism of P-gp inhibition is not interactions (Leonard et al., 2002). Several third generation
yet known, polymeric excipients might act via one or more P-gp inhibitors such as zosuquidar (LY3359797) and
mechanisms that include competing with the substrate-binding tariquidar (XR9576) have been developed and ongoing studies
site on the efflux transporter, altering the membrane lipid fluidity, being explored in clinical studies (Planting et al., 2005; Wang
protecting the drug while by-passing the efflux transporter, et al., 2014).
inhibiting the efflux pump ATPase activity, or directly acting
on the P-gp protein on the mucosal surface (Takano et al., 2006). Lipid-Based Formulations
Examples of P-gp substrates include cyclosporine A and Lipid-based formulations have been used for the oral
vancomycin hydrochloride formulated with TPEGS. These administration of drugs that are poorly soluble in water, such
studies indicate that the improved oral bioavailability of drugs as BCS classes II and IV drugs. Such formulations represent 3% of
administered with TPEGS might, in part, be attributed to the the total drug products available in the market (Hauss, 2013).
inhibition of P-gp pump (Dintaman and Silverman, 1999). In one Depending on their composition, size, and chemical
study, a formulation containing paclitaxel and TPEGS in 1:2 ratio characteristics, lipid-based systems can be further classified
led to 6-fold improvement in the oral bioavailability of paclitaxel into lipid solutions, lipid suspensions, emulsions, multiple
to approximately 32% in rats (Varma and Panchagnula, 2005). emulsions, micro- and nanoemulsions, self-emulsifying and
Mucoadhesive polymers such as dextran, chitosan, polycarbophil, self-micro-emulsifying systems, solid lipid nanoparticles, solid
and polyacrylic acid have been shown to affect the activity of lipid dispersions, niosomes, and liposomes. Lipid-based
intestinal protease enzymes, mainly trypsin, chymotrypsin, and formulations are an attractive approach for oral application
carboxypeptidases, which might be useful for the oral delivery of owing to their inherent biocompatibility, particle size
metabolically labile drugs as well as increase their residence time. versatility, scaling-up ability, and cost-effectiveness (Hauss,
The co-administration of grapefruit juice and ketoconazole was 2007). A representative list of lipid-based formulations
shown to reduce the pre-systemic metabolism by CYP3A4 marketed for oral administration is shown in Table 8. Most of
present in the intestinal enterocytes (Dresser et al., 2000). these formulations can be administered as liquid-filled hard
Similarly, the administration of erythromycin was found to capsules or tablets as well as oral liquids in the form of
increase the oral bioavailability of cyclosporine by selectively solutions or suspensions. Moreover, these dosage forms can be
inhibiting hepatic CYP3A4 metabolism. Even though this utilized for sustained- or immediate-release formulations. A
approach seemed to be effective, the co-administration of lipid-based carrier is effective for the oral delivery of small
metabolism inhibitors and dietary components such as hydrophobic molecules via several mechanisms. One of the
grapefruit juice might not likely be approved by the FDA and main mechanisms is to enhance the dissolution rate and
other regulatory agencies for routine clinical practice. Initially, solubility in the GI tract. The digestion of lipids is started in
drugs were not particularly developed to inhibit P-gp activity; the stomach by gastric lipases. Shear forces in the digestive tract
basically, they had other therapeutical properties, as well as a low and stomach emptying assist in the emulsification of the drug
affinity for transporters. For instance, the first-generation P-gp before emptying into the duodenum. Secretion of pancreatic
inhibitors such as verapamil (Nobili et al., 2006). However, most enzyme lipase together with its co-factor co-lipase facilitates
of these drugs were less specific and had more adverse effects. the breakdown of intake glycerides to diglycerides,

TABLE 8 | Representative examples of marketed oral lipid-based formulations.
Lipid-based formulation Drug molecule BCS class Trade name Therapeutic use
Solutions Dutasteride II Avodart (GlaxoSmithKline) Hyperplasia of prostate

Efavirenz II Sustiva (Bristol–Myers Squibb) Antiviral
Suspensions Clofazimine II Lamprene (Novartis) Leprosy
Isotretinoin II Accutane (Roche) Acne vulgaris
Progesterone II Prometrium (AbbVie) Hormone therapy
Bexarotene II Targretin (Ligand Pharmaceuticals) Antineoplastic
Tocopherol nicotinate – Juvela (Eisai) Hypertension, hyperlipidemia
Valproic acid I Convulex (Pharmacia) Antiepileptic
Ciprofloxacin IV Cipro (Bayer) Antibiotic
SEDDS Cyclosporine A II Sandimmune (Novartis) Immunosuppressant
Ritonavir IV Norvir (AbbVie) Antiviral
Saquinavir IV Fortovase (Roche) Antiviral
Lopinavir IV Kaletra (AbbVie) Antiviral
SMEDDS Cyclosporine A II Neoral (Novartis) Immunosuppressant
monoglycerides, and fatty acids. The existence of fatty diets in the derivatives such as stearic acid, oleic acid, hydrogenated castor
intestine also stimulates the gallbladder biliary secretions of bile oil, and glyceryl trimyristate have been developed to sustain the
salt, cholesterol, and phospholipids. Due to the presence of bile release of water-soluble drugs (Jannin et al., 2008). The sustained-
salt, the yields of lipid digestion are consequently assembled into a release formulations prepared as a semi-solid lipid matrix filled in
colloidal structure, including vesicles, mixed micelles, and hard gelatin capsules seem to prolong the absorption of drugs
micellar carrier. These carriers increase the solubilization of even under a fed state, which could be attributed to the delay in
the drugs in the intestine. Furthermore, the nature and the gastric emptying effect. Although lipid-based delivery systems
composition of the formulation (such as lipids, surfactants, co- have the potential as drug carriers, obtaining the overall
solvents, and complexation agents) as well as bile salts and consistency, including in physicochemical properties, drug
phospholipids contribute to the enhanced absorption (Hauss, encapsulation, drug-release kinetics, and particle size, is
2007; Savla et al., 2017). Thus, lipid-based formulations maintain difficult, especially with liposomes and solid lipid nanoparticles
a higher drug concentration gradient for facilitating the diffusion (Phan et al., 2014). Furthermore, the ability of lipids to
of drugs across the unstirred aqueous layer and then to the incorporate drugs differs in regard to their crystallization and
mucosal membrane. Interestingly, the co-administration of a polymorphism properties, which usually results in undesirable
fatty food has also been shown to provide similar advantages interactions and inconsistency (Parve et al., 2014). In addition,
to improve drug dissolution and bioavailability (McClements and the availability and range of lipid-based excipients is limited
Xiao, 2014). This also explains why most lipid-based (Dahan and Hoffman, 2008). Another major disadvantage of
formulations have reduced food effects compared to lipid-based systems is the physical and/or chemical instability
conventional oral formulations (Fatouros et al., 2007). Poorly issues, especially during long-term storage and handling.
water-soluble drugs administered using lipid-based systems can
be protected against enzymatic degradation. Interestingly, lipid- Polymeric Micellar Carriers
based carriers such as liposomes have been shown to be absorbed Drug solubility can be enhanced and drug precipitation after
in an intact state by pinocytosis across the epithelial membrane exposure to the GI environment can be avoided by incorporating
and occasionally through the lymphatic system (Lee, 2020). poorly soluble compounds in surface-active agents, known as
Lymphatic transport of lipophilic drugs (e.g., cyclosporine) copolymers. Micellar systems occur in dynamic equilibrium in
occurs mainly through the mesenteric lymph and can thus three systems in a surfactant solution: monomeric surfactant,
avoid the hepatic first-pass metabolism (O’Driscoll, 2002). In micellar aggregates, and surfactants adsorbed as a film at the
addition, pancreatic lipase digestion results in the breakdown of interface. Micellar carriers are formed when the concentration of
triglycerides into monoacylglyceride and free fatty acid molecules surfactant is above the critical micellar concentration (CMC)
that can interact with fatty acid transporters present on the apical (Ribeiro et al., 2018). Amphiphilic copolymers comprising of
membrane and mediate drug absorption. While the common hydrophobic and hydrophilic blocks freely associated into
forms of lipids such as cholesterol, phospholipid, and tocopherol micelles when dissolved in an aqueous environment. The
are absorbed via the chylomicron pathway, the majority of lipids hydrophobic domains of the copolymers form the core and
and lipid digestion products are absorbed via fatty acid the hydrophilic tails form the external shell of the micelles.
transporters (Porter et al., 2007). Recently, more evidence The lipophilic core serves as a container for loading lipophilic
suggests that lipid-based formulations inhibit the efflux drugs, whereas the corona stabilizes the interface between the
transporter P-gp (Sachs-Barrable et al., 2007). This might be hydrophobic drug and aqueous medium. Micellar carriers can be
beneficial for BCS class IV drugs that are substrates of the P-gp utilized to increase the solubility of lipophilic drugs by
transporter pump. In addition to improving the oral incorporating them in the micellar core (Gaucher et al., 2005).
bioavailability of BCS class II/IV drugs, several lipid Recently, amphiphilic block copolymers have been developed as

Frontiers in Pharmacology | www.frontiersin.org
Alqahtani et al.
TABLE 9 | List of nanocarrier applications in oral drug delivery.
Nano-system Composition Drug molecule Size (nm) Cell line/animal model Disease or targeted organs References
size (nm)
Dendrimers G3.5 PAMAM SN38 – Caco-2 cells and HT-29/female CD-1 Colorectal cancer metastases (Goldberg et al.,
mice 2011)
Ethylene diamine and Methyl acrylate SN38 camptothecin 13 CD-1 mice Oral chemotherapy of hepatic colorectal (Sadekar et al., 2013)
cancer metastases
PAMAM Short hairpin RNA 107–315 Tca8113 cells/BALB/c nude mice Oral cancer therapy (Liu et al., 2011)
Mic(Sadekar et al., Polyethylene oxide–polypropylene Paclitaxel 180 Female C57BL/6J mice Oral cancer therapy (Yoncheva et al.,
2013)e lles oxide–polyethylene oxide (PEO–PPO–PEO) 2012)
N-octyl-O-sulfate chitosan (NOSC) Paclitaxel Caco-2/SD rats Improved oral bioavailability (Mo et al., 2011)
Bovine β-casein Celecoxib, Paclitaxel 20 Human N-87 gastric cancer cells Rheumatoid arthritis, osteoarthritis, and (Bachar et al., 2012;
gastric carcinoma Shapira et al., 2012)
Tocopherol succinate glycol chitosan Ketoconazole 101 Caco-2 cell monolayer Improved oral bioavailability (Duhem et al., 2012)
conjugates
Mixed Micelles Pluronic copolymers and LHR conjugate Paclitaxel 140 MCF-7 cells Oral anticancer delivery system (Dahmani et al.,
2012)
Vesicles PLA-P85-PLA Insulin 178 OVCAR-3 cells/diabetic mice Oral insulin delivery (Xiong et al., 2013)
Liposomes Lecithins Curcumin 263 Sprague–Dawley (SD) rats Improved oral bioavailability (Takahashi et al.,
2009)
11
SLN lyceryl monostearate (GMS) Vinpocetine 70–200 Male Wistar rats Improved oral bioavailability (Luo et al., 2006)
Polymeric Chitosan and alginate Insulin 5–7 μm Male SD rats Diabetes mellitus (Zhang et al., 2011)
microspheres
Polymeric PLGA Cyclosporine 143 nm Male SD rats Improved oral bioavailability (Italia et al., 2007)
nanoparticles Silica Resveratrol 90 nm Caco-2 cell monolayer Enhanced the solubility, permeability and (Juere et al., 2017)
anti-inflammatory activity of resveratrol
encapsulated in NPs
Polymeric Chitosan and alginate Insulin 5–7 μm Male SD rats Diabetes mellitus (Zhang et al., 2011)
microspheres
Polymeric PLGA Cyclosporine 143 nm Male SD rats Improved oral bioavailability (Italia et al., 2007)
nanoparticles Silica Resveratrol 90 nm Caco-2 cell monolayer Enhanced the solubility, permeability and (Juere et al., 2017)
anti-inflammatory activity of resveratrol
encapsulated in NPs
February 2021 | Volume 12 | Article 618411
Multifunctional Galactose-modified trimethyl shRNA and siRNA 130–160 Caco-2 cells/tumor-bearing mice Targeted treatment of hepatoma (Han et al., 2014)
polymeric chitosan–cysteine conjugates with various nm
nanoparticles galactose grafting densities
Mannose-modified trimethyl chitosan- Tumor necrosis factor- 152.9 nm Caco-2 cells, RAW 264.7 (monocyte/ Treatment of systemic inflammatory (He et al., 2013)
α (TNF-α) siRNA

cysteine (MTC) conjugate macrophage-like cells)/ acute hepatic conditions
injury induced mice
Lectin-conjugated PLGA-NPs Betamethasone 475 nm TNBS-induced induced colitis mice Treatments of ulcerative colitis and (Moulari et al., 2014)
inflammatory bowel disease
TABLE 10 | List of patented formulations related to nanoparticles for oral drug delivery.
Patent number Assignee Invention References
WO2008073558A2 Johns Hopkins University, USA The invention provided new orally bioavailable smart NPs for delivery of poorly (Maitra et al., 2014)
soluble drugs, showing improved pharmacokinetics and bioavailability
WO2015057751A1 NanoSphere Health Sciences Investigation disclosed the composition and development method for (Kaufman, 2018)
Inc., USA nutraceuticals encapsulated within phospholipids-based NPs by emulsification
Method
US20120003306A1 NanoMega Medical Co., USA The report disclosed a protein/peptide delivery system composed of chitosan and (Sung et al., 2012)
poly-γ-glutamic acid (γ-PGA). The NPs were suggested to enhance the epithelial
permeability and thus are efficient for oral drug delivery
WO2004098564A2 University of Illinois, USA Reported the development of biodegradable NPs containing streptomycin with (Popescu and
high loading efficiency of 50% or higher for tuberculosis treatment. The NPs also Onyuksel, 2004)
can contain other aminoglycosides drugs, which are a known substrate for the
multidrug efflux P-glycoprotein (Pgp)
US7674767B2 Samyang Biopharmaceuticals Co., The invention described the compositions and preparation of orally administrable (Pai et al., 2010)
Korea NPs containing complexes of water-soluble drugs and counter-ion substances.
The NPs enhanced drug entrapping and resistance against lipases, thereby
increased drug absorption
WO2015023797A9 Northwestern University, USA The patent disclosed the development and evaluation of drug loaded (Thaxton et al., 2020)
nanostructures comprising an inorganic core and a lipid layer shell. The NPs
showed the potential in the treatment of cancer, vascular disease and infectious
disease
WO2014197640A1 South Dakota State University, USA Disclosed the composition and preparation method of core-shell NPs. These NPs (Perumal and Alqahtani,
comprising food grade proteins along with therapeutic agent suitable for 2015)
pediatrics
WO2007042572A1 Advanced In Vitro cell Technologies The invention described NPs comprising chitosan and heparin prepared by ionic (Pena et al., 2008)
S.A., Spain gelation method. The NPs were stable in gastrointestinal fluids and presented an
excellent in vivo effectiveness and bioavailability
CN102120781B China Pharmaceutical University, The invention related to the preparation of oral insulin NPs. The NPs mainly (Zhang et al., 2013)
China contained N-amino acid chitosan as a carrier and insulin for the treatment of
diabetes. The NPs were stable after oral administration with a better effect of
reducing blood sugar in vivo
US10420731B1 King Saud University, Saudi Arabia The invention disclosed the synthesis and preparation method of lignin NPs (Alqahtani et al., 2019)
crosslinked and stabilized by citric acid for oral administration. The NPs improved
the oral bioavailability of curcumin by increasing curcumin solubility, stability,
sustained its release, enhanced intestinal permeability, and inhibition of P-gp
mediated efflux
WO2011034394A2 JW Pharmaceutical Co., Korea The invention reported the preparation of oxaliplatin-loaded NPs using (Lee et al., 2016)
supercritical fluid gas technology for oral chemotherapy
WO2010015688A1 BioAlliance Pharma Co, USA The patent disclosed the composition and preparation method of (Bonnafous et al., 2011)
chemotherapeutic formulation containing polymer and cyclic oligosaccharide
capable of complexing and delivering anticancer drugs for effective cancer
treatments
solubility enhancers (Simões et al., 2014). Poloxamers surfactant to their accumulation in the liver, mainly in the absence of
series is one of the most commonly used block copolymers in adequate target antigens (Musacchio and Torchilin, 2019).
drug delivery. The CMC of these copolymers range from 10–5 to
10–8 M, whereas that of standard low molecular weight Polymeric Nanocarriers
surfactants range from 10–3 to 10–4 M (Kwon and Okano, The exponential development of nanotechnology has allowed the
1996). As micelles have the CMC of 10–6 M, their ability to development of new oral drug delivery systems. Numerous
withstand dilution than is greater than that of surfactants with natural or synthetic based polymers have been utilized to
low molecular weight. In one study, pH-sensitive micellar carriers prepare oral drug delivery systems. Some natural polymers
were used to enhance the oral bioavailability of a commonly used include dextran, chitosan, gelatin, and
hypercholesterolemia drug, fenofibrate by 15% compared to alginate, and the synthetic based polymers used as oral drug
that of its coarse suspension. The study showed that the delivery carriers include polylactide-coglycolide (PLGA),
micellar composition was important in determining the polylactide (PLA), polycaprolactone (PCL), polyglycolide,
desired drug release profile (Sant et al., 2005). Moreover, these polycyanoacrylate, and polyaziridine (Ritika et al., 2012). The
micellar systems can be chemically modified through the nanotechnology approach involves the formulation of drugs by
conjugation of antibodies on their side chains for improved using particles that are in the nanometer size range of
target specificity. It is worth noting that antibody-conjugated 10–1,000 nm. Nanocarriers can be prepared using many
micelles may undergo rapid clearance from blood circulation due methods that can be divided into two groups.

FIGURE 2 | Schematic representation of the drug absorption barriers and mechanisms of nanoparticle transport across the intestinal epithelium, which include
transcellular transport, receptor-mediated transport, and M-cell-mediated transport.
Top-down techniques: They are based on the reduction of the delivery of drugs are shown in Table 10. A continues knowledge
particle size of relatively large polymers into small particles; they of the mechanisms implicated in micro/nanocarriers uptake is
involve processes that apply high shear, ultrasonication, required for the design of novel nanocarriers and new-targeted
cavitations, homogenization, microfluidization, spray drying, systems for the oral route. A schematic representation of different
or milling (Pinto Reis et al., 2006). barriers to oral drug delivery and micro/nanocarriers uptake
Bottom-up techniques: They are based on the growth of mechanisms in the intestine are shown in (Figure 2). In
particles formed from individual particles; they are mainly general, particles or drugs reach the blood circulation when
known as phase separation methods. Examples include spray- they are absorbed via the enterocytes, whereas intact particles
freezing liquid, coordinated crystallization during freeze-drying, are delivered to the lymphoid tissue after being transcytosed via
and pharmaceutical technologies that are based on supercritical M cell uptake which occurs in the Payer’s patch (Brayden et al.,
fluid (de Waard et al., 2011). 2005). Nanoparticle uptake by enterocytes or M cells and stability
Reducing the particle sizes to the nanometer scale results in in the GI tract depend mainly on the particle size, surface
larger effective surface area, eventually enhancing the dissolution characteristics, molecular weight, and chemical composition
rate and solubility of drugs (Mei et al., 2013). Examples of (Kulkarni and Feng, 2013). For oral drug delivery, particle size
nanocarriers used for the oral drug administration are shown plays an important role because it influences particle adhesion
in Table 9. Polymeric nanocarriers can be used to deliver and interaction with the mucosal membrane and the drug-release
insoluble drugs, target the drugs to specific regions of the GI kinetics (Kulkarni and Feng, 2013; Alqahtani, 2017). Particles
tract, minimize food effect on drug absorption, facilitate having sizes below 50, 100–500 nm, and below 5 μm pass through
transcytosis of drugs across the mucosal membrane, and the GI barriers via paracellular channels, endocytosis by
permit receptor-mediated intracellular drug delivery (Mei enterocytes, and cellular uptake by M cells of the Peyer’s
et al., 2013; Ottenbrite and Kim, 2019). Another attribute that patch, respectively (Desai et al., 1996). Several studies have
makes micro/nanocarriers efficient oral drug carriers is that they indicated that the uptake of particles with size diameters of
can carry a wide array of agents for diagnosis and therapy, 100 nm is higher than that of larger particles in the rat GI
ranging from small molecules to peptides, proteins, and mucosa (Desai et al., 1996; Janer et al., 2014). Biodegradable
nucleic acids, and releasing them in a controlled manner. polymers used in drug delivery have many advantages over non-
Thus, polymeric nanocarrier-based drug delivery can enhance biodegradable polymers; the former are safe and undergo
the specificity, tolerability, and efficacy of therapeutic agents. complete degradation after drug release. For example, PLGA
Examples of patented nano-formulations employed for the oral nanoparticles degrade into lactic acid and glycolic acid via

TABLE 11 | Representative list of marketed pediatric formulations.
Oral pediatric formulations Technology and advantages Examples

® ®
Disintegrating tablets (DTs) DTs are designed to disintegrate in the oral cavity usually in Prevacid (lansoprazole), Zofran (ondansetron), and
® ®
less than a minute. Different than regular tablets that need to Clarinex RediTabs (desloratadine)
be swallowed essentially, DTs reduce the need of tablet
swallowing and therefore appropriate for older children.
They can be manufactured using different techniques,
including freeze-drying process, compaction process and
molding candy process
® ®
Disintegrating films or strips (DFs) DFs is a strip that disintegrates quickly in the tongue without PocketPaks (Listerine), Triaminic Thin Strips (Phenylephrine
® ®
requiring chewing or swallowing. The casting method and HCl), Theraflu (Diphenhydramine HCl), Setofilm
hot-melt extrusion method are used to prepare ODFs (Ondansetron)
® ®
Mini-tablets Mini-tablet is an alternative to address swallowing difficulty in Lamisil (terbinafine), Orfiril long (Valproic Acid sodium)
pediatric patients. It has a less than 3 mm diameter. As a
substitute of regular tablets, mini-tablets can be easily
swallowed by patients less than 10 years old. Its advantage
is the ease of manufacturing by using a regular tablet
compression machine
® ®
Multi-particulates (constituted to a Small particles (e.g., granules or pellets) can be mixed with Medikinet (methylphenidate), Artequin Pediatric
®
suspension or as sprinkles in apple sauce or food matrices. Multi-particulates are formulated using pearl (mefloquine), Lopimune Sprinkles (lopinavir/ritonavir)
yogurt) milling, phase separation, or high-pressure homogenization
hydrolysis, polycyanoacrylate nanoparticles degrade into carriers. However, the use of protein polymers for oral drug
cyanoacetate and formaldehyde, and protein nanoparticles are delivery has been less studied, especially with regard to the
enzymatically degraded to basic amino acids and peptides understanding of enzymatic stability, drug-release kinetics, and
(Ratnaparkhi and Gupta Jyoti, 2013). Polymers for oral absorption mechanism. The challenges relate to nano-
delivery of drugs often have an upper limit on the formulations yield, polydispersity, sonochemistry and
concentration of polymers that is nontoxic (Islam et al., 2019). throughput, are still the biggest obstacle against the
For sustained release applications of potent drugs, the precise widespread application of these systems, this prevents them
concentration of drug desired should be calculated and the from being scaled up to commercial levels and from entering
formulation optimized accordingly by tuning the polymeric the mass production for pharmaceutical industry (Pathak and
constituents or formulation process. Bioerosion or swelling of Thassu, 2016).
polymers results in the diffusion of drugs from the nanoparticles
in tunable release profile. Polymers can be modified to exhibit the
preferred release profile through cross-linking or chemical PEDIATRIC ORAL DRUG DELIVERY
conjugation of the encapsulated drug (Alqahtani et al., 2019).
Polymers can also be combined with hydrogels or scaffolds to Pediatric patients represent 23% of the total US population and
further fine-tune the desired release profile (Liu, 2018). consist of newborns babes, infants, children, and adolescents
Biopolymers such as protein-based nanoparticles have been (Madill, 2017). The upper age limit used to distinguish the
used owing to their desirable features, including generally pediatric population differs between countries; usually,
recognized as safe (GRAS) status and biodegradability and adolescents are considered up to the age of 18 or 21 years.
correspond to amino acids. Some protein-based polymers that Different age groups have different physiological and
have been investigated for oral delivery include whey proteins, pharmacokinetic considerations, as well as ability to handle
casein, gelatin, soy proteins, zein, and wheat proteins (Shukla and formulations. Although efforts have been made to develop and
Cheryan, 2001; Dong et al., 2004). They can be used as drug design new pediatric formulations, the development of an
delivery systems and in the food industry (Hurtado-Lopez and acceptable pediatric formulation remains a challenging task.
Murdan, 2005; Liu et al., 2005; Parris et al., 2005; Wang et al., Furthermore, the development of pediatric formulations is
2005; Lai and Guo, 2011; Chen et al., 2014). Furthermore, the hindered by the absence of market share or economic
amphiphilic characteristic of proteins allows them to interact stimulus, since the majority of the patients is comprised of
equally well with both the drug and intestinal mucosa (Islam adults; dilemma in developing formulations that are
et al., 2019). Therefore, nanoparticles obtained from natural adequately taste-masked; methodology and ethical
proteins have an enhanced tendency for biological interaction requirements for clinical trials in children; and high costs
and facilitate surface modification for the attachment of associated with development research, manufacturing, and
numerous drugs and target specific areas by using ligands. storage (Strickley, 2019). Many physiological and maturational
Protein-based nanoparticles have been synthesized using both changes occur in growing children. These age-related changes
water-soluble and non-soluble proteins (Perumal and Podaralla, impact the absorption, disposition, and metabolism of drugs. For
2019). Human serum albumin and bovine albumin are examples example, the pH of the GI tract is different between adults and
of water-soluble carriers, whereas zein and gliadin are lipophilic children (Lam et al., 2013). Similarly, differences also exist in

gastric residence time, gastric emptying time, intestinal transit causing pediatric deaths (Nahata, 1999). Hence, pediatric drug
time, P-gp expression in the GI tract, and bacterial population formulations have attracted considerable attention from private
composition (Strolin Benedetti and Baltes, 2003). In addition, and government institutes. Excipients are the inactive ingredients
differences exist in the total body water content, enzymatic in drug formulations and should be safe for human use. However,
activity, and blood flow as well as in fat content. From the some additives that are safe in adults might not be suitable for
formulation prospective, many pharmaceutically active pediatrics, especially in infants and newborns babes owing to
ingredients have poor water solubility, stability, or an their physiological features and age-related maturation of tissue
unpleasant taste, thereby rendering pediatric drug functions (Nunn, 2003). Further, as child friendly formulations
development a challenging task. Children cannot swallow large are inadequate, incompliance to the prescribed regimen of
tablets and capsules and are unable to accept formulations that medication is noted in children, resulting in the lack of
taste bitter or bad. In addition to children, many geriatric and ill therapeutic effect (Standing et al., 2005). This is especially
adults, such as patients in surgeries or recovering from comas, critical in the case of cancer or infectious diseases in the
also unable to swallow tablets and capsules, thereby expanding pediatric population. Hence, to date, parents and nurses
the need for pediatric formulation. Clinically desirable pediatric continue to use extemporaneous compounding to help
dosage forms involve a solid dosage form or an orally dissolvable children take the current adult formulations.
formulation that is tasteless; formulated with safe and minimal In 1997, the FDA implemented pediatric regulations and
additives; and in a appropriate dosage form that is stable even legislation in the US. Furthermore, draft guidance on pediatric
after exposure to heat and humidity. Liquid pediatric dosage clinical studies have been published by the American Academy of
forms have limited storage stability, palatability, and handling Pediatrics and FDA (Food and Drug Administration, 1998)
(Standing and Tuleu, 2005). Conversely, solid formulations such (Shaddy and Denne, 2010). In addition, the World Health
as powders or granules are devoid of these issues. In 1937, Organization (WHO) published a position report for desired
sulfanilamide was formulated into a solution by using the pediatric dosage forms and integrated it in a Model Essential
diethylene glycol (DEG) as a solvent, which resulted in the Medicines List for Children (World Health Organization, 2010).
death of around 100 children. Diethylene glycol is still used in This report stated a policy on oral pharmaceuticals suitable to
developing countries owing to the lack of pediatric formulations, children, especially in the developing countries, and specified the
FIGURE 3 | Advantages of proteins as drug delivery carriers.

need for solid oral dosage forms for easy transport in pediatrics, CONCLUSIONS AND FUTURE
since they do not require refrigeration, are easy to reconstitute PERSPECTIVES
with tap water, and can be given at the right dose, such as orally
disintegrating dosage forms, multi-particulate formulations in the Oral drug delivery is one of the most common route of drug
form of powders/sprinkles, mini-tablets, and chewable tablets. administration in both adult and pediatric patients. Conventional
However, formulations for pediatrics are not commercially oral formulations can raise issues and complications that could be
available in the developing world owing to the difficulties in addressed by advanced formulation strategies. One such strategy is
the development and storage of such formulations (Sosnik et al., the use of nanocarriers that could improve drug solubility,
2012). Although most pediatric formulations of BCS classes 1 and permeability and bioavailability. Better understanding of the
3 drugs are in the liquid form, many drugs, including those for effects of common diet and inter-patient variation in drug
chemotherapy or HIV, belong to BCS classes II and IV, which are absorption is needed. In vast preclinical studies, the transition
poorly soluble in water and bitter in taste, and thus pose from the fed to the fasted state is overlooked, which can affect
challenges in oral drug development (Milne and Davis, 2014). the mechanism and rate by which drug compounds are absorbed.
Drug solubility and taste can be altered by chemically One critical aspect that still deserves more consideration in the future
modifying, masking by encapsulation, or adding sweeteners to is the establishment of a reliable in vitro-in vivo correlation models to
the drugs. Drug absorption is affected by the choice of polymers predict better in vivo performance and to generate data that offer cost
or excipients. In addition to taste masking, polymeric benefit over existing formulations. This will help accelerate the
encapsulation can improve the drug solubility and stability transition of more realistic and more relevant formulations from
and allow controlled drug release and absorption (Weuts et al., laboratory to commercial production scale. Additionally, the target
2011). These polymers can either be natural or synthetic or act as population of patients must be taken into account when designing
a barrier to control drug release and prevent the degradation of new formulations. Future research can be directed toward the
drugs after oral administration or during storage. A list of development of better pediatric formulations by using
marketed oral pediatric formulations is shown in Table 11. nanoparticle technologies that are currently used for developing
Oral bioavailability of solid dispersible forms of drugs for drug formulations for adults. Prospect studies on nanocarriers
pediatric use can be improved by using nanoparticle technologies technology to develop oral formulations need to consider the use
(Das and Chaudhury, 2011). Novel nanoparticle formulations for of safe and effective excipients. As the landscape of delivery
treating child cancers, infections, and asthma have shown technologies changes, formulation development and excipient
superior advantages (Yellepeddi et al., 2019). A recent study screening will continue to evolve consequently. It is expected that
showed the efficacy of dexamethasone-loaded polymeric the overall time for formulation development will be shorter than the
nanoparticles to potentially treat childhood leukemia. The current existing one to bring a lead compound from drug discovery
nanoparticles made of the copolymer of PEG and PCL to to clinical trials. However, there are numerous obstacles that
deliver dexamethasone effectively induced cell death and pharmaceutical researchers will have to face to accomplish with
improved survival in pediatric population, even at a low dose better and more effective oral formulations that can provide better
of the drug (Krishnan et al., 2012). Food-grade proteins are a therapy.
versatile class of biopolymers and are generally recognized as safe
(GRAS) (Abd El-Salam and El-Shibiny, 2012; Alqahtani et al.,
2017). Their main benefits as drug delivery carriers, especially for AUTHOR CONTRIBUTIONS
oral drug delivery, include edibility, safety, and biodegradability.
The advantages of using proteins as drug delivery carriers are All authors listed have made a substantial, direct, and intellectual
listed in (Figure 3). Moreover, milk proteins such as caseins contribution to the work and approved it for publication.
possess many favorable characteristics suitable for the
development of polymeric nanocarriers, such as
amphiphilicity, biodegradability and good biocompatibility, ACKNOWLEDGMENTS
particularly for pediatrics (George et al., 2019). However,
studies on the use of food-based proteins along with other The authors extend their appreciation to the Deanship of
GRAS excipients to develop nanocarriers for pediatric drug Scientific Research at King Saud University for funding this
delivery are far away from the clinical translation. work through research group no. RG-1441-528.
Alqahtani, M. S., Podaralla, S., Kaushik, R. S., Reineke, J., Woyengo, T., et al. (2017).
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"Microenvironmental pH-modified solid dispersions to enhance the
dissolution and bioavailability of poorly water-soluble weakly basic GT0918, Copyright © 2021 Alqahtani, Kazi, Alsenaidy and Ahmad. This is an open-access
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micelles in oral absorption processes. J. Pharm. Sci. 99 (3), 1336–1345. No use, distribution or reproduction is permitted which does not comply with
doi:10.1002/jps.21919 these terms.

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published: 19 February 2021

Advances in Oral Drug Delivery

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are intercalated with enterocytes and joined by zonula occludens

TABLE 1 | Physiological features of the human gastrointestinal tract.

GI tract Approx. Approx. pH Epithelial type Approx. Major enzymatic activities

Oral cavity – 0.01 6.5 Stratiﬁed – Polysaccharidase

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Physiological factors Physicochemical factors Formulation factors Miscellaneous

I. Physiology of GIT i. Drug stability in the GI ﬂuid i. Solutions i. Age

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Advances in Oral Drug Delivery

TABLE 5 | Formulation approaches for various BCS class drugs.

Solubility Permeability BCS % of marketed Formulation approaches

High High I 35 Conventional capsule or tablet

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TABLE 6 | Representative examples of prodrugs used for oral drug delivery.

Prodrug type Oral application Commercial examples

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TABLE 7 | Representative examples of solid dispersion formulations.

Nanocrystal (wet media milling) Rapamycin II Rapamune Tablets Immuno-suppressant

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TABLE 8 | Representative examples of marketed oral lipid-based formulations.

Solutions Dutasteride II Avodart (GlaxoSmithKline) Hyperplasia of prostate

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Advances in Oral Drug Delivery

Patent number Assignee Invention References

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TABLE 11 | Representative list of marketed pediatric formulations.

Oral pediatric formulations Technology and advantages Examples

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FIGURE 3 | Advantages of proteins as drug delivery carriers.

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