For PK

Journal of Drug Delivery Science and Technology 61 (2021) 102178
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Journal of Drug Delivery Science and Technology

journal homepage: www.elsevier.com/locate/jddst
Review article
A comprehensive review of the strategies to improve oral drug absorption

with special emphasis on the cellular and molecular mechanisms
Tanmay Padhye, Kavya Sree Maravajjala, Karnam Laxmi Swetha, Swati Sharma,
Aniruddha Roy *
Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Vidya Vihar, Rajasthan, 333031, India
A R T I C L E I N F O A B S T R A C T
Keywords: Oral drug delivery is the most convenient and cost-effective route of administration, due to which most of the
Oral drug delivery drugs are administered through the oral route. Apparently, oral delivery is the easiest approach for drug
Permeation barriers administration; however, in reality, it is one of the most complicated routes. Although the gastrointestinal (GI)
Permeation enhancers
tract offers a large surface area for absorption, the GI epithelium is designed for the permeation of molecules with
Enterocyte uptake
Nanoparticles
a specific set of physicochemical properties only. Due to this, different drugs exhibit considerable variabilities in
absorption; one can show more than 90% absorption, while others may show less than 10%. To improve the oral
absorption of low bioavailable drugs, multiple strategies have been developed, with variable success. To design a
successful strategy, a thorough understanding of the GI physiology and the mechanism of drug absorption is
pivotal. Different parts of the GI tract have significant variations, all of which have a profound impact on drug
absorption. In this comprehensive review, we have done a cross-disciplinary exploration of the cellular physi
ology of different barriers present in the GI tract, how they impact drug absorption, and also discussed the
diverse strategies developed to overcome absorption barriers present in the GI tract.
1. Introduction the drugs into four groups: Class I: high permeability, high solubility;
Class II: high permeability, low solubility; Class III: low permeability,
Oral delivery is the most preferred route of administration for most high solubility; and Class IV: low permeability, low solubility (Fig. 1)
of the drug molecules due to the advantages associated with it, including [1]. As solubility and permeability are the two major parameters
ease of delivery, self-administration, non-invasiveness, safety, economic influencing oral bioavailability of a drug, concerted efforts have been
viability etc. However, oral delivery comes with significant challenges made to improve both of them. There are many clinically successful
as well, among which reduced bioavailability is the most significant one. strategies to enhance the solubility of a drug molecule [2], and, as a
As there are multiple absorption barriers present in the gastrointestinal result, a majority (41%) of the marketed drug molecules fall under the
(GI) tract to prevent the entry of any foreign materials in our body, only BCS class II category [3]. However, enhancing permeability is more
some selected types of molecules can pass through it. Low molecular complicated. There are varieties of permeability barriers present in the
weight, non-polar molecules can pass relatively easily, however, for GI tract. Diverse formulation strategies have been evaluated for crossing
high molecular weight or polar molecules, it provides a significant those barriers, with variable success. Though there are several reviews
obstruction. Multiple physicochemical properties of the drug molecule, previously published focusing on the formulation strategies for
including lipophilicity, ionic strength (pKa), presence of rotatable improving oral bioavailability, a cross-disciplinary exploration of the
bonds, hydrogen bonding ability, and molecular size regulate their ab mechanism of GI absorption, the permeation barriers present in the GI
sorption through the epithelial barrier of the GI tract. A precise balance tract, and the strategies to overcome the same is lacking. For designing
between these properties has to be maintained to improve oral an effective oral delivery system, the researchers need to have a
absorption. comprehensive understanding of the GI physiology and the corre
Based on the solubility and permeability of a drug, biopharmaceu sponding permeation barriers present in the GI tract, along with stra
tical classification system (BCS) have been established which categorizes tegies to overcome the same. In the present review, we are going to focus
* Corresponding author.
E-mail address: [email protected] (A. Roy).
https://doi.org/10.1016/j.jddst.2020.102178
Received 2 September 2020; Received in revised form 8 October 2020; Accepted 21 October 2020
Available online 27 October 2020
1773-2247/© 2020 Elsevier B.V. All rights reserved.
T. Padhye et al. Journal of Drug Delivery Science and Technology 61 (2021) 102178
initially on the GI physiology to understand the absorption pathway and [4]. It involves the passage of drugs between the adjacent epithelial cells
the absorption barriers present; then we will discuss different factors at the tight junctions, which majorly occurs through drug diffusion via
controlling permeability. Finally, different approaches to improve the leak pathway or pore pathway [5]. Linnankoski et al. reported that the
permeability will be discussed, with an emphasis on the molecular pore size of the paracellular route varies from 5 to 15 Å [6]. As a net
mechanism of that approach. negative charge is found to be associated with the junctional complex,
positively charged molecules can permeate more efficiently [7]. How
2. Mechanism of gastrointestinal drug absorption ever, the paracellular pathway presents a limited absorption window
and accounts for only <0.1% of the total surface area of the intestinal
For systemic absorption, the orally administered drug has to mucosa. Besides, as the drug travels from the jejunum towards the colon,
permeate through the intestinal epithelium. The outermost cells present the junctions between cells become tighter [8]. Permeation enhancers
in the intestinal epithelium are called enterocytes, which acts as the and chelation of calcium are some strategies that are employed in
primary absorptive cells. The penetration of molecules through the loosening the tight junctions to improve drug delivery using this route
enterocytes occurs via transcellular or paracellular transport (Fig. 2). [9].
Paracellular pathway involves drug diffusion through the tight junctions
between the intestinal enterocytes. On the other hand, in transcellular 2.2. Transcellular absorption
passage, the molecules have to pass through the enterocytes. Depending
on the drug’s physicochemical properties, two primary mechanisms are Majority of the drug molecules get absorbed through the trans
involved in the transcellular passage of drugs: passive diffusion and cellular pathway. It involves the passage of the molecules across the
carrier-mediated transport. Passive diffusion is an energy independent, epithelia, through intracellular transfer, to blood circulation. The
concentration dependent process. In contrast, carrier-mediated trans transfer follows either passive partitioning from the intestinal lumen to
port is an energy-dependent, concentration independent process, which the systemic circulation, across the enterocyte cell membrane, or any
operates through a highly specific (in terms of molecular structure and other specific uptake mechanism via active transport. The physico
binding site) mechanism. chemical properties of the drug control the rate of passive drug ab
sorption. Mainly low molecular weight, lipophilic molecules are
absorbed through this route. A small number of molecules take the path
2.1. Paracellular absorption of active uptake, which is a more specific route depending on the
recognition by the transporter proteins [10].
Generally, drugs that are absorbed through the paracellular pathway
are low molecular weight drugs (MW < 250 Da) and polar (c log P < 0)
Fig. 1. Relationship between BCS classification and physicochemical characteristics of different drugs. ARCS: Absorption rate control step; PSA: Polar surface area;
clogP: Partition coefficients calculated by considering the contribution of functional groups; MW: Molecular weight.
2
Fig. 2. Mechanism of gastrointestinal drug

absorption. Any molecule can be absorbed
either by the paracellular pathway where
they cross the epithelial lining through the
space between the enterocytes, or they can
take the transcellular route, where they pass
through the enterocytes by crossing the
apical membrane and the basolateral mem
brane, consecutively. Transcellular absorp
tion can be of two different types, passive
diffusion and active transport. In passive
diffusion, absorption happens due to simple
diffusion of the drug through the membrane,
whereas in active transport, the drug is
taken up by some specific uptake
mechanism.
3. Drug absorption barriers present in the GI tract which help in the constant regeneration of the intestinal epithelium
[12]. A variable mucus layer is present in the intestine: thin and
Any orally administered drug should be able to bypass the barriers discontinuous layer is observed in the small intestine [13], whereas
present in the GI tract for its systemic absorption. A brief discussion of thick two-layered mucus is present in the colon [14]. This variability
the major absorption barriers is included below. comes from the distribution of mucus-producing goblet cells in the in
testine, ranging from 4% in the duodenum to 16% in the distal colon
[15]. The intestinal epithelium also has specialized cells, named Paneth
3.1. Gastro-intestinal epithelium cells, which help in the production and secretion of antimicrobial pep
tides, including cryptdins and α-defensins [16] (Fig. 3B). These anti
Significant differences exist between different parts of the GI mucosa microbial peptides help to maintain a healthy microbiome.
in terms of cellular structure and function, leading to region-dependent Enteroendocrine cells are also present in the intestine, where they
characteristics affecting drug absorption. regulate enzyme secretion, motility, and metabolism.
The most abundant cell type present in the GI tract are the enter Intestinal mucosa also has specialized lymphoid follicles, named as
ocytes, which is uniformly present in all part of the GI tract. Neverthe Peyer’s patches, to tackle pathogenic bacteria in the GI tract. The
less, different specialized cells are also present in different parts of the GI follicular part of the Peyer’s patch lies beneath the epithelial layer. A
tract for specific functions (Fig. 3). The stomach has numerous gastric specialized enterocyte named M (microfold) cell is seen in the follicle-
glands, which form a pit-like structure and secrete different substances associated epithelium (Fig. 3C). The major function of the M cell is to
into the lumen. The openings of these gastric pits are lined by foveolar uptake extracellular materials like macromolecules, bacteria, and vi
cells, which produce mucus to prevent damage from the concentrated ruses and transfer it at the basolateral side [17]. The basal membrane in
HCl present in the stomach. In the basal part of the gastric gland, a large the M-cells forms an extracellular pocket, which is populated by
number of HCl-secreting parietal cells, pepsinogen secreting chief cells, monocytes and lymphocytes. The formation of this pocket makes the
and enteroendocrine cells are present (Fig. 3A). The enteroendocrine cytoplasm thinner in the apical surface, leading to a short transcellular
cells assist in the secretion of HCl by the release of histamine. pathway. Particles uptaken by M-cells are generally delivered to the
The intestinal epithelium has an extensive villi structure, resulting in follicular immune cells and carried over in the lymphatic system [18].
an absorptive surface area of about 32 m2 [11]. The villi are primarily The advantage of lymphatic absorption is the avoidance of the first-pass
made up of the enterocytes, the primary absorptive cells present in the metabolism in the liver [19]. A large number of nanoparticle delivery
GI tract. Epithelial invaginations, named ‘crypts of Lieberkühn,’ are system targets the M cells for efficient oral delivery [20].
present surrounding the villi. Intestinal stem cells are present here,
3
Fig. 3. Structural variability in different parts of the GI tract. A. Stomach B. Intestine C. Peyer’s patches.
Intestinal epithelial tissue is developed from the pluripotent stem junctional stability is maintained by desmosomes, one of the strongest
cells located at the bottom of the villi, which forms 5 types of epithelial protein structures for cell-to-cell adhesion [30]. The tight junctions are
cells: enterocytes, goblet cells, endocrine cells, Paneth cells, and M cells dynamic structures, as they regulate intestinal penetration of drug
[21]. Monolayers of these cells make the intestinal epithelial barrier. molecules across the epithelium. An alteration of the balance in these
The cohesion and polarity of these epithelial cells apical are maintained proteins increases the mucosal permeability by allowing the passage of
by the junctional complex, which is comprised of tight junctions, endoluminal molecules into the deeper layers [31]. Some penetration
adherens junctions, and desmosomes (Fig. 4). Both tight junctions and enhancers function by relaxing the tight junctions and facilitating the
adherens junctions are formed by the different concentrations of paracellular absorption [32].
occludin, claudin, junctional adhesion molecules (JAM), and tricellulin
[22]. All of these are transmembrane proteins, with extracellular loop
structure. These loops bind to the corresponding loops of a neighboring 3.2. Mucus
cell, creating a tight junction between the two cells [23]. The intracel
lular domains of occludin and claudin are directly bound to the zonula Mucus mainly acts as a shield for epithelial tissue, protecting it from
occludens 1, a peripheral scaffolding protein, which in turn is connected digestive enzymes, acids, harmful microorganisms, and antigens and
to cytoskeletal proteins such as actin, myosin, and microtubules [24]. also acts as a lubricant for intestinal motility. The mucosal layer can be
The tightness of the junctional complex can be modulated by phos divided into two parts: the inner and outer layers. Both the layers are
phorylation of these scaffolding proteins [25]. Claudins are responsible organized around glycosylated protein mucin, that forms a polymer like
for the charge selectivity of the paracellular pathway [26,27]. JAM is coat secreted by foveolar cells and goblet cells [33]. The inner mucosal
responsible for barrier function, where increased permeability is layer is very dense, blocking penetration. The inner mucus layer grad
observed with JAM deficiency [28]. Tricellulin maintains the structure ually expands its volume due to the proteolytic activities by the host
and function of cellular contacts between neighboring cells [29]. The enzymes like proteases and glycosides, which allows it to get converted
into the outer layer, which is less dense and easier to penetrate [34].
4
Fig. 4. Structure of the intestinal epithelial junctional complex. The intestinal epithelium is consists of a single layer of enterocytes. Adjacent cells are strongly bound
with each other by different junctional complexes. As the junctional proteins are connected to the cytoskeletal proteins, contraction of the cytoskeletal proteins leads
to the opening of the junctional complex, facilitating paracellular absorption.
Mucus is critically responsible for modulating GI permeability. and increases to 7–8 on reaching colon and rectum [40]. At acidic pH,
Mucus secretion varies significantly along with the GI tract and is pre conformational changes, from random coil to elongated structure, have
dominantly composed of 95% water and remaining as glycoprotein been observed in the mucus layer [41]. This elongated conformation can
(mucin), electrolytes etc. In the stomach, the key mucin proteins are facilitate cross-linking in the mucin macromolecules, forming a gel
MUC1, MUC5AC, and MUC6, whereas, in the small intestine and the structure and preventing drug permeation [41].
colon, MUC2 is the most abundant mucin [35]. GI mucus barrier de Mucin also undergoes swelling and hydration, which is mediated by
creases the permeability and diffusion of drugs and other electrostatic forces, mostly by exchanging H+ and divalent Ca2+ with
macromolecules. monovalent cations (Na+ and K+). Due to the presence of sialic acid and
Mucus has multiple-barrier properties which can be categorized into sulfate moieties, mucin glycoproteins have a net-negative surface charge
3 types: dynamic barrier, steric barrier and interactive barrier [37]. The which can interact with cations [42]. It was shown that mucus viscosity
dynamic barrier is composed of continuously secreting mucus; there decreases with an increase in ion concentration, improving permeability
fore, drugs need to diffuse in the upstream in order to reach and cross the [43,44].
epithelium. In the steric barrier, there is a network of mucin which forms A detailed review of the impact of mucus on intestinal drug ab
a size-exclusion filter for larger compounds, making it a size-dependent sorption was reported by Leal et al. [36].
barrier [38]. The interactive barrier is dependent on the ability of mucin
to form multiple low-affinity bonds via hydrophobic or ionic in 3.3. Gut microbiota
teractions or hydrogen bond formation with drugs [37].
Drug permeation through mucus also depends on viscoelasticity, pH, Gut microbiota plays many physiological functions as immune
and ionic strength of the mucus (Fig. 5). Viscoelastic property of mucus stimulation, barrier synthesis, metabolism, etc. Alteration in the intes
is dependent on the presence of mucins, DNA, lipids, and other mucus tinal microbiota affects the pharmacokinetics of many drugs. For
proteins [36]. Mucus pH varies throughout the GI tract, in stomach example, prodrug loperamide oxide in the presence of gut microbiota
mucus pH varies from 1 to 2 [39], while the pH of duodenal mucus is 6.1 converts to active loperamide, which reduces the growth of enterocytes,
Fig. 5. Impact of mucus on drug absorption. The mesh structure produced by the mucus can prevent the diffusion of larger molecules. The viscoelastic nature of the
mucus can also impact drug diffusion. Depending on the pH of the medium, nature of the mucus changes, influencing drug interaction as well as stiffness of the
mucus. Ionic strength and charge also have similar effects. Adapted from: Physicochemical properties of mucus and their impact on transmucosal drug delivery [36].
5
leading to an increase in intestinal permeability [45]. Digoxin, used as a partition coefficient takes into account only the unionized form of the
cardiac glycoside in the treatment of congestive heart failure, becomes molecule, and many molecules with pKa values lower or higher than
inactive when the lactone ring is reduced, producing dihydrodigoxin. It biological pH are present in their ionized form. To resolve this issue,
was observed that co-administration of antibiotics prevented dihy LogP is substituted with logD (Distribution coefficient). logD takes into
drodigoxin production, indicating that gut microbiota may have a role in consideration the concentration of both the ionized and unionized parts
these transformations [46]. It was later identified that gut residing of the molecule present in the aqueous phase [51]. As the majority of
Eggerthella lenta is the microbe responsible for this transformation [47]. drug absorption is carried out through passive transcellular pathway,
Change in the gut microbiota composition impairs the barrier func lipophilic drugs show better absorption (Fig. 6B). However, very high
tion of epithelial junctions as well as the mucus layer. The effect of gut lipophilicity should be avoided because of a range of factors including
microbiota on drug metabolism and pharmacokinetics has been elabo increased protein binding (which will reduce permeability), reduced
rately reviewed by Haiser and Turnbaugh [48] and Zhang et al. [49]. solubility, and inappropriate tissue distribution.
4. Drug physicochemical parameters that influence oral 4.3. Ionization

absorption
Only non-ionic molecules can be absorbed by the passive diffusion
Apart from the gut physiology, the physicochemical properties of a process (Fig. 6C). When administered orally, the extent of ionization of a
drug molecule play an equally important role in its absorption. Assess drug molecule depends on the specific pKa value of the drug and pH
ment of the physicochemical properties of a drug is an essential step value of the medium. As different regions of the GI tract have varying pH
while designing a formulation for oral delivery. In this section, we will values, significant variation in the ionization is observed. Weak bases
individually examine some of the major physicochemical properties, are absorbed at a faster rate from the intestine (pH 7.0–8), and weak
known as Lipinski’s rule of five, influencing the membrane diffusion of acids are absorbed at a faster rate from the stomach (pH 1.2–2). Apart
drugs (Fig. 6). from the permeability, ionization capacity also affects the steady-state of
distribution of a drug in different compartments, if there is any pH dif
4.1. Molecular weight ference [52].
It is one of the most significant parameters affecting the rate of 4.4. Hydrogen bonding affinity of the drug
passive absorption of drugs across intestinal epithelia. Camenisch et al.
conducted a study to analyze the absorption of drug molecules in a Calculating polar surface area (PSA) is one of the efficient methods
weight range of 150–670 Da [50]. It was observed that molecules less used in determining the H-bonding capacity of a drug molecule. Polar
than 200 Da molecular weight can pass through the intestinal mucosa surface area could be linked with a molecule’s ability to permeate
via both paracellular and transcellular transport, depending on their through the intestinal membrane. PSA can be explained as sum total of
lipophilicity. Paracellular transport is preferred for hydrophilic mole polar atom’s surfaces in a compound obtained by different computation
cules and transcellular pathway for lipophilic molecules. Molecules with techniques (CONCORD, topology of molecule, conformational sampling
weight more than 500 Da exhibited reduced permeation as diffusion was etc.) [53] Palm et al. have demonstrated an inverse correlation between
constrained, though they can adopt different endocytosis mechanisms dynamic PSA and permeability coefficients [54]. In a similar investi
for their absorption (Fig. 6A). gation, Kelder et al. found an inverse relationship between the polar
surface area and brain penetration [55]. They demonstrated that the
4.2. Hydrophobic nature of the molecule CNS drugs which were orally absorbed had a PSA value less than (60-70
Å), and the orally absorbed non-CNS drugs displayed a PSA value less
Hydrophobicity is an important property of a molecule concerning than 120 Å.
its absorption and distribution. Generally, two descriptors, logP, and
logD are used in defining the hydrophobicity of a molecule. LogP is the 4.5. Solubility
partition coefficient of the molecule which is defined as the ratio of
concentrations of the drug molecule in a mixture of two immiscible Solubility measures the amount of drug present in a saturated solu
solvents, usually water (polar) and n-octanol (non-polar). However, the tion at a specific pH and temperature. Temperature, pH, crystal lattice
Fig. 6. Different physicochemical parame

ters of the drug influence passive diffusion.
A. Molecular weight: (a) very low molec
ular weight polar molecules can pass
through the aqueous pores present on the
cell membrane. (b) Low to medium molec
ular weight non-polar molecules can pass
through the membrane by passive diffusion.
(c) High molecular weight molecules, irre
spective of polarity, can only permeate the
cell membrane by receptor-mediated uptake.
B, C. Lipophilicity and Ionization: Lipo
philic and non-ionic molecules (L, N) can
only traverse the cell membrane by passive
diffusion, which route is non-accessible for
hydrophilic and ionic molecules (H, I). D.
Solubility: Solubilization is highly impor
tant. Only solubilized molecules can be
absorbed; insoluble molecules cannot un
dergo diffusion due to the formation of large
aggregates.
6
are some of the factors which impact the equilibrium solubility. Solu strategies for oral delivery of these macromolecules [60]. Techniques
bilization of the drug is a prerequisite for absorption through passive like site-specific delivery, use of permeation enhancers,
diffusion (Fig. 6D). Nanoparticles, which are not real solutions, gener particulate-carrier systems and bioadhesive systems are being investi
ally absorbed via different endocytic pathways. gated for peptide delivery. Some of these strategies are discussed in
Recently, several orally bioavailable compounds are discovered section 7 of this review. For a more detailed perspective on the oral
which venture beyond the Lipinski’s rule of five, demanding us to revise delivery of macromolecules, refer to the following reviews [61–63].
the aforementioned guidelines [56]. Doak et al. have found out a set of
182 approved drugs for oral delivery that has a MW > 500 Da [56]. 5. Approaches towards enhancing intestinal permeability
Important examples include roxithromycin, which has a molecular
weight of 837 and PSA of 218, however, shows 78% oral bioavailability 5.1. Prodrugs
[57]; josamycin (MW: 828, PSA: 207) shows high oral bioavailability
[58]; rifampicin (MW: 823, PSA: 224) with more than 90% oral The most clinically successful strategy to improve the oral bioavail
bioavailability [59], etc. These examples indicate that drug absorption ability of a poorly permeable drug has been the use of prodrugs. Pro
through the oral route is more convoluted then presumed before. A drugs are useful in overcoming several drug absorption barriers such as
thorough understanding of the physicochemical properties of drugs poor solubility, instability, insufficient absorption, rapid first-pass
would help us to extend the horizon of orally administered drugs. metabolism etc [64]. Prodrugs are designed to improve either the pas
In contrast to the small molecules discussed above, macromolecules sive diffusion or active transport of the drug molecule. As we have dis
like peptides/proteins (MW > 5 kDa) do not follow the passive pathways cussed previously, permeability is highly influenced by the partition
to reach the systemic compartment, and unlike small molecules, no coefficient (log P) of the drug. Based on that, many researchers have
molecular descriptor has been reported to predict their oral bioavail modified the parent drug to increase its lipophilicity in order to increase
ability. Researchers are extensively working on exploring various permeability. Different strategies have been employed to increase the
Fig. 7. Different prodrugs used for enhancing oral absorption.
7
logP of a drug, including modification of functional groups such as hy Table 1

droxyl, carboxylic, carbonyl, amine, and phosphate groups, by making Examples of different types of permeation enhancers and their mode of action.
esters, phosphate esters, amides, and oximes [65]. Esters are one of the Type of the Mechanism of action Examples References
most common prodrugs which can enhance membrane partitioning of permeation
polar drugs by converting the polar functional groups into a non-polar enhancer
one. After absorption, the ester bond can be easily hydrolyzed by the Fatty acids • Modulating tight • Sodium caprate [82–92]
esterase found in the liver, blood, tissues and other organs. Temozolo junction opening by (C10) [GIPET®],
mide is one of the successful examples in this category. Temozolomide is activation of Sodium caprylate
phospholipase C- (C8) [TPE®]
a derivative of MTIC (3-methyl-(triazen-1-yl) imidazole-4-carboxamide) dependent inositol • SNAC, 5-CNAC [Eli
which is an anti-cancer drug generally prescribed for glioblastoma and triphosphate/ gen®] etc.
anaplastic astrocytoma, it can be administered orally and parenterally. diacylglycerol
Intracellularly, it transforms into an alkylating agent MTIC; which re pathway to increase
intracellular calcium
sults in cell apoptosis [66] (Fig. 7A). Another drug, Famciclovir, which is
• Lipophilic complex
used in the treatment of Herpes zoster, is a deoxy-diacetate ester analog formation, increasing
of penciclovir. The ester formation increases the lipophilicity and im membrane fluidity.
proves diffusion of penciclovir [64] (Fig. 7B). Similar examples include EDTA • Depletion of POD® [93,94,96]
adefovir [67,68], cytarabine [69], mesalamine [70] (Fig. 7C) etc. extracellular
calcium, activation
Apart from making lipophilic prodrugs, modifying the drugs with of protein kinase C
active transport ligands is another strategy that has been exploited by Quaternary • Reducing the Acyl carnitine [97,98]
many researchers. A wide range of transporters has been evaluated for ammonium concentration of [Peptilligence®]
this purpose, including bile acid transporters, monocarboxylate trans compound intracellular claudin,
thereby opening of
porter 1 (MCT-1), cholesterol transporter (ABCG5/8), organic cation
the tight junction.
transporter (OCT), organic anion transporter (OAT), etc. [10,71,72]. Surfactants • Disintegration and Polyoxyethylene esters [100–106]
Among different types of transporter present in the intestine, amino acid fluidization of and ethers, Lactose
transporters are one of the most abundant types [73]. Many clinically membrane oleate, Labrasol® etc.
successful prodrugs have been developed targeting these amino acid • Moderating tight
junction opening and
transporters to improve the absorption of polar drugs, like valacyclovir
facilitating
(Fig. 7D), valganciclovir, etc. Valacyclovir is a valyl ester prodrug of paracellular route
acyclovir, use of which can increase the oral absorption of acyclovir 3 to Bile Acids • Creation of aqueous Sodium deoxycholate, [109,
10-fold [74]. Gabapentin enacarbil (Fig. 7E), a prodrug of gabapentin, is channels in the taurocholate, tauro- 111–118]
membrane. lithocholate, sodium
absorbed by the MCT-1 transporter, present throughout the intestinal
• Reducing the ursodeoxycholate
tract [75], which showed very good bioavailability [76]. resilience and [Capsulin®], Sodium
viscosity of mucus cholate [Tregopil®] etc.
5.2. Permeation enhancers layer.
• Promoting the
paracellular
When changing the physicochemical nature of the drug by the pro transport by
drug approach is not feasible, the use of permeation enhancers can loosening up the
enhance the transport of poorly absorbed drugs. A highly diverse set of tight junctions.
compounds have shown to modify the epithelial barrier to increase • Moderates
expression of
absorption [77,78]. A list of such compounds with their mechanism of
transporter proteins
action is included in Table 1. Permeation enhancers can function via • Distortion of
both paracellular or transcellular routes. Paracellular permeation en membrane integrity
hancers act through the opening of the tight junctions, either by • Improving solubility
changing intracellular signaling mechanisms (via Ca2+ signaling) or by and membrane
interaction of both
direct disruption of the adhesion proteins [79]. Transcellular perme hydrophobic and
ation enhancers can either produce reversible fluidization of the hydrophilic drugs
epithelial plasma membrane [78], or they can increase the membrane through micelle and
interaction of the drug (e.g., by micelle/reverse micelle formation) to reverse micelle
formation.
improve passive transcellular permeation [80]. Though there is a
significantly higher number of molecules that exhibited transcellular
permeation enhancing capacity than that of paracellular permeation improved absorption of polyethylene glycols and mannitol from Caco-2
enhancer, more numbers of transcellular permeation enhancers have cells when sodium caprate (sodium salt of capric acid, C10) was used
been tested clinically [78]. This may be due to the intrinsic adverse ef [82]. They have demonstrated that this is mediated through the acti
fects associated with the non-specific perturbation of the cell membrane vation of phospholipase C-dependent inositol triphosphate/diacylgly
seen with the transcellular permeation enhancers. cerol pathway to increase intracellular calcium (Fig. 8) [83]. Tomita
et al. have further exhibited that the function of sodium caprate is
5.2.1. Paracellular permeation enhancers dependent on the calmodulin-dependent contraction of actin/myosin
Paracellular permeation enhancers can be categorized into 1st gen filament (Fig. 8) [84]. Lindmark et al. have demonstrated that sodium
eration and 2nd generation; while 1st generation molecules act via caprate can enhance the paracellular transport of molecules with an MW
modulation of intracellular signaling, 2nd generation molecules can of < 1 kDa, whereas the permeation of molecules larger than 4 kDa was
disrupt the cell adhesion protein interaction at cell adhesion recognition found to be insignificant [85]. It is now utilized in certain countries as an
(CAR) sequences. Though there are several 2nd generation permeation excipient in rectal suppositories [86]. Sodium caprate based excipient
enhancers developed [81], till now, 1st generation molecules have GIPET® (Merrion Pharma, Ireland) has been tested clinically for ab
shown more clinical viability [78]. The most promising among them are sorption enhancing effect using alendronate, desmopressin and
fatty acids. Among different types of fatty acids, medium-chain fatty low-molecular-weight heparin as the model drugs, which have shown
acids are mostly used for this purpose [77]. Lindmark et al. found
8
Fig. 8. Mode of action of different paracellular permeation enhancers. Most of the paracellular permeation enhancers act by modulating contraction of the cyto
skeletal proteins. They may act through PLC-IP3/DAG pathway (fatty acids), leading to cytoskeletal contraction and increased tight junction permeability, or can
deplete extracellular Ca2+ (EDTA), induces PKC which leads to actomyosin contraction and loosening of the apical junction. Some can directly reduce the amount of
junctional proteins (acylcarnitine).
improved bioavailability with no serious adverse effects [87]. A sodium the drug absorption by the use of surfactants can be linked to fluidiza
caprylate (C8) based excipient, TPE® (Chiasma, Israel) has also tion and disintegration of membranes caused by them (Fig. 9A). Ionic
exhibited good permeation enhancing efficacy with octreotide in the surfactants are not very useful for this purpose as they cause toxicity to
monkey model [88]. the intestinal mucosa, and mostly non-ionic surfactants are used for this
Another group of fatty acid derivatives, N-[8-(2-hydroxybenzoyl) purpose [99]. Since surfactants are amphiphilic molecules, it is reported
amino]caprylate (SNAC) and N-(8-2hydroxy-5-chloro-benzoyl)-amino- that the size and structure of both the hydrophilic as well as lipophilic
caprylate (5-CNAC) have shown high efficacy as permeation enhancers part influence the absorption enhancing activity [77]. Non-ionic sur
(Eligen®, Emisphere, USA). There is some debate regarding the mode of factant poly-oxyethylene esters and ethers have been extensively used in
action of these molecules. It has been proposed that they may make ocular drug delivery to enhance permeation [100]. Intestinal absorp
lipophilic complexes by physical interactions with polar molecules, tivity of PABA (para-aminobenzoic acid) was found to be augmented
thereby improving passive diffusion [78]. SAR analysis has indicated when poly-oxyethylene esters were used as permeation enhancers
that lipophilicity [89] and hydrogen bonding ability [90] may modulate [101]. Perninelli et al. studied a new sugar-based surface-active agent
the intestinal permeation enhancement. On the other hand, it has been lactose oleate, the possible pathway could be the opening of tight
demonstrated that SNAC can increase membrane fluidity [91]. SNAC junctions facilitating the paracellular route; the transcellular path can
has been clinically approved for the delivery of an oral vitamin B12 also be involved [102].
supplement [92]. Labrasol® (Gattefossé, France) is one commercially available PEG-
EDTA (ethylenediaminetetraacetic acid) has also been extensively based excipient which is found to improve the oral bioavailability of
used as a paracellular permeation enhancer. It has been demonstrated drugs [103]. It is composed of free PEG as well as PEG ester of caprylic
that EDTA depletes extracellular calcium by chelation and activates and capric acid. In pre-clinical studies, it was found to improve the
protein kinase C (Fig. 8) [93], resulting in the expansion of the para permeation of heparin [104], erythropoietin [105], and dextran [106].
cellular route by the loosening of apical junctions via ROCK-II depen As surfactants have membrane fluidizing effect, they can also impact
dent activation of actomyosin, increasing its contractility [94]. It has other membrane transportation processes and the dynamic property of
also been reported that depletion of extracellular Ca2+ by EDTA can the cell membrane. Danielsen et al. have reported that a group of sur
disrupt Ca2+ dependent E-cadherin, leading to loosening of the tight factants (1-decanoyl-rac-glycerol, nonaethylene glycol monododecyl
junctions [95]. EDTA based excipient POD® (Oramed, Israel) has been ether, and lauroyl-L-carnitine) can fuse brush border microvilli and
clinically tested for oral delivery of insulin, which exhibited good effi block all types of endocytic pathways [107].
cacy [96].
Quaternary ammonium compound derivative acylcarnitine (Peptil 5.2.2.2. Bile acids. Attributing to their biocompatible nature, bile salts
ligence®, Enteris Biopharma, USA) have also exhibited permeation are extensively studied as absorption enhancers. Bile acids are biological
enhancing activity via reducing the concentration of certain claudin surface-active agents synthesized by the liver from cholesterol. Bile
subtypes like claudin 1, 4 and 5 [97]. Peptilligence® has successfully acids are stored in the gall bladder and released when ingested food
completed a phase III clinical trial for the delivery of oral calcitonin arrives in the duodenum. They assist in increasing the pH of the medium,
[98]. It is being evaluated for the oral delivery of leuprolide (phase II) improve the intestinal uptake of dietary fats by emulsification, and
and tobramycin (phase I) as well. maintain cholesterol homeostasis [108]. Only a small quantity of bile
acids is newly synthesized as an effective recirculation mechanism for
5.2.2. Transcellular permeation enhancers bile acids is present. They are reabsorbed from the terminal part of the
intestine to get conveyed back to hepatocytes from where they are
5.2.2.1. Surface active agents as permeation enhancers. Improvement in rereleased again, each molecule can repeat it 4–12 times per day.
9
Fig. 9. Mode of action of different transcellular permeation enhancers. Two important examples of transcellular permeation enhancers are surface-active agents and
bile acids. A. Surface active agents mostly act as a membrane destabilizing agent and produce either fluidization or disintegration in the cell membrane, improving
the transport of molecules through the membrane. B. Bile acids enhance transcellular permeation through a variety of pathways. Due to their amphiphilic nature, bile
acids can improve the solubility of non-polar drugs by micelle formation and enhance their interaction with the membrane. They can entrap polar drugs by forming
reverse-micelles. Reverse-micelles can get integrated into the membrane and form aqueous pores. They can also get integrated into the membrane, increasing the
fluidity of the membrane. Bile acids can also inhibit the function of P-gp, preventing drug efflux.
Bile acids can improve permeation through both the transcellular India) exhibited good efficacy in a phase I trial [117,118].
and paracellular pathways. It has been shown that bile acids can in A detailed review of different permeation enhancers has been re
crease the absorption of both hydrophilic and hydrophobic drugs, by ported by Maher et al. [78].
enhancing the fluidity of biological membranes in the former, and
assisting in the solubilization of the latter (Fig. 9B) [109,110]. When 6. Use of mucoadhesive polymers for enhancing intestinal
used with polar drugs, bile acids act by enhancing both the paracellular absorption
and transcellular transport. Aqueous channels are formed when bile
acids are incorporated inside the biological membrane to form reverse Sustained-release, enhanced retention time, and delivery at a specific
micelles, which assists in the transcellular permeation of polar moieties target site are some of the benefits of using mucoadhesive agents for
[109]. Increment in the paracellular transport is attributed to the drug delivery [119]. Chitosan, a polycationic polysaccharide, is one of
opening of tight junctions, which may be the consequence of its binding the most exploited polymers for making mucoadhesive formulations
with the calcium ion [109]. Certain bile acids hydroxyl group at position [120]. Multiple pathways have been discovered through which chitosan
12 (like tauro-chenodeoxycholate, glycochenodeoxycholate) are re can show absorption enhancing property. Due to positive charge, chi
ported to possess the property of Pgp-efflux inhibition, possibly due to tosan can interact with the negatively charged mucus, which helps in the
alterations made by them in the lipidic environment of the transporter mucoadhesion of the chitosan-coated particles [121]. After binding with
protein [111]. Modifications are made in the structure of bile acids to the mucus, chitosan mostly enhances paracellular transport via a com
reduce their membranolytic effect and enhance the membrane perme plex mechanism. Ranaldi et al. have observed reversible opening of the
ation. Song et al. examined the absorption of salmon calcitonin with tight junction and an increase in paracellular fluxes with chitosan [122].
different bile salts and found that sodium taurodeoxycholate shows the Rosenthal et al. demonstrated that the increase in reversible paracellular
highest increment in permeability among all bile salts, which delivered transport with chitosan was associated with the activation of chloride
by forming a complex with the peptide [112,113]. bicarbonate exchanger [123]. Activation of the chloride bicarbonate
Due to the presence of acidic groups, bile acids have also been uti exchanger causes an alteration in intracellular pH which can modulate
lized to make an ionic complex with polar drugs to improve their ab the tight junction barrier, probably by affecting scaffold proteins (ZO-1).
sorption. Gaowa et al. have demonstrated improvement in the Chitosan-based nanoparticles can also be absorbed via the M-cells by
absorption of an EGFR (epidermal growth factor receptor) targeted endocytosis [124].
hybrid peptide by making an electrostatic complex with bile acid [114]. For its activity, chitosan needs to bind with the epithelial surface
Significant improvement in the oral bioavailability of a highly polar which requires a specific pH environment. At higher pH, the deproto
xenobiotic drug ceftriaxone was also observed when it was complexed nation of chitosan weakens its binding and permeation effect. To over
with deoxycholyethylamine [115]. come this issue, derivatives of chitosan were synthesized (i.e. Trimethyl
One formulation containing sodium ursodeoxycholate complexed chitosan and carboxymethyl chitosan) which exhibited improved ac
with insulin (Capsulin®, Proxima, UK) has exhibited high efficacy in tivity [125–127]. Besides chitosan, some anionic mucoadhesive poly
humans [116]. It is currently undergoing a phase IIb trial. Another so mers such as carbomer and polycarbophil have also shown to enhance
dium cholate based formulation of insulin (Insulin Tregopil®, Biocon, intestinal permeation [128]. Borchard et al. compared between
10
chitosan-glutamate and carbomer and found out that carbomer was siRNA and anti-Survivin shRNA [145]. They have used chitosan and
more efficient in opening tight junctions and improving paracellular cysteine in forming the nanoparticles which enhanced the mucoadhe
transport [129]. sion and intestinal permeation. The nanoparticles were decorated with
Neutral polymers like PEG has also been exploited for their galactose which promoted clathrin- and caveolin-mediated endocytosis,
mucoadhesive property. It was demonstrated that while PEG of molec mostly via the M-cells. However, the effect of this delivery on the
ular weight less than 5 kDa enhances muco-penetration, PEG of mo enterocyte cells is not clear from the study. He et al. have also evaluated
lecular weight 10 kDa shows mucoadhesive property [130,131]. a mannose functionalized trimethyl chitosan nanoparticles for the oral
Mahlert et al. showed PEGylated PLGA nanoparticles have a higher delivery of Tumor necrosis factor-alpha (TNFα) siRNA, which exhibited
cellular uptake in mucus-producing HT29 MTX cells compared to the enhanced M-cell uptake through caveolae-mediated pathway as well as
chitosan-coated particles [132]. When compared with negatively and macropinocytosis [146]. Lipid nanoparticles (SLN (solid-lipid
charged polystyrene nanoparticles, PEG-coated lipid nanocapsules nanoparticles), NLC (nanostructured lipid carriers) etc.) have been
exhibited faster diffusion through gastric mucin barrier [133]. shown to use both caveolin and clathrin-dependent pathway for their
uptake [147,148]. The enterocytes are also capable of phagocytosis via a
7. Absorption enhancing techniques based on nanomedicine TLR4 mediated pathway [149]. In Table 2, we have listed some of the
representative nanoparticles which had been evaluated to be uptaken
Nanomedicine has recently attracted considerable attention for oral through these pathways.
drug delivery [134]. Employing nanoparticles as drug carriers have After the nanoparticles get endocytosed, there are several possibil
several advantages such as selective targeting, sustained and control ities for their fate. It may get degraded in the lysosomes, or it may get
lable release, improved intracellular uptake, etc. However, oral delivery accumulated in a cell organelle, or it is exocytosed (Fig. 10) [136]. To
of nano-drug carriers has to overcome several hurdles even before reach the systemic circulation, the nanocarriers need to be designed in
encountering the epithelial cells for absorption. They have to remain such a way that it can escape or bypasses the endolysosomal compart
stable in the harsh environment of the GI tract as well as have to cross ment. Utilizing the intestinal bile acid pathway can be one such
the mucosal barrier, which acts as a mesh and can prevent nanoparticle approach that can be employed for this purpose. Samstein et al. reported
interaction with the enterocytes [135]. For entering into the systemic that deoxycholic acid can improve the stability of PLGA nanoparticles in
circulation, nanoparticles have to permeate through the apical mem the GI lumen and increased its bioavailability [150]. Deoxycholic acid
brane of the enterocytes, escape from the endolysosomal degradation, exploits the intestinal bile acid pathway to facilitate the cellular entry
and then exocytose from the basolateral membrane. Due to the presence and intracellular transfer of nanoparticles. There are two primary
of so many barriers, designing a clinically successful oral nano components of this pathway, namely, sodium-dependent bile acid
formulation is highly challenging [136]. Currently, there is no FDA transporter (ASBT) present in the apical surface and ileal bile acid
approved nanoformulation available for oral delivery. Nevertheless, binding protein (IBABP) present in the cytosol. The former is associated
multiple advanced formulations have been developed and tested at with the cellular entry, and the latter mediates the intracellular transfer
various stages of preclinical evaluation. of bile-acid conjugates. Fan et al. utilized this pathway for improving the
GI absorption of nanoparticles can occur via three possible mecha oral bioavailability of insulin [151]. ASBT-regulated internalization
nisms, transport through the transcellular route, transport through the helped the Deoxycholic acid nanoparticles (DNPs) to traverse inside the
paracellular route, and transport via the M-cells of the Peyer’s patch. intestinal epithelium. Inside the cell, DNPs escape from lysosomal
Nanoparticle size, charge, and surface properties have a significant degradation due to the membrane disrupting property of deoxycholic
impact on endocytosis mechanisms and efficiency. Bannunah et al. have acid [152]. Lastly, due to the specificity of IBABP towards bile acids, the
exhibited that nanoparticles with positive charge show better uptake by DNPs gets transferred out of the enterocyte. Kim et al. have demon
the intestinal epithelial cells compared to nanoparticles with negative strated that nanoparticles delivered through this pathway transported to
charge [137]. A similar observation was made by Du et al. as well [138]. the systemic circulation via the lymphatic system [153].
Mechanism wise, positively charged nanoparticles are endocytosed via a The retrograde pathway, which leads endosomes to the endoplasmic
mixture of the micropinocytosis, clathrin-mediated pathway, and reticulum/Golgi apparatus can also be employed in avoiding lysosomal
cholesterol-dependent pathway, whereas negatively charged nano degradation. Some studies have exhibited that caveolae-dependent up
particles are uptaken mainly via lipid raft pathway [137]. Among take can bypass lysosomes [154–157]. It has been demonstrated that the
different shapes, rod-shaped particles were found to have a longer content of caveosomes is generally transported to the endoplasmic re
residence time in the GI tract compared with spherical particles [139]. It ticulum or the Golgi apparatus [158–161]. Nanoparticles that can
was shown that smaller particles (less than 100 nm in diameter) can bypass the lysosomal degradation and can enter the ER (endoplasmic
enter into enterocytes, whereas larger ones (more than 500 nm in reticulum) or Golgi, can get exocytosed via vesicles of the conventional
diameter) remain adhered to villi surfaces [140]. Banerjee et al. have secretory pathway. Malik et al. did an extensive study on caveolae
demonstrated that intestinal cell uptake of nanoparticles is inversely dependent transcytosis. Transcytosis of caveolar vesicles is said to be
related to their size, and rod-shaped particles can be uptaken and controlled by SNARE (soluble NSF attachment protein receptor) pro
transported more efficiently compared to spherical particles, which teins. Vesicles anchor on the basolateral membrane activates the SNARE
further increases with active targeting [141]. Receptor-mediated endo machinery which results in the expulsion of vesicular contents outside
cytosis is a widely evaluated mechanism for nanoparticle uptake. Roger the cell [162–164]. One of the critical observations was that the
et al. have demonstrated that folic acid-functionalized nanoparticles can size-dependent nature of caveolar transport; small-sized nanoparticles
improve oral absorption by folate-receptor mediated endocytosis [142]. (20–40 nm) were more efficiently transcytosed than larger ones (100
In another similar study, Pridgen et al. formulated nanoparticles that nm) [162,163]. Transcytosis can also be dependent on the cytoskeleton
were aimed at targeting the neonatal Fc receptor (FcRn), which and motor protein regulation [165,166]. Another scheme to evade the
exhibited a two-fold increase in transcellular transport of insulin lysosomal degradation can be incorporating nanocarriers with
compared to the non-functionalized ones [143]. Surface modification of endo-lysosome-disrupting agents [167]. Fujiwara et al. demonstrated
nanoparticles with wheat germ agglutinin (WGA), which displays a that a cell-penetrating peptide decorated liposomes could accumulate in
selectivity in binding with N-acetyl D-glucosamine and sialic acid pre the Golgi apparatus, which implies that it had escaped the lysosomal
sent on the intestinal epithelium can also improve through degradation [168].
clathrin-mediated endocytosis process [144]. A dual approach of M-cell mediated transport is another significant pathway through
mucoadhesion and galactose targeting has been exploited by Han et al. which nanoparticles can be directly absorbed into the systemic circu
for oral delivery of anti-VEGF (vascular endothelial growth factor) lation from the GI tract. M-cells are modified enterocytes which have
11
Table 2
Examples of selective nanoparticles used for oral delivery and their uptake pathway.
Uptake pathway Ligands used Cargo Comments References
Utilizing the Intestinal bile-acid Deoxycholic acid modified nanoparticles Insulin Escorts the nanoparticle outside the basolateral membrane [151]
pathway (ASBT-mediated and helps in escaping endolysosomal degradation.
endocytosis)
Transport through both caveolin Galactose modified trimethyl chitosan- shRNA (Survivin) Use of chitosan and cysteine enhanced the mucoadhesion [145]
and clathrin dependent cysteine nanoparticles + siRNA (VEGF) and intestinal permeation. Galactose as a ligand promoted
pathway the clathrin- and caveolin- mediated endocytosis
Saqiunavir embedded in nanostructures Saqiunavir Caveolin and clathrin dependent pathway were involved in [148]
lipid carrier both endocytosis and transcytosis of nanoparticles.
Peptide Ligand CSK and IRQ Salmon calcitonin Separate SLNs were prepared with CSK and IRQ, CSK possess [147]
goblet cell targeting property while IRQ is a cell penetrating
peptide. Increased absorption of salmon calcitonin was
observed with peptide-modified SLNs.
Folate- receptor targeted Folic-acid Paclitaxel Folate receptors are expressed on the cell surface which [142,196]
transcytosis uptake the nanoparticles by caveolin-mediated
transcytotic pathway.
Lectin-mediated uptake through Wheat germ agglutinin (WGA-receptor Calcitonin Adhesive interaction occurs with the biological surface and [144,197]
glycoprotein receptor targeted transport of liposomes) the glycoprotein receptors present on the intestinal
epithelium and the uptake of liposomes occurs mostly by the
clathrin mediated pathway.
WGA, Ulex eurapeous agglutinin 1 and Insulin WGA remains stable in the GI tract and its receptors are [198]
tomato lectin present in different types of cells constituting the intestinal
membrane.
Biotin-receptor targeted Liposome decorated with biotin-conjugated Insulin Clathrin-mediated endocytosis is the proposed pathway [199]
endocytosis DSPE (1, 2-distearoyl-sn-glycero-3-phos for uptake of biotin functionalized liposomes.
phatidyl ethanolamine)
Neonatal-Fc receptor targeted IgG Fc fragments Insulin Neonatal Fc receptor facilitates the transcytosis of IgG across [143]
transcytosis and fluid-phase the cell.
pinocytosis Functionalized NPs crossed the intestinal epithelium more
significantly than the non-specific NPs (approx. 11.2 folds
more).
Uptake through M-cells Arginine-glycine-aspartic acid (RGD Ovalbumin RGD ligand gets attached to the β-1 integrin protein on M- [200]
peptide) cells.
CKS9 (M-cell homing peptide) Oral vaccine M-cell selectivity of the chitosan nanoparticles was [173]
delivery, Bmpb enhanced by conjugating it with CKS9 peptide. Intake of
vaccine peptide-conjugated NPs was observed to be 1.5 times more
than the conventional chitosan nanoparticles.
Recombinant protein (HA-HT) with CPE-30 Oral vaccination CPE-30 is a peptide ligand binding to claudin-4 receptor. It [201]
(Clostridium perfringens enterotoxin) at C- was incorporated in PLGA nanoparticle which exhibited an
terminus as claudin-4 targeting ligand. increases M-cell uptake.
Utilizing the vitamin B-12 Insulin Insulin was enclosed in dextran nanoparticles that are [202]
transport system (Intrinsic coated with Vitamin B-12 derivative, these NPs take
-receptor targeted advantage of vit. B-12 uptake pathway and get endocytosed
endocytosis) via intrinsic factor receptor to enter the systemic circulation.
very high uptake capacity and are situated at the Peyer’s patches present resulting in disruption of membranes and leakage of the drug [175]. If
in the intestinal epithelium [18]. The most efficient way of targeting they remain stable, intact liposomes can be uptaken by the enterocytes
M-cells is through active targeting. However, only a few of these re via clathrin or caveolae-dependent endocytosis, macrocytosis or mem
ceptors are currently known, and many of them are co-expressed by brane fusion [176]. Designing a liposome that survives in the GI tract is a
neighboring enterocytes, jeopardizing the targeting strategy [169]. The highly challenging task. Selecting appropriate lipid type, optimizing the
identified receptors include platelet-activating factor receptor (PAF), composition and modulating surface structure are some techniques
toll-like receptors (TLR), apical glycoprotein (GP2) and α5β1 integrins investigated to improve the stability of liposomes [176]. Increased sta
[169,170]. The ligands used for targeting these receptors include bility and reduced disruption of the liposomal membrane was observed
mannose and derivatives, lectin-binding ligands, wheat germ agglutinin when bile salts were inserted inside lipid bilayers [177,178]. Incorpo
(WGA), RGD (arginylglycylaspartic acid) peptide, LDV (Leu-Asp-Val) rating bile-salts in the bilayer of liposome leads to the formation of
derivative etc [18]. bilosomes that can be utilized as an orally-stable drug carrier. Niu et al.
Various researchers have evaluated M-cell targeting to enhance the developed such a delivery system for oral administration of insulin,
oral bioavailability of drugs. For example, Lubben et al. have shown where they incorporated bile salts in liposomes which have enclosed
enhanced uptake of chitosan microparticles in the Peyer’s patches insulin in the aqueous core [177]. Golocorbin-Kon et al. prepared bilo
[171]. Liu et al. have developed a poly(N-(2-hydroxypropyl) meth somes for oral delivery of cefotaxime and observed a 9-fold increase in
acrylamide) with vitamin B12-modified chitosan in lipid polymeric oral bioavailability than conventional liposomes [179]. For protecting
nanoparticles which have exhibited absorption through Peyer’s patch the liposomes from gastric acid, an enteric coating can be done using
[172]. Yoo et al. have used a phage display technique to select an M polymers like Eudragit L100, Eudragit S100 [180].
cell-targeting peptide and used that for making an M cell-targeted chi
tosan nanoparticle [173]. 8. Ion pair complex approach
Among different types of nanoformulations developed, liposomes
have the highest number of clinical success [174]. However, oral de The ionic nature of a drug molecule is one of the most significant
livery of liposomes is highly challenging due to its instability in the GI absorption barriers. To improve the permeation of an ionic drug through
tract. The presence of bile salts and lipolytic enzymes in the gastric juice the GI epithelium, one interesting approach is to make a neutral complex
has damaging effects on the structural integrity of the liposomes, of that molecule with a suitable counter-ion. This interaction depends on
12
Fig. 10. Different nanoparticle uptake pathways active in the enterocytes. Receptor-mediated endocytosis, caveolae or clathrin-mediated pathway, micropinocytosis,
and phagocytosis are the major uptake processes observed. In the conventional pathway (blue arrow), cargo from all these uptake pathways may end up in the
lysosome, leading to the metabolism of the cargo. An alternate pathway exists (red arrow), where endosomes may transport the cargo to the endoplasmic reticulum
through Golgi complex, from where they may get exocytosed by the secretory pathway. (For interpretation of the references to colour in this figure legend, the reader
is referred to the Web version of this article.)
the ionic potential (positive or negative) of the two moieties involved, ion-pair complex approach to improve penetration of alendronate using
and in turn, on the nature and pKa of the ionizable groups and on the pH arginine and phenazopyridine as the counter ion [187].
of the medium and composition [181]. Ion pair complexation can Ionic complexation has also been exploited for the modulation of
effectively form non-ionic complexes, reducing the polarity and posi drug release behavior. Sumaila et al. developed a sustained release
tively influencing drug absorption through passive diffusion. Construc formulation of rifampicin in which rifampicin was incorporated in a
tion of an ion-pair complex depends on the intermolecular hydrogen nanostructured ion-pair complex of low-molecular weight chitosan and
bonds, Van der Waals forces and electrostatic interactions. The interplay soy-lecithin which improved the permeability [188,189]. Srinivas et al.
between these interactive forces results in the creation of a temporary developed a sustained release formulation of diclofenac sodium by
network between the polymers. The mechanism of drug uptake depends forming a complex between carbopol and polyvinyl pyrrolidone (PVP)
upon the type of polymer chosen for complex formation. Selecting [190]. The optimized formulation demonstrated comparable dissolution
suitable polymers for complex formation can increase the retention time profile with commercially available prolonged release product. Liu et al.
at the absorption site, shield the drug from gastric degradation, increase investigated an innovative approach for enhancing oral bioavailability
solubility, enhance paracellular transport and provide site-specific de of insulin by forming ion-pair complexes which imitate a virus envelope.
livery for the drug [182,183]. In vivo studies showed the hypoglycemic effect in rats and this response
Polyelectrolytes or ion-pairing agents are classified based on their was amplified when SDS was used as a coating material for poly
ionic nature as anionic and cationic polymers. Alginic acid, hyaluronic electrolyte complexes which protected it from enzymatic degradation
acid, carboxymethyl cellulose are some of the examples of anionic ion- and increased permeation through mucus layer [191].
pairing agents. Chitosan and Eudragit are examples of cationic ion-
pairing agents [184]. 9. Conclusion and perspectives
Various scientists have evaluated different counter-ions to make ion-
pair complexes with different drugs. Negatively charged polymer As oral administration is the most preferable route for long term
λ-carrageenan was complexed with cationic tropsium chloride (used as a treatment, any drug development approach is generally focused on
model compound representing BCS class III drug), improvement in molecules which can be delivered through this route. As a result,
bioavailability was observed which was attributed to the interaction experimental molecules with a particular set of physicochemical pa
between mucus and the ion-pair complex [182]. Bigucchi et al. tried to rameters gets significant priority, which may eliminate a group of highly
achieve targeted delivery and improved absorption for vancomycin by potential lead molecules at the very early stage of drug discovery.
incorporating it in chitosan/pectin polyelectrolyte complexes [185]. Instead of the current approach of drugs with inherent absorption
Complexes were prepared with varying proportions of chitosan and property, if we can focus on the bioactivity only at the early design stage,
pectin to attain a ratio suitable for colonic delivery. Increasing the ratio that will increase the spectrum of molecules to choose from. If the
of pectin in complex formation resulted in improved mucoadhesion and formulation scientists have enough logistics in their arsenal for
a better swelling property appropriate for colonic delivery. In another improving oral bioavailability, we can have a multitude of drug candi
study, Miller et al. increased log P values of two highly hydrophilic dates for different disorders.
antiviral agent zanamivir and oseltamivir by forming a polyelectrolyte Drug formulation as a scientific stratagem has come a long way since
complex with 1-hydroxy-2-naphthoic acid (HNAP) [186]. the time of tinctures and lotions. In the case of oral delivery, we can now
Zanamivir-HNAP complex exhibited improved permeability compared protect drug degradation at the extreme gastric pH, we can precisely
to the free drug in a rat jejunum assay [186]. Samiei et al. used the control drug release at a specific site in the GI tract, we can make fast-
13
dissolving or controlled release formulations, we can also make the introduce intricate variabilities which are difficult to control, mini
formulation to stay at a particular location in the GI tract for a prolonged mizing translational potential. A thorough understanding of the physi
period, slowly releasing the drug, etc. These novel advancements have ology and cell biology of the GI epithelium would help us in
significantly impacted the clinical outcome of various drugs delivered understanding the natural absorption process which we can modulate
through the oral route [192,193]. However, till now, we have achieved for favourable outcomes. There are tremendous potentials for a well
only limited success in delivering drugs which have low permeability. designed oral formulation and through a concerted conception of
Though some of the permeation enhancers showed clinical success, physiology, cell biology, chemistry, and formulation design, we can
more focused research is needed for overcoming the absorption barriers achieve this “holy grail” of the formulation scientists.
present in the intestinal epithelium. GI uptake is found out to be highly
selective; some molecules can be absorbed very easily, whereas for
others, it presents a complex, multifaceted barrier. The complexities Declaration of competing interest
associated with these barriers stem from their diversity. GI tract is
composed of highly heterogeneous cells and tissues, which creates an The authors declare that they have no known competing financial
extremely diversified barrier, changing the barrier property from one interests or personal relationships that could have appeared to influence
region to another. Due to this reason, one uniform approach is not very the work reported in this paper.
effective, as that may be applicable to a small fraction of the total GI
surface only. A combination of multiple approaches would be a potential References
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Journal of Drug Delivery Science and Technology 61 (2021) 102178

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

A comprehensive review of the strategies to improve oral drug absorption

Fig. 2. Mechanism of gastrointestinal drug

4. Drug physicochemical parameters that influence oral 4.3. Ionization

Fig. 6. Different physicochemical parame

Fig. 7. Different prodrugs used for enhancing oral absorption.

logP of a drug, including modification of functional groups such as hy Table 1

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Journal of Drug Delivery Science and Technology 61 (2021) 102178

Contents lists available at ScienceDirect

Journal of Drug Delivery Science and Technology

A comprehensive review of the strategies to improve oral drug absorption

Fig. 2. Mechanism of gastrointestinal drug

4. Drug physicochemical parameters that influence oral 4.3. Ionization

Fig. 6. Different physicochemical parame­

Fig. 7. Different prodrugs used for enhancing oral absorption.

logP of a drug, including modification of functional groups such as hy­ Table 1

You might also like

Fig. 6. Different physicochemical parame

logP of a drug, including modification of functional groups such as hy Table 1