Pharmaceutics 12 00068 v2

pharmaceutics
Review
Strategic Approaches for Colon Targeted Drug
Delivery: An Overview of Recent Advancements
Sang Hoon Lee † , Rajiv Bajracharya † , Jeong Youn Min, Ji-Won Han, Byeong Ju Park
and Hyo-Kyung Han *
College of Pharmacy, Dongguk University-Seoul, Dongguk-ro 32, Ilsan-Donggu, Goyang 10326, Korea;
[email protected] (S.H.L.); [email protected] (R.B.); [email protected] (J.Y.M.);
[email protected] (J.-W.H.); [email protected] (B.J.P.)
* Correspondence: [email protected]; Tel.: +82-31-961-5217
† These authors contributed equally to this work.

Received: 29 November 2019; Accepted: 10 January 2020; Published: 15 January 2020
Abstract: Colon targeted drug delivery systems have gained a great deal of attention as potential
carriers for the local treatment of colonic diseases with reduced systemic side effects and also for the
enhanced oral delivery of various therapeutics vulnerable to acidic and enzymatic degradation in
the upper gastrointestinal tract. In recent years, the global pharmaceutical market for biologics has
grown, and increasing demand for a more patient-friendly drug administration system highlights
the importance of colonic drug delivery as a noninvasive delivery approach for macromolecules.
Colon-targeted drug delivery systems for macromolecules can provide therapeutic benefits including
better patient compliance (because they are pain-free and can be self-administered) and lower
costs. Therefore, to achieve more efficient colonic drug delivery for local or systemic drug effects,
various strategies have been explored including pH-dependent systems, enzyme-triggered systems,
receptor-mediated systems, and magnetically-driven systems. In this review, recent advancements in
various approaches for designing colon targeted drug delivery systems and their pharmaceutical
applications are covered with a particular emphasis on formulation technologies.
Keywords: colon; noninvasive drug delivery; inflammatory bowel diseases; colorectal cancer;
protein drugs
1. Introduction
In the past few decades, the prevalence of colonic diseases has increased worldwide, demanding the
effective local treatment of colonic diseases for more efficacious and safer drug therapies. Among colonic
diseases, colorectal cancer (CRC) causes the most cancer-related deaths in Europe (accounting more
than 200,000 deaths annually) [1], and it is the third most commonly diagnosed cancer worldwide [1,2].
The incidence of inflammatory bowel disease (IBD) is also increasing at an alarming rate in previously
low-incidence areas such as Asia [3]. Consequently, the effective treatment of colonic diseases has
become an important worldwide public healthcare issue.
For the local treatment of colonic diseases, colon-targeted drug delivery systems have been actively
pursued since conventional non-targeted therapy may have undesirable side-effects and low efficacy
due to the systemic absorption of drug before reaching the target site [4,5]. In addition to the topical
delivery, colon-targeted drug delivery systems are also applicable to improve the bioavailability of
drugs vulnerable to acidic and/or enzymatic destabilization in the upper gastrointestinal (GI) tract,
particularly macromolecules such as proteins and peptides due to lower protease activity in the
colon [6–8]. Although colonic delivery of macromolecules has been explored less extensively compared
Pharmaceutics 2020, 12, 68; doi:10.3390/pharmaceutics12010068 www.mdpi.com/journal/pharmaceutics

Pharmaceutics 2020, 12, 68 2 of 20
to small molecules, continuous research may reveal its potential as an effective oral delivery system
for macromolecules.
Colon targeted drug delivery systems are designed to selectively release a drug in response to the
colonic environment without premature drug release in the upper GI tract. Therefore, it is imperative
to consider the physiological properties of the colon and the microenvironment surrounding disease
site(s) for the successful development of colon-targeted drug delivery systems. In general, GI tract
undergoes dynamic changes in motility, fluid contents, enzymatic activity, and pH from the stomach
to the intestine [9]. Furthermore, the microenvironment surrounding a disease site in the colon is
markedly different from normal and healthy regions. Patients with colonic diseases produce high
levels of reactive oxygen species (ROS) and inflammatory cytokines, have an imbalance of important
antioxidants, and suffer from mucosal injury [10]. Given that the pathophysiological changes in the
microenvironment surrounding disease sites should be considered during formulation development,
various formulation approaches have been explored to optimize the colonic drug delivery, including
pH-sensitive systems, enzyme-triggered systems, and magnetically-driven systems. To enhance the
specificity at disease sites, receptor-mediated systems have also been studied, which preferentially
interact with specific receptors overexpressed at the site(s) of the disease. This review covers recent
advancements in various formulation approaches in designing colon-targeted drug delivery systems
and their pharmaceutical applications.
2. Formulation Approaches for Colon Targeted Drug Delivery
2.1. pH-Dependent Drug Delivery Systems

The colon exhibits a relatively higher pH than the upper GI tract, and this can be used
as a targeting strategy for colonic drug delivery. Accordingly, a colon-targeted drug delivery
system is designed by using pH-dependent polymers such as cellulose acetate phthalates (CAP),
hydroxypropyl methyl-cellulose phthalate (HPMCP) 50 and 55, copolymers of methacrylic acid and
methyl methacrylate (e.g., Eudragit® S 100, Eudragit® L, Eudragit® FS, and Eudragit® P4135 F) [11,12].
Particularly, Eudragit® polymers are the most widely used synthetic copolymers for colonic drug
delivery that offer mucoadhesiveness and pH-dependent drug release [13,14]. The ideal polymer
should be able to withstand the low pH of the stomach and the proximal part of the small intestine but
be dissolved by the pH of the terminal ileum and the colon. As a result, drug delivery systems coated
with pH-dependent polymers having a dissolution threshold of pH 6.0–7.0 are expected to delay the
drug dissolution and prevent premature drug release in the upper GI tract before reaching colonic
sites [15]. However, this pH-dependent system has demonstrated significant variability in drug release
and failure in vivo due to the vast inter- and intra-subject variability in critical parameters including
pH, fluids volumes, GI transit times, and motility [16]. Furthermore, pH ranges of GI tract can be
significantly altered by diet, disease state, water intake, and microbial metabolism [17]. For example,
patients with ulcerative colitis exhibit more acidic colonic pH compared to healthy humans, leading
to incomplete drug release from enteric coated systems at the target site [16]. Thus, the dynamic pH
change by many internal and external factors may attenuate the efficiency of pH-dependent drug
release systems, often leading to poorly site-selective drug release. Ibekwe et al. [18] also revealed that
Eudragit® S coating was not suitable for the colon-targeted drug release, either due to disintegration
failure at the target site or early drug release before the target site. In the subsequent human studies,
Ibekwe et al. [19] confirmed the lack of site-selective drug release of Eudragit® S coated tablets,
suggesting that disintegration of these tablets is affected by multiple physiological factors including
gastrointestinal pH, feed status, and intestinal transit time.
To overcome this limitation of pH-dependent delivery systems, there have been attempts to use the
combination of pH-dependent systems with other delivery systems including time-dependent systems
and enzyme-triggered systems. For example, Eudragit® S were blended with high-amylose maize
starch for the integration of pH-dependent system and colonic microbial degradation systems [16,20].
Liu et al. [21] adopted dual coating approach by using the alkaline aqueous solution of Eudragit® S
with buffering agents for inner layer and the organic solution of Eudragit® S for outer layer, accelerating
the drug dissolution at pH > 7. Subsequently, Varum et al. [22] evaluated in vivo performance of this
dual coated system in humans, demonstrating more consistent disintegration of dual coated tablets
mainly in the lower intestinal tract. Hashem et al. [23] developed microspheres combining time-and
pH-dependent systems for colonic delivery of prednisolone. By using a combination of Eudragit® S and
ethyl cellulose, they achieved greater colonic drug delivery while preventing premature drug release in
the upper intestine [23]. Eudracol® is another example of a multi-unit technology providing targeted
drug delivery to the colon, with delayed and uniform drug release. This system is based on coating the
pellet with Eudragit® RL/RS and Eudragit® FS 30D, providing colon-specific drug release in a pH-and
time-dependent manner [24]. Overall, integrated systems of the different release-triggering mechanisms
are more helpful to overcome the pathophysiological variability compared to pH-dependent system
alone, although there is still need for further improvement. In addition, nano-/micro-particles also hold
great potential for specifically targeting inflamed colonic tissues and enhance drug uptake. Accordingly,
various formulations that have combined a pH-dependent system with particle size reduction have
been developed for colon-targeted drug delivery.
2.1.1. Polymer-Based Nano-/Micro-Particles

Many studies have demonstrated that pH-dependent polymeric nanoparticles are effective
as colonic drug delivery systems [25,26]. Mutalik et al. [27] used novel pH-sensitive hydrolyzed
polyacrylamide-grafted-xanthan gum (PAAm-g-XG) for the colon-targeted delivery of curcumin
nanoparticles. The amount of drug released from the PAAm-g-XG-modified nanoparticles was
minimal in acidic conditions (pH 1.2 and 4.5), while faster and higher drug release from nanoparticles
was observed at pH 7.2 [27]. Accordingly, the nanoparticles were effective in attenuating colonic
inflammation and weight loss in IBD rat models. Furthermore, the blended mixture of two different
pH-sensitive polymers can be used to control the drug release rate. Sahu and Pandey [28] developed
the HBsAg-loaded nanoparticles by using the combination of Eudragit® L100 and Eudragit® S100 for
effective colonic immunization, confirming the effective distribution of nanoparticles at the colon along
with the improved immune response [28]. To improve the site-specificity to the colon, Naeem et al. [29]
fabricated budesonide-loaded pH-/time-dependent nanoparticles for the effective treatment of colitis.
These nanoparticles were prepared with Eudragit® FS30D and Eudragit® RS100, using an oil-in-water
emulsion solvent evaporation method. Eudragit® FS30D is a pH-dependent polymer that dissolves in
an environment above pH 7.0, while Eudragit® RS100 is a time-dependent, controlled-release polymer
having low permeability. Combining these two polymers effectively minimized premature drug release
in the upper GI tract and achieved sustained-drug release throughout the colon. Furthermore, in colitis
mice models, these pH-/time-dependent nanoparticles delivered drugs more efficiently to the inflamed
colonic sites [29].
2.1.2. Lipid-Based Formulations

Liposomes are an efficient drug delivery system composed of double-layered phospholipids [10,30,31].
Liposomes are biodegradable, biocompatible, and amenable to the incorporation of both hydrophilic
and lipophilic drugs [32,33]. The surface of liposomes can be coated with pH-dependent polymers
to avoid the destabilization of liposomes in acidic conditions and also with ligands to improve the
site-specificity. For example, Zhao et al. [34] developed colon-targeted liposomal formulations for
sorafenib by coating the surface of anionic liposomes with glycol chitosan and pH-dependent Eudragit®
S100. These liposomes showed high stability at acidic and neutral pHs with minimal drug leakage,
which enhanced the systemic exposure of sorafenib in rats [34].
Solid lipid nanoparticles are also a superior system in terms of drug protection, entrapment
efficiency, and increasing the amount of drug released at specific sites [10,35,36]. The lipid matrix of
solid lipid nanoparticles degrades at a slow rate and allows for extended drug release [10].
Self-microemulsifying drug delivery system (SMEDDS) have immense potential for enhancing the
oral bioavailability of various hydrophobic drugs, which can be useful in the design of colon-targeted
drug delivery systems [37–41]. Zhang et al. [42] prepared folate-modified SMEDDS (FSMEDDS)
containing curcumin, which were then filled into soft capsules coated with Eudragit® S 100.
This curcumin-loaded FSMEDDS formulation efficiently bound to folate receptors on colon cancer
cells. These results demonstrated that colon-targeted FSMEDDS capsules are a viable means through
which curcumin can be delivered to the colon [42].
2.1.3. Tablets and Capsules

Colon targeted drug delivery can be achieved with film coated tablets or capsules [4,43] even
though there are few commercially available products. Figure 1 is a schematic diagram that illustrates
colonic drug release from a pH-sensitive polymer-coated drug delivery system. This system is applicable
to macromolecules as well as low molecular synthetic drugs. Recently, Crowe et al. [44] developed the
Eudragit L100-coated tablets for the colonic delivery of a novel anti-tumor necrosis factor α domain
antibody (V565). This tablet exhibited the sustained drug release at pH ≥ 6 but no drug release
during 2-hr incubation in acidic conditions. In vivo studies in monkeys also supported the sustained
release of V565 in the intestine for the topical treatment of IBD [44]. In addition, the drug release
profiles can be manipulated by using a combination of copolymers with varying the ratios [44]. This
combination system may be superior to tablets coated with a single polymer for colon-targeted drug
delivery. However, the tablets coated only with pH-sensitive enteric polymers still face the issues
of premature drug release due to the variability of pH in GI tract [45]. In addition, variability in the
GI fluid composition, feeding status, and GI transit time affect the site-specific drug release from the
pH-dependent system [45]. Therefore, there have been continuous efforts to improve the targeting
effectiveness via the multi-unit formulations based on the integration of the different mechanism-based
systems with pH-dependent coating [46]. For example, Park et al. [46] prepared a bisacodyl-loaded
multi-unit tablet by coating with different combinations of pH-dependent polymers (Eudragit S and
Eudragit L) and time-dependent polymer (Eudragit RS). Drug release from the optimized tablet was
minimal in the simulated gastric and intestinal fluids while extensive drug release was observed in the
colonic fluid [46]. Recently, Foppoli et al. [47] also reported the effective colonic delivery system of
5-aminosalicylic acid based on the combination of time-dependent and pH-dependent approaches,
which was prepared by successive coating of a tablet core with low-viscosity HPMC and Eudragit® L.
Furthermore, based on a γ-scintigraphy study in human, they confirmed that there was no premature
drug release before reaching the colon in both fed and fasted states [47].
Zein is a potential carrier for controlled-release solid dispersion systems delivering poorly water
soluble drugs to the colon since it is resistant to low pH environments [48]. Recently, a single-layer
film coating of tablets using biopolymer Zein in combination with Kollicoat® MAE 100P showed high
potential to prevent the drug release in the upper GI tract for the delayed drug release in the colon [49].
The ratio of the coating components and the thickness of the coating layer play an important role in the
performance of coated tablets for colonic drug delivery.
In recent years, new coating technology has been actively pursued to improve the targeting
effectiveness of pH-dependent delivery systems. For example, ColoPulse technology is an innovative
pH responsive coating technology, which incorporates super-disintegrant in the coating matrix to
accelerate the disintegration at the target site [50–52]. The incorporation of a super-disintegrant in a
non-percolating mode leads to a more reliable and pulsatile drug release. Previous studies demonstrated
that ColoPulse tablets enabled the site-specific delivery of the active substance to the ileo-colonic region
of Crohn’s patients as well as healthy subjects [50,51]. Furthermore, food and time of food intake did not
affect the targeting effectiveness of ColoPulse delivery systems [51]. Recently, Gareb et al. [52] adopted
this technology to develop the ileo-colonic-targeted zero-order sustained-release tablets of budesonide
for the topical treatment of IBD. The results indicated that drug release from the developed tablet
began in the simulated ileum, and the release rate remained constant throughout the entire simulated
colon [52]. They also developed and validated the production process of oral infliximab tablet coated
with ColoPulse technology for the local treatment of ileo-colonic IBD [53]. Preparation of capsule shell
with built-in gastroresistance is another approach for site-specific drug delivery. These gastroresistant
Pharmaceutics 2020, 12, x 5 of 19
capsule shells may have some advantages including large production using a typical high-speed
capsule
large filler, encapsulation
production of diverse
using a typical drugs, and
high-speed potentially
capsule reducing research
filler, encapsulation and development
of diverse drugs, and
costs. Barbosa et al. [54] reported a simple method for producing enteric capsule
potentially reducing research and development costs. Barbosa et al. [54] reported a simple methodshells without any
additional coating steps. They prepared different enteric capsule shells to target various
for producing enteric capsule shells without any additional coating steps. They prepared different region of GI
tract, bycapsule
enteric using cellulose derivatives
shells to target various(HPMC
regionAS-LF and HP-55)
of GI tract, by usingalong with acrylic/methacrylic
cellulose derivatives (HPMC acidAS-
derivatives (Eudragit ® L100 and Eudragit® S100). Although the effectiveness of ready-made enteric
LF and HP-55) along with acrylic/methacrylic acid derivatives (Eudragit L100 and Eudragit S100).
® ®
capsules for
Although thecolonic drug delivery
effectiveness has not been
of ready-made thoroughly
enteric capsules evaluated
for colonicyet, thisdelivery
drug may provide another
has not been
option for targeted
thoroughly evaluated drug
yet,delivery.
this may provide another option for targeted drug delivery.
Figure 1. Drug
Drug release
release in
in the
the colon from pH-sensitive polymer-based system.
2.2. Enzyme-Sensitive
2.2. Enzyme-Sensitive Drug
Drug Delivery
Delivery Systems
Systems
2.2.1. Polysaccharide-Based Systems

2.2.1. Polysaccharide-Based Systems
Microbiota-activated delivery systems have shown promise in colon-targeted drug delivery
Microbiota-activated delivery systems have shown promise in colon-targeted drug delivery due
due to the abrupt increase of microbiota and the associated enzymatic activities in the lower GI
to the abrupt increase of microbiota and the associated enzymatic activities in the lower GI tract.
tract. These systems are dependent on the specific enzyme activity of the colonic bacteria and
These systems are dependent on the specific enzyme activity of the colonic bacteria and the polymers
the polymers degradable by colonic microorganisms. Particularly, polysaccharides such as pectin,
degradable by colonic microorganisms. Particularly, polysaccharides such as pectin, guar gum,
guar gum, inulin, and chitosan have been used in colon-targeted drug delivery systems, because
inulin, and chitosan have been used in colon-targeted drug delivery systems, because they can retain
they can retain their integrity in the upper GI tract but are metabolized by colonic microflora
their integrity in the upper GI tract but are metabolized by colonic microflora to release the entrapped
to release the entrapped drug [55]. Recently, new polysaccharides including arabinoxylans and
drug [55]. Recently, new polysaccharides including arabinoxylans and agave fructans are also being
agave fructans are also being explored for colonic drug delivery systems [56,57]. Furthermore,
explored for colonic drug delivery systems [56,57]. Furthermore, structural modifications or
structural modifications or derivatives of polysaccharides can improve drug release behavior,
derivatives of polysaccharides can improve drug release behavior, stability, and site specificity [58].
stability, and site specificity [58]. Mucoadhesiveness of polysaccharides can be advantageous for
Mucoadhesiveness of polysaccharides can be advantageous for drug uptake via the prolonged
drug uptake via the prolonged contact between the mucosal surface and drug delivery carriers.
contact between the mucosal surface and drug delivery carriers. Polysaccharide-based delivery
Polysaccharide-based delivery systems also have some additional advantages including availability
systems also have some additional advantages including availability at large scale, relatively low
at large scale, relatively low cost, low toxicity and immunogenicity, high biocompatibility, and
cost, low toxicity and immunogenicity, high biocompatibility, and biodegradability [55,59].
biodegradability [55,59]. Consequently, the polysaccharide-based, microbiota-triggered system is
Consequently, the polysaccharide-based, microbiota-triggered system is promising strategy for
colon-specific drug delivery. However, polysaccharides-based delivery systems also have some
potential drawbacks, which include broad range of molecular weights and variable chemistry of
polysaccharides [59,60]. In addition, low solubility in most organic solvents limits the chemical
modification of polysaccharides, while hydrophilicity and excessive aqueous solubility of
polysaccharides may cause the early and undesirable drug release in the upper GI tract [60,61].
promising strategy for colon-specific drug delivery. However, polysaccharides-based delivery systems
also have some potential drawbacks, which include broad range of molecular weights and variable
chemistry of polysaccharides [59,60]. In addition, low solubility in most organic solvents limits the
chemical modification of polysaccharides, while hydrophilicity and excessive aqueous solubility
of polysaccharides may cause the early and undesirable drug release in the upper GI tract [60,61].
Accordingly, cross-linking agents are often used to overcome this issue. In addition, the lack of
film forming ability, along with swelling and solubility characteristics of polysaccharides limits their
application for colonic drug delivery.
To overcome these issues and also to avoid premature drug release in the upper GI tract,
polysaccharide-based systems can be prepared by using the combination of polysaccharides and
polymers. For example, water insoluble polymers such as Eudragit RS and ethyl cellulose are commonly
used along with various polysaccharides for colonic drug delivery [62]. Overall, the use of blended
mixture of polysaccharides or other polymers appeared to be more effective in achieving colon-specific
drug delivery compared to the use of a single polysaccharide [62]. The drug release rate is dependent
on the nature and the concentration of polysaccharides in the combined mixture. Recently, Song
et al. [63] developed an oral drug delivery system with programmed drug release and magnetic
resonance imaging properties for orthotopic colon cancer therapy. They selected polyacrylic acid
(PAA) as a pH-responsive polymer and chitosan (CS) as an enzyme sensitive moiety degradable
by β-glycosidase in the colon, which were anchored on Gd3+ -doped mesoporous hydroxyapatite
nanoparticles (Gd-MHAp-NPs). After oral administration, CS and PAA could prevent premature drug
release and enhanced drug concentrations at the colon tumor sites [63]. Furthermore, encapsulating
both 5-fluorouracil and gefitinib in Gd-MHAp NPs produced a synergistic therapeutic effect, suggesting
that this novel delivery system could be a promising treatment strategy for orthotopic colon cancer
with programed drug release within the colonic environment [63]. Some of the selected examples for
polysaccharide-based systems using the combination of polysaccharides and polymers were presented
in Table 1.
Collectively, despite the main drawbacks and limitations of polysaccharide-based delivery systems,
their positive aspects and benefits have polysaccharides still used extensively in pharmaceutical
applications with various efforts to overcome the barriers.
Table 1. Selected examples of polysaccharides-based colonic delivery system.
Polysaccharide Delivery System API Mechanism Ref

pH responsive, enzyme sensitive, and
Alginate Calcium alginate beads coated with Eudragit® S-100 Curcumin [64]
mucoadhesiveness
Alginate Calcium alginate-Carboxymethyl cellulose beads 5-fluorouracil [65]
mucoadhesiveness
Alginate/Chitosan Chitosan succinate-Sodium alginate beads Capecitabine [66]
mucoadhesiveness
Alginate/Portulaca Portulaca-Sodium alginate/Borax composite microbeads 5-fluorouracil [67]
mucoadhesiveness
Alginate/Chitosan/Konjac Chitosan coated konjac glucomannan/Sodium pH responsive, enzyme sensitive, and
Ciprofloxacin [68]
glucomannan alginate/Graphene oxide microspheres mucoadhesiveness
Alginate/Pectin Sodium alginate liposome coated with pectin Salmon calcitonin [69]
mucoadhesiveness
Alginate/Chitosan Alginate/Chitosan microcapsules Interleukin-1Ra [70]
mucoadhesiveness
Alginate/Chitosan/Kappa- Dual layered pH-sensitive Alginate/Chitosan/Kappa- pH responsive, enzyme sensitive, and
5-Flurouracil [71]
carrageenan carrageenan microbeads mucoadhesiveness
Pectin/Chitosan beads containing drug loaded in potato
Pectin/Chitosan Doxorubicin Enzyme sensitive and mucoadhesiveness [58]
starch
Modified citrus pectinate-chitosan nanoparticle
Pectin/Chitosan Curcumin Enzyme sensitive and mucoadhesiveness [72]
(MCPCNP)
Modified citrus pectinate-chitosan nanoparticle Cetuximab
Pectin/Chitosan Enzyme sensitive and mucoadhesiveness [73]
(MCPCNP) Curcumin
Chitosan-Zinc-Pectinate-Polyethylene glycol (PEG)
Pectin/Chitosan Resveratrol Enzyme sensitive and mucoadhesiveness [74]
nanoparticles (NPs)
Chitosan/Nutriose PEG-containing vesicles coated with chitosan/nutriose Quercetin Enzyme sensitive and mucoadhesiveness [75]
Pectin Pectin-Zinc acetate beads coated with Eudragit S100 Pterostilbene pH responsive and enzyme sensitive [76]
Pectin/Polyethylene glycol hydrogel system containing
Pectin Bovine serum albumin Enzyme sensitive and mucoadhesiveness [77]
in-situ mineralized calcium carbonate microparticle
Guar Gum Guar Gum capped mesoporous silica nanoparticles 5-Flurouracil Enzyme sensitive and Nanoparticle [78]
Ethylene glycol dimethacrylate cross-linked guar gum pH responsive, enzyme sensitive, and
Guar Gum Ibuprofen [79]
oleate-graft-poly (methacrylic acid) hydrogel mucoadhesiveness
Inulin Cinnamate inulin microsphere hydrogel system Methotrexate Enzyme sensitive and mucoadhesiveness [80]
2.2.2. Phloral® Technology

Ibekwe et al. [20] reported a novel colonic coating technology which integrated pH-dependent
and bacterially-triggered systems into a single layer matrix film. Tablets were film-coated by using
a mixture of Eudragit S and biodegradable polysaccharide. Gamma scintigraphy study in human
volunteers confirmed the consistent disintegration of these tablets in the colon regardless of feeding
status, suggesting that this dual-mechanism coating may overcome the limitation of single trigger
systems and improve the colonic drug targeting [20]. Subsequently, Phloral® (Figure 2) coating
technology demonstrated the precise and fail-safe drug release in the colon in both healthy and
diseased states [81]. This system consists of an enzyme-sensitive component (natural polysaccharide)
and a pH-dependent polymer, where these pH and enzymatic triggers work in a complementary
manner to facilitate site-specific release [81]. Even if the dissolution threshold of the pH-dependent
polymer is not reached, the enzyme-sensitive component is independently digested by enzymes
secreted by colonic microflora. This additional fail-safe mechanism overcomes the limitations of
conventional pH-dependent systems. This innovative technology has been validated in clinical studies
for consistent drug release with reduced-intra subject variability in patients and healthy subjects [81,82].
It is also applicable for the oral delivery of macromolecules such as peptides, proteins, and vaccines.
Recently, Dodoo et al. [83] investigated the applicability of this technology in the colonic delivery of
probiotics. The commercial products as well as in-house freeze-dried Lactobacillus acidophilus strain
were encapsulated into capsules using dual-trigger coating technology to target the delivery into lower
small intestines or colon. The viabilities of approximately 90% were retained after these capsules were
exposed to gastric environment for 2 h while the unencapsulated probiotics showed poor tolerance to
the gastric environment [83]. Based on a comparative cohort analysis in patients, Allegretti et al. [84]
also demonstrated the effective colon-targeting of the fecal microbiota transplantation capsules coated
with a blend of enzyme-triggered and pH-responsive polymers.
Opticore™ that stands for optimized colonic release is a novel starch-based coating technology.
It has been developed based on the Phloral® technology and utilizes both pH-triggered and
enzymatic-triggered release. This coating technology consists of two trigger systems in an outer coating
layer and an accelerator in an inner coating layer to ensure the consistent drug release within the
colon [82]. 2020, 12, x
Pharmaceutics 8 of 19
Figure 2. Schematic illustration of Phloral® tablet (A) and the drug release from Phloral® tablet (B).
2.3. Ligand/Receptor-Mediated Drug Delivery System

For a more effective local treatment of colonic disease with reduced toxic side effects,
ligand/receptor-mediated systems have been explored that increase target specificity via the
interaction between targeting ligands on the carrier surface and specific receptors expressed at
disease sites (Figure 3) [85]. Ligand/receptor-mediated system can be designed using various ligands
(e.g., antibodies, peptides, folic acid, and hyaluronic acids) selected based on the functional
expression profiles of specific receptors/proteins at the target cells/organs. It can be also combined
For a more effective local treatment of colonic disease with reduced toxic side effects,
For a more effective
ligand/receptor-mediated localhave
systems treatment of colonic
been explored disease target
that increase with reduced toxic
specificity sideinteraction
via the effects,
ligand/receptor-mediated systems have been explored that increase target specificity via the
between targeting ligands on the carrier surface and specific receptors expressed at disease sites
interaction between targeting ligands on the carrier surface and specific receptors expressed at
(Figure 3) [85]. Ligand/receptor-mediated system can be designed using various ligands (e.g., antibodies,
disease sites (Figure 3) [85]. Ligand/receptor-mediated system can be designed using various ligands
peptides, folic acid, and hyaluronic acids) selected based on the functional expression profiles of
(e.g., antibodies, peptides, folic acid, and hyaluronic acids) selected based on the functional
specific receptors/proteins at the target cells/organs. It can be also combined with pH-dependent
expression profiles of specific receptors/proteins at the target cells/organs. It can be also combined
systems to maximize its GI stability and site specificity, if needed. Some of the ligands used in colon
with pH-dependent systems to maximize its GI stability and site specificity, if needed. Some of the
specific
ligands used inare
delivery as described
colon below. are as described below.
specific delivery
Figure
Figure 3. Schematic
3. Schematic illustrationofofrepresentative
illustration representativeligand/receptor-mediated
ligand/receptor-mediated drug
drugdelivery
deliverysystem.
system.
2.3.1. Antibodies
2.3.1. Antibodies
Harel
Harel et al.et[86]al.prepared
[86] prepared anti-transferrin
anti-transferrin receptor antibody-conjugated
receptor antibody-conjugated liposomes,
liposomes, demonstrating
demonstrating better cellular internalization of the conjugated liposomes than
better cellular internalization of the conjugated liposomes than unconjugated liposomes. Furthermore, unconjugated
liposomes. Furthermore,
anti-transferrin anti-transferrin receptor
receptor antibody-conjugated liposomes antibody-conjugated liposomes
exhibited preferential exhibited
distribution to the
preferential
inflamed mucosa distribution
rather than to the inflamed
normal mucosaresulting
mucosa, rather than normal mucosa,
in greater resulting
accumulation at in
thegreater
site of
accumulation
inflammation at thethan
(more site of inflammation
4-fold (morecompared
higher) when than 4-foldtohigher)
that ofwhen compared
normal to that
mucosa. Xiaoofetnormal
al. [87]
mucosa. Xiao et al. [87] also developed nanoparticles fabricated with single-chain
also developed nanoparticles fabricated with single-chain CD98 antibodies on their surface CD98 antibodies
on their surface (scCD98-functionalized)
(scCD98-functionalized) for IBD therapy. for IBD therapy.
CD98 CD98 is a heterodimeric
is a heterodimeric neutral aminoneutral
acid amino acid
transporter,
which is overexpressed in intestinal macrophages and colonic epithelial cells in mice with colitis.
scCD98-functionalized nanoparticles exhibited a high affinity for CD98-overexpressed cells [87].
In mice with colitis, scCD98-functionalized nanoparticles containing CD98 siRNA (siCD98) reduced
the expression levels of CD98 and the severity of colitis in mice.
2.3.2. Folic Acid

Folic acid, a water-soluble vitamin, is a tumor-selective targeting ligand because the folate receptor
is overexpressed in many types of cancers [88]. Many studies have demonstrated that nanoparticles
decorated with folic acid can facilitate tumor-selective drug uptake. For example, Xiong et al. [89]
reported that folic acid-conjugated liposomes improved the anti-cancer activity of daunorubicin
by facilitating folate receptor-mediated drug uptake. Handali et al. [90] also fabricated folic acid
(FA)-conjugated liposomes containing 5-fluorouracil (5-FU). 5-FU loaded FA-liposomes exhibited
higher cytotoxicity and significantly reduced tumor volume when compared to free drug. These results
indicate that folic acid-targeted liposomes may be an effective drug carrier that can increase selective
drug delivery to cancer cells. Previously, Zhang et al. [42] had also investigated a folate-modified
self-microemulsifying drug delivery system (FSMEDDS) containing curcumin as a means of improving
drug solubility as well as its delivery to the colon. Their results confirmed that an FSMEDDS could reach
the colon efficiently and release its drug payload rapidly [42]. Furthermore, the FSMEDDS formulation
could actively target tumor cells overexpressing folate receptors, indicating that an FSMEDDS may be
a promising carrier for the colonic delivery of curcumin.
2.3.3. Hyaluronic Acid

Hyaluronic acid (HA) is a natural polysaccharide consisting of disaccharide units of d-glucuronic
acid and N-acetyl-d-glucosamine. Since HA has a high affinity for the CD44 receptor, which is
overexpressed in various cancers, HA-conjugated drug delivery systems have been examined for
target-selective drug delivery [91]. For example, previous studies [91,92] have examined the effectiveness
of HA-modified mesoporous silica nanoparticles targeting the CD44-overexpressing cancer cells.
Vafaei et al. [93] developed self-assembled HA nanoparticles as colonic carriers of budesonide for
targeting inflamed intestinal mucosa. Budesonide loaded HA nanoparticles exhibited higher uptake in
inflamed cells over-expressing CD44 receptors, leading to a decrease in IL-8 and TNF-α secretion in an
inflamed cell model [93]. Accordingly, HA-conjugated nanoparticles appear to be a promising targeted
drug delivery system for IBD treatment.
Xiao et al. [94] investigated an HA nanoparticle-based combination chemotherapy to create
synergistic, targeted drug delivery system for colon cancer therapy. They prepared HA-functionalized
camptothecin (CPT)/curcumin (CUR)-loaded polymeric NPs (HA-CPT/CUR-NPs) approximately
289 nm in size with a negative zeta potential. HA-CPT/CUR-NPs exhibited significant cancer-targeting
capability against Colon-26 cells [94]. They also investigated a simultaneous delivery system of
curcumin (CUR) and CD98 siRNA (siCD98), using hyaluronic acid (HA)-functionalized polymeric
nanoparticles [95]. Compared to the single drug-based monotherapy, co-delivery of siCD98 and
CUR by HA-functionalized nanoparticles exhibited an enhanced therapeutic effect against ulcerative
colitis by protecting the mucosal layer and alleviating inflammation [95]. Therefore, HA-functionalized
polymeric nanoparticles may be an efficient colonic delivery carrier for combination drug therapy.
Recently, Prajapati et al. [96] developed HA-conjugated PEGylated multi-walled carbon nanotubes
containing gemcitabine (GEM/HA-PEG-MWCNTs) for colon cancer targeting. HA was conjugated
to the surface of PEGylated multi-walled carbon nanotubes (MWCNTs). This formulation showed
promising results for effective colon cancer targeting including improved anti-proliferative activity
and pharmacokinetic behaviors [96].
2.3.4. Peptides
Peptide gains a great attention as a potential ligand for targeted drug delivery. Peptides possess
many advantages including biocompatibility, cost-effectiveness, chemical diversity, and stimuli
responsiveness [97,98]. In addition, compared to small molecule ligands, peptide ligands exhibit
much higher binding affinity and specificity due to the large binding interfaces with receptors [99,100].
Peptide ligands are also advantageous due to their accessibility of high-throughput screening and ease
of synthesis by using automated solid-phase peptide synthesis devices. Furthermore, the metabolic
instability by proteases can be overcome via the modification of the peptide sequences, promoting the
application of peptide ligands in targeted drug delivery systems. Particularly, peptide-conjugated drug
delivery systems are explored as a viable approach for tumor-targeted drug delivery. For example,
Ren et al. [101] investigated the application of synthesized 12-residue peptide (TWYKIAFQRNRK,
TK peptide) for the colon-specific delivery of anticancer drugs. TK has high affinity to integrin α6 β1 ,
subtype of integrins that is upregulated in human colon cancer cells. Therefore, TK peptide was
conjugated to doxorubicin-loaded PEG-PLA micelles as a targeting ligand. This TK-conjugated micelles
exhibited significantly stronger cytotoxicity and more effectively penetrated the tumor spheroids,
suggesting TK peptide as a promising targeting ligand for colon-targeted therapy [101]. Guo et al. [102]
fabricated colon-specific nanoparticles co-modified with amphipathic chitosan derivatives (ACS) and
cell penetration peptide (CPP) to improve the oral bioavailability of insulin. ACS modification could
protect CPPs from degradation in the upper GI tract and achieved colon-specific drug delivery. Once
CS-CPP NPs reached the colon, ACSs on the surface of the NPs were gradually degraded and the
exposed CPPs facilitated the drug penetration across the colonic epithelium [102]. The results from
in vitro and in vivo evaluation suggest that CS-CPP NPs may be an effective colon-specific drug
delivery system to improve the oral absorption of proteins and peptides.
2.4. Magnetically-Driven Drug Delivery System

Magnetic microcarriers including magnetic microspheres, magnetic nanoparticles, magnetic
liposomes, and magnetic emulsions are emerging novel formulations for controlled and targeted drug
delivery (Figure 4). To improve the targeted treatment of colorectal cancer by mAb198.3 (a FAT1-specific
monoclonal antibody), Grifantini et al. [103] developed two different novel drug delivery systems
having magnetic properties to improve the targeted treatment of colorectal cancer by mAb198.3
(a FAT1-specific monoclonal antibody), where mAb198.3 was directly bound to super-paramagnetic
nanoparticles or embedded into human erythrocyte-based magnetized carriers. They observed that
both systems were very effective at targeting colon cancer cells and inhibiting cancer growth at
significantly lower antibody doses [103]. This study demonstrated the potential of magnetically-driven
drug delivery systems at improving the bioavailability and target specificity of anti-FAT mAb198.3,
opening a new avenue for colon-targeted drug delivery [103]. Another previous study improved the
efficacy of hydrocortisone using a magnetic belt on rats [104]. This nanodevice consisted of magnetic
mesoporous silica microparticles loaded with hydrocortisone. The outer surface of the drug-loaded
nanoparticles was functionalized with a bulky azo derivative with urea moieties. The nanodevices
remained capped at neutral pHs, but a noticeable payload release occurred in the presence of sodium
dithionite because it reduced the azo bonds in the capping joint [104]. They also observed the improved
efficacy in rats wearing magnetic belts, particularly being more effective when a magnetic field was
externally applied to lengthen the retention time in the areas of interest [104]. This study demonstrated
that the use of a magnetic belt increased the drug efficacy in the treatment of IBD due to enhanced
retention time of the drugs in the colon. Recently, Kono et al. [105] developed magnetically-directed
cell delivery systems via the incorporation of superparamagnetic iron oxide nanoparticles (SPIONs)
and plasmid DNA (pDNA) into RAW264 murine macrophage-like cells. They also demonstrated that
this magnetic2020,
Pharmaceutics cell12,
delivery
x system could enhance the colonic delivery of macrophages in mice [105].
11 of 19
Figure4.4.Schematic
Figure Schematic illustration of magnetic
illustration of magneticnanocarrier
nanocarrierdrug
drugdelivery
delivery system.
system.
3. Complementary Tools for Designing the Effective Colonic Drug Delivery Systems
3. Complementary Tools for Designing the Effective Colonic Drug Delivery Systems
Optimizing drug formulations using traditional approach requires many experiments including
Optimizing drug formulations using traditional approach requires many experiments including
various in vitro and in vivo tests, which are often tedious, time-consuming, high-cost tasks [106].
various in vitro and in vivo tests, which are often tedious, time-consuming, high-cost tasks [106].
Furthermore,
Furthermore,many manydrugdrug delivery systems are
delivery systems are promising
promisingininvitro
vitrobutbutoften
often
failfail
in in vivo,
vivo, which
which is is
mainly
mainlydueduetoto the lack of
the lack ofmechanistic
mechanistic insight
insight fromfrom experiments
experiments basedbased onand
on trial trialerror
and[107].
errorThe
[107].
Thecomputational methods including molecular modeling and simulation, data mining, and an artificial an
computational methods including molecular modeling and simulation, data mining, and
artificial intelligence
intelligence technique
technique are useful
are useful to expedite
to expedite the rational
the rational formulation
formulation design.
design. It canIt can
savesave much
much
experimentation
experimentationeffort
effortand
andtime
timeby
byidentifying the critical
identifying the criticalfactors
factorsfor
forthe
theoptimization
optimization of of formulations
formulations
and selecting the promising candidates for further experimental confirmation. For example,
Metwally and Hathout [106] have proven that the combined use of several chemo/bio informatics
and statistical tools could effectively predict the loading efficiency of drugs in a carrier and also
elucidate the effect of certain molecular descriptors of drugs on their docked binding energies on
carriers [106]. This would allow the accurate estimation of entrapment efficiencies and loading
and selecting the promising candidates for further experimental confirmation. For example, Metwally
and Hathout [106] have proven that the combined use of several chemo/bio informatics and statistical
tools could effectively predict the loading efficiency of drugs in a carrier and also elucidate the effect of
certain molecular descriptors of drugs on their docked binding energies on carriers [106]. This would
allow the accurate estimation of entrapment efficiencies and loading capacity in drug delivery systems
without exhaustive laboratory experiments.
In general, computer modeling techniques allow the identification of critical variables for
the optimization of formulations and also provide detailed information on molecular interaction
of drug-carrier, entrapment efficiency, drug distribution/localization in delivery systems, stability,
drug release behavior, and so on [107]. Consequently, these computational methods are capable
of complementing experiments and assist more rational formulation design and optimization.
Furthermore, integration of such computational tools with other technology for targeted drug delivery
has led to a new era of revolutionized drug delivery systems such as electronic drug delivery devices and
radiofrequency drug delivery devices. Some of selected examples on the application of computational
and device-based approaches to assist the colon-specific formulation design are discussed below.
3.1. Computer-Assisted Formulation Design

Chemo/bio-informatics tools and statistical methods are useful to assist the rational formulation
design and complement experiments. The computational approach is also applicable for investigating
the performance of drug delivery systems along with the effect of various environmental conditions
including pH, temperature, salt concentration, external stimulus, and the interaction with other
biomolecules in the body. Patra et al. [108] synthesized biopolymeric glycogen-based fluorescent gel
for the colon specific drug delivery of metronidazole and ciprofloxacin. In addition to the experimental
evaluation, they carried out ab initio molecular dynamics study to investigate the probable interaction
of drugs with hydrogel in molecular level. They also performed Quantum mechanical/Molecular
mechanics calculations to investigate the pH-responsive swelling and drug release from the developed
hydrogel [108]. The results indicated the physical interaction between hydrogel and drug molecules
during its swelling and also confirmed the pH-dependent drug release patterns, in correspondence with
the experimental observations [106]. Markovic et al. [109] suggest a novel phospholipid (PL)-based
prodrug approach for colon-specific drug delivery, by targeting the phospholipase A2 (PLA2 ) as the
PL-prodrug activating enzyme overexpressed in the inflamed colonic tissues. First, they selected
Fmoc (fluorenylmethyloxycarbonyl) as a model compound and synthesized PL-Fmoc conjugates with
different linker lengths between the PL and the drug moiety. Then, they evaluated experimentally
the PLA2 -mediated activation of the PL-Fmoc conjugates. Furthermore, they also conducted a novel
molecular dynamics simulation of the transition state of the conjugate in the PLA2 enzyme complex, in
order to determine the optimal linker length for the clinically relevant drug in ulcerative colitis such
as methotrexate. The simulation results indicated that the free energy of the PL-prodrug binding to
the transition state geometry of the enzyme dictated the rate of PLA2 -mediated activation, and the
linker length of 6 should be optimal with the highest extent of PLA2 -mediated activation, while shorter
linkers were activated to a lower extent. This study suggests that these highly reliable computational
methods allow the optimization of the chemical structure of the molecular linker between the PL and
drug moiety and also reduce the amount of chemical synthesis needed for the development of effective
prodrugs for colon-specific delivery [109].
Recently, SIMGI (SIMulator Gastro-Intestinal) as an automated in silico model, enables to simulate
the physiological processes in GI tract and also to reproduce the microbiota in the colon [110].
This computational model is applicable to examine the food effects on modulating the gut microbiota
and its metabolic activity. This model may be beneficial while designing a more efficient colon-targeted
delivery system in a quick and economical way, although it has a short history, and some drawbacks of
this system are on the way to be overcome [110].
Collectively, computational approach can offer an efficient toolbox for designing the
optimal colon-targeted drug delivery systems and predicting the in vivo performance of the
developed formulations.
3.2. Electronic Device-Assisted Formulation Design

For the successful development of colon-specific drug delivery systems, in vivo characterization
of drug absorption throughout the GI tract is essential. Accordingly, there is a strong need for a quick
and simple way to precisely and reliably assess the drug release properties within the GI tract to
determine whether the tested formulation is valid for modified drug release. In that sense, the use of
electronics brings a new approach for integration of data from multiple sources. IntelliCap® is the
world’s first intelligent electronic drug delivery and monitoring device, which combines controlled
drug release, patient monitoring, and real-time wireless communication [111,112]. Since this electronic
capsule features real-time wireless data recording, it can provide care givers the ability to monitor
the progress of the capsule through the GI tract. Furthermore, simultaneous measurement of pH and
transit, along with accurately targeting drug delivery, makes in vivo data available for a formulation
design [111,112]. Consequently, IntelliCap® technology provides a fast and convenient tool for the
controlled drug release to specific sites in the GI tract. By using Intellicap® system, Maurer et al. [50,51]
confirmed the ileo-colonic drug release of ColoPulse tablets in humans, supporting that the ColoPulse
system is a promising colonic drug delivery system.
In addition to many benefits, there are also some disadvantages associated with electronic capsules
including high cost, manufacturing difficulties, biocompatibility issues, and potential risk of device
failure [111,112]. Hence, there should be continuous efforts to overcome these disadvantages in order
to make electronic delivery systems more widely compatible. In the long run, electronic drug delivery
system is a promising new approach for the controlled drug release at the desired target sites.
4. Summary
Colon-targeted drug delivery is an essential strategy for more effective local treatment of colonic
diseases such as IBD and colorectal cancers. It may offer many benefits over conventional dosage
forms in terms of safety, efficacy, and patient compliance. In addition, colon-targeted delivery systems
are applicable to improve the systemic exposure of acid-and/or enzyme-labile drugs including
macromolecules. Although advancements in biotechnology and protein engineering have expanded
the therapeutic application of proteins and peptides, most biologics on the pharmaceutical market
are in parenteral formulations due to their low permeability and physicochemical and metabolic
instability in the GI tract. Therefore, colon-targeted delivery systems gain great attention as an effective
formulation strategy to improve the oral bioavailability of macromolecules.
In this review, various formulation approaches to develop the effective colon-targeted delivery
systems were discussed with some case studies. All of these formulation strategies possess their own
advantages and disadvantages, requiring continuous refinement to improve their therapeutic efficiency.
For the successful development of colon-targeted drug delivery systems, it is imperative to consider the
physiological and pathophysiological properties of the colon and the microenvironment surrounding
disease site(s). However, the dynamic changes in the physiological conditions in GI tract and also
the pathophysiological changes in the microenvironment surrounding disease sites make optimal
formulation design more complicated, often leading to in vivo failure with lack of site specificity.
For example, the dynamic pH change in GI tract by many internal and external factors may attenuate
the efficiency of pH-dependent drug release systems, resulting in premature drug release in upper GI
tract, or incomplete drug release at the target site. Accordingly, the combined systems of the different
release-triggering mechanisms are actively pursued to overcome the pathophysiological variability
issues. In addition, nano-/micro-particles hold great potential for enhancing drug targeting as well
as drug uptake. Therefore, various formulations with particle size reduction may be beneficial for
colon-targeted drug delivery. Computer-assisted and electronic device-assisted formulation design also
allow more rational formulation design and optimization, reducing the time and cost for experiments.
Taken together, to overcome the limitations of current formulation approaches, there should be
continuous efforts to invent new formulation technologies. These efforts include the discovery of
the new biocompatible functional materials, the development of more precise drug delivery devices,
and utilization of big data.
Author Contributions: Conceptualization, writing, and manuscript-review and editing, H.-K.H.; writing—
preparing the original draft, S.H.L., R.B., J.Y.M., and J.-W.H.; support in the collection of literature information
B.J.P. All authors have read and agreed to the published version of the manuscript.
Funding: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the
Korea government (MSIT) (No. 2019R1A2C2004873 and No. 2018R1A5A2023127).
Conflicts of Interest: The authors declare no conflict of interest.
References
1. Ferlay, J.; Colombet, M.; Soerjomataram, I.; Dyba, T.; Randi, G.; Bettio, M.; Gavin, A.; Visser, O.; Bray, F.
Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018.
Eur. J. Cancer 2018, 103, 356–387. [CrossRef] [PubMed]
2. Keum, N.; Giovannucci, E. Global burden of colorectal cancer: Emerging trends, risk factors and prevention
strategies. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 713–732. [CrossRef] [PubMed]
3. Ng, S.C.; Bernstein, C.N.; Vatn, M.H.; Lakatos, P.L.; Loftus, E.V.; Tysk, C.; O’morain, C.; Moum, B.;
Colombel, J.F.; Epidemiology and Natural History Task Force of the International Organization of
inflammatory Bowel Disease (IOIBD). Geographical variability and environmental risk factors in inflammatory
bowel disease. Gut 2013, 62, 630–649. [CrossRef] [PubMed]
4. Patole, V.C.; Pandit, A.P. Mesalamine-loaded alginate microspheres filled in enteric coated HPMC capsules
for local treatment of ulcerative colitis: In Vitro and in vivo characterization. J. Pharm. Investig. 2018, 48,
257–267. [CrossRef]
5. Rahier, J.F.; Magro, F.; Abreu, C.; Armuzzi, A.; Ben-Horin, S.; Chowers, Y.; Cottone, M.; de Ridder, L.;
Doherty, G.; Ehehalt, R.; et al. Second European evidence-based consensus on the prevention, diagnosis and
management of opportunistic infections in inflammatory bowel disease. J. Crohns. Colitis. 2014, 8, 443–468.
[CrossRef] [PubMed]
6. Wang, X.; Yu, D.G.; Li, X.Y.; Bligh, S.W.; Williams, G.R. Electrospun medicated shellac nanofibers for
colon-targeted drug delivery. Int. J. Pharm. 2015, 490, 384–390. [CrossRef] [PubMed]
7. Vats, A.; Pathak, K. Exploiting microspheres as a therapeutic proficient doer for colon delivery: A review.
Expert Opin. Drug Deliv. 2013, 10, 545–557. [CrossRef]
8. Duran-Lobato, M.; Niu, Z.; Alonso, M.J. Oral delivery of biologics for precision medicine. Adv. Mater. 2019,
e1901935. [CrossRef]
9. Hua, S.; Marks, E.; Schneider, J.J.; Keely, S. Advances in oral nano-delivery systems for colon targeted drug
delivery in inflammatory bowel disease: Selective targeting to diseased versus healthy tissue. Nanomedicine
2015, 11, 1117–1132. [CrossRef]
10. Guo, Y.; Zong, S.; Pu, Y.; Xu, B.; Zhang, T.; Wang, B. Advances in pharmaceutical strategies enhancing the
efficiencies of oral colon-targeted delivery systems in inflammatory bowel disease. Molecules 2018, 23, 1622.
[CrossRef]
11. Newton, A.; Prabakaran, L.; Jayaveera, K. Pectin-HPMC E15LV vs. pH sensitive polymer coating films
for delayed drug delivery to colon: A comparison of two dissolution models to assess colonic targeting
performance in-vitro. Int. J. Appl. Res. Nat. Prod. 2012, 5, 1–16.
12. Nidhi; Rashid, M.; Kaur, V.; Hallan, S.S.; Sharma, S.; Mishra, N. Microparticles as controlled drug delivery
carrier for the treatment of ulcerative colitis: A brief review. Saudi Pharm. J. 2016, 24, 458–472. [CrossRef]
[PubMed]
13. Naik, J.B.; Waghulde, M.R. Development of vildagliptin loaded Eudragit® microspheres by screening design:
In vitro evaluation. J. Pharm. Investig. 2018, 48, 627–637. [CrossRef]
14. Hua, S. Orally administered liposomal formulations for colon targeted drug delivery. Front. Pharmacol. 2014,
5, 138. [CrossRef] [PubMed]
15. Maroni, A.; Zema, L.; Loreti, G.; Palugan, L.; Gazzaniga, A. Film coatings for oral pulsatile release. Int. J.
Pharm. 2013, 457, 362–371. [CrossRef] [PubMed]
16. Maroni, A.; Moutaharrik, S.; Zema, L.; Gazzaniga, A. Enteric coatings for colonic drug delivery: State of the
art. Expert Opin. Drug Deliv. 2017, 14, 1027–1029. [CrossRef]
17. Bak, A.; Ashford, M.; Brayden, D.J. Local delivery of macromolecules to treat diseases associated with the
colon. Adv. Drug Deliv. Rev. 2018, 136–137, 2–27. [CrossRef]
18. Ibekwe, V.C.; Liu, F.; Fadda, H.M.; Khela, M.K.; Evans, D.F.; Parsons, G.E.; Basit, A.W. An investigation into
the in vivo performance variability of pH responsive polymers for ileo-colonic drug delivery using gamma
scintigraphy in humans. J. Pharm. Sci. 2006, 95, 2760–2766. [CrossRef]
19. Ibekwe, V.C.; Fadda, H.M.; McConnell, E.L.; Khela, M.K.; Evans, D.F.; Basit, A.W. Interplay between intestinal
pH, transit time and feed status on the in vivo performance of pH responsive ileo-colonic release systems.
Pharm. Res. 2008, 25, 1828–1835. [CrossRef]
20. Ibekwe, V.C.; Khela, M.K.; Evans, D.F.; Basit, A.W. A new concept in colonic drug targeting: A combined
pH-responsive and bacterially-triggered drug delivery technology. Aliment. Pharmacol. Ther. 2008, 28,
21. Liu, F.; Moreno, P.; Basit, A.W. A novel double-coating approach for improved pH-triggered delivery to
the ileo-colonic region of the gastrointestinal tract. Eur. J. Pharm. Biopharm. 2010, 74, 311–315. [CrossRef]
[PubMed]
22. Varum, F.J.; Hatton, G.B.; Freire, A.C.; Basit, A.W. A novel coating concept for ileo-colonic drug targeting:
Proof of concept in humans using scintigraphy. Eur. J. Pharm. Biopharm. 2013, 84, 573–577. [CrossRef]
[PubMed]
23. Hashem, F.M.; Shaker, D.S.; Nasr, M.; Ragaey, R. In Vitro and in vivo evaluation of combined time and
pH-dependent oral colonic targeted prednisolone microspheres. Br. J. Pharm. Res. 2013, 3, 420–434.
[CrossRef]
24. Patel, M.M. Cutting-edge technologies in colon-targeted drug delivery systems. Expert Opin. Drug Deliv.
2011, 8, 1247–1258. [CrossRef]
25. Zeeshan, M.; Ali, H.; Khan, S.; Khan, S.A.; Weigmann, B. Advances in orally-delivered pH-sensitive
nanocarrier systems; an optimistic approach for the treatment of inflammatory bowel disease. Int. J. Pharm.
2019, 558, 201–214. [CrossRef]
26. Ma, X.; Williams, R.O. Polymeric nanomedicines for poorly soluble drugs in oral delivery systems: An update.
J. Pharm. Investig. 2018, 48, 61–75.
27. Mutalik, S.; Suthar, N.A.; Managuli, R.S.; Shetty, P.K.; Avadhani, K.; Kalthur, G.; Kulkarni, R.V.; Thomas, R.
Development and performance evaluation of novel nanoparticles of a grafted copolymer loaded with
curcumin. Int. J. Biol. Macromol. 2016, 86, 709–720. [CrossRef]
28. Sahu, K.K.; Pandey, R.S. Development and characterization of HBsAg-loaded Eudragit nanoparticles for
effective colonic immunization. Pharm. Dev. Technol. 2019, 24, 166–175. [CrossRef]
29. Naeem, M.; Choi, M.; Cao, J.; Lee, Y.; Ikram, M.; Yoon, S.; Lee, J.; Moon, H.R.; Kim, M.S.; Jung, Y.; et al.
Colon-targeted delivery of budesonide using dual pH- and time-dependent polymeric nanoparticles for
colitis therapy. Drug Des. Devel. Ther. 2015, 9, 3789–3799.
30. Seo, J.; Kim, M.J.; Jeon, S.O.; Oh, D.H.; Yoon, K.H.; Choi, Y.W.; Bashyal, S.; Lee, S. Enhanced topical delivery
of fish scale collagen employing negatively surface-modified nanoliposome. J. Pharm. Investig. 2018, 48,
31. Han, S.M.; Na, Y.G.; Lee, H.S.; Son, G.H.; Jeon, S.H.; Bang, K.H.; Kim, S.J.; Lee, H.J.; Cho, C.W. Improvement
of cellular uptake of hydrophilic molecule, calcein, formulated by liposome. J. Pharm. Investig. 2018, 48,
32. Yoon, S.W.; Shin, D.H.; Kim, J.S. Liposomal itraconazole formulation for the treatment of glioblastoma using
inclusion complex with HP-β-CD. J. Pharm. Investig. 2019, 49, 477–483. [CrossRef]
33. Lee, M.K. Clinical usefulness of liposomal formulations in cancer therapy: Lessons from the experiences of
doxorubicin. J. Pharm. Investig. 2019, 49, 203–214. [CrossRef]
34. Zhao, M.; Lee, S.H.; Song, J.G.; Kim, H.Y.; Han, H.K. Enhanced oral absorption of sorafenib via the
layer-by-layer deposition of a pH-sensitive polymer and glycol chitosan on the liposome. Int. J. Pharm. 2018,
544, 14–20. [CrossRef]
35. Gupta, B.; Yong, C.S.; Kim, J.O. Solid matrix-based lipid nanoplatforms as carriers for combinational
therapeutics in cancer. J. Pharm. Investig. 2017, 47, 461–473. [CrossRef]
36. Pokharkar, V.; Patil-Gadhe, A.; Kaur, G. Physicochemical and pharmacokinetic evaluation of rosuvastatin
loaded nanostructured lipid carriers: Influence of long-and medium-chain fatty acid mixture. J. Pharm.
Investig. 2018, 48, 465–476. [CrossRef]
37. Singh, D.; Tiwary, A.K.; Bedi, N. Canagliflozin loaded SMEDDS: Formulation optimization for improved
solubility, permeability and pharmacokinetic performance. J. Pharm. Investig. 2019, 49, 67–85. [CrossRef]
38. Nekkanti, V.; Rueda, J.; Wang, Z.; Betageri, G.V. Comparative evaluation of proliposomes and self
micro-emulsifying drug delivery system for improved oral bioavailability of nisoldipine. Int. J. Pharm. 2016,
505, 79–88. [CrossRef]
39. Rahman, M.A.; Mujahid, M.; Hussain, A.; Iqbal, Z. Development and pharmacokinetic evaluation of
spray-dried self-nanoemulsifying drug delivery system of sertraline. J. Pharm. Investig. 2017, 47, 325–333.
[CrossRef]
40. Madhav, K.V.; Kishan, V. Self microemulsifying particles of loratadine for improved oral bioavailability:
Preparation, characterization and in vivo evaluation. J. Pharm. Investig. 2018, 48, 497–508. [CrossRef]
41. Ahsan, M.N.; Verma, P.R.P. Enhancement of in vitro dissolution and pharmacodynamic potential of olanzapine
using solid SNEDDS. J. Pharm. Investig. 2018, 48, 269–278. [CrossRef]
42. Zhang, L.; Zhu, W.; Yang, C.; Guo, H.; Yu, A.; Ji, J.; Gao, Y.; Sun, M.; Zhai, G. A novel folate-modified
self-microemulsifying drug delivery system of curcumin for colon targeting. Int. J. Nanomed. 2012, 7, 151–162.
43. Yoshida, T.; Lai, T.C.; Kwon, G.S.; Sako, K. pH- and ion-sensitive polymers for drug delivery. Expert Opin.
Drug Deliv. 2013, 10, 1497–1513. [CrossRef]
44. Crowe, J.S.; Roberts, K.J.; Carlton, T.M.; Maggiore, L.; Cubitt, M.F.; Ray, K.P.; Donnelly, M.C.; Wahlich, J.C.;
Humphreys, J.I.; Robinson, J.R.; et al. Oral delivery of the anti-tumor necrosis factor alpha domain antibody,
V565, results in high intestinal and fecal concentrations with minimal systemic exposure in cynomolgus
monkeys. Drug Dev. Ind. Pharm. 2019, 45, 387–394. [CrossRef]
45. Lin, C.; Ng, H.L.; Pan, W.; Chen, H.; Zhang, G.; Bian, Z.; Lu, A.; Yang, Z. Exploring different strategies for
efficient delivery of colorectal cancer therapy. Int. J. Mol. Sci. 2015, 16, 26936–26952. [CrossRef]
46. Park, H.J.; Jung, H.J.; Ho, M.J.; Lee, D.R.; Cho, H.R.; Choi, Y.S.; Jun, J.; Son, M.; Kang, M.J. Colon-targeted
delivery of solubilized bisacodyl by doubly enteric-coated multiple-unit tablet. Eur. J. Pharm. 2017, 102,
47. Foppoli, A.; Maroni, A.; Moutaharrik, S.; Melocchi, A.; Zema, L.; Palugan, L.; Cerea, M.; Gazzaniga, A.
In Vitro and human pharmacoscintigraphic evaluation of an oral 5-ASA delivery system for colonic release.
Int. J. Pharm. 2019, 572, 118723. [CrossRef]
48. Nguyen, M.N.U.; Vo, T.V.; Tran, P.H.L.; Tran, T.T.D. Zein-based solid dispersion for potential application in
targeted delivery. J. Pharm. Investig. 2017, 47, 357–364. [CrossRef]
49. Nguyen, M.N.U.; Tran, P.H.L.; Tran, T.T.D. A single-layer film coating for colon-targeted oral delivery. Int. J.
Pharm. 2019, 559, 402–409. [CrossRef]
50. Maurer, J.M.; Schellekens, R.C.; van Rieke, H.M.; Stellaard, F.; Wutzke, K.D.; Buurman, D.J.; Dijkstra, G.;
Woerdenbag, H.J.; Frijlink, H.W.; Kosterink, J.G. ColoPulse tablets perform comparably in healthy volunteers
and Crohn’s patients and show no influence of food and time of food intake on bioavailability. J. Control.
Release 2013, 172, 618–624. [CrossRef]
51. Maurer, J.M.; Schellekens, R.C.; van Rieke, H.M.; Wanke, C.; Iordanov, V.; Stellaard, F.; Wutzke, K.D.;
Dijkstra, G.; van der Zee, M.; Woerdenbag, H.J.; et al. Gastrointestinal pH and transit time profiling in
healthy volunteers using the IntelliCap system confirms ileo-colonic release of ColoPulse tablets. PLoS ONE
2015, 10, e0129076. [CrossRef]
52. Gareb, B.; Dijkstra, G.; Kosterink, J.G.W.; Frijlink, H.W. Development of novel zero-order release budesonide
tablets for the treatment of ileo-colonic inflammatory bowel disease and comparison with formulations
currently used in clinical practice. Int. J. Pharm. 2019, 554, 366–375. [CrossRef]
53. Gareb, B.; Posthumus, S.; Beugeling, M.; Koopmans, P.; Touw, D.J.; Dijkstra, G.; Kosterink, J.G.W.; Frijlink, H.W.
Towards the oral treatment of ileo-colonic inflammatory bowel disease with Infliximab tablets: Development
and validation of the production process. Pharmaceutics 2019, 11, 428. [CrossRef]
54. Barbosa, J.A.C.; Al-Kauraishi, M.M.; Smith, A.M.; Conway, B.R.; Merchant, H.A. Achieving gastroresistance
without coating: Formulation of capsule shells from enteric polymers. Eur. J. Pharm. Biopharm. 2019, 144,
55. Kotla, N.G.; Rana, S.; Sivaraman, G.; Sunnapu, O.; Vemula, P.K.; Pandit, A.; Rochev, Y. Bioresponsive drug
delivery systems in intestinal inflammation: State-of-the-art and future perspectives. Adv. Drug Deliv. Rev.
2019, 146, 248–266. [CrossRef]
56. Morales-Burgos, A.M.; Carvajal-Millan, E.; Rascón-Chu, A.; Martínez-López, A.L.; Lizardi-Mendoza, J.;
López-Franco, Y.L.; Brown-Bojorquez, F. Tailoring reversible insulin aggregates loaded in electrosprayed
arabinoxylan microspheres intended for colon-targeted delivery. J. Appl. Polym. Sci. 2019, 136, 47960.
[CrossRef]
57. Miramontes-Corona, C.; Escalante, A.; Delgado, E.; Corona-González, R.I.; Vázquez-Torres, H.; Toriz, G.
Hydrophobic agave fructans for sustained drug delivery to the human colon. React. Funct. Polym. 2019, in
press. [CrossRef]
58. Zhu, J.; Zhong, L.; Chen, W.; Song, Y.; Qian, Z.; Cao, X.; Huang, Q.; Zhang, B.; Chen, H.; Chen, W.
Preparation and characterization of pectin/chitosan beads containing porous starch embedded with
doxorubicin hydrochloride: A novel and simple colon targeted drug delivery system. Food Hydrocoll.
2019, 95, 562–570. [CrossRef]
59. Barclay, T.G.; Day, C.M.; Petrovsky, N.; Garg, S. Review of polysaccharide particle-based functional drug
delivery. Carbohydr. Polym. 2019, 221, 94–112. [CrossRef]
60. Jain, V.; Shukla, N.; Mahajan, S. Polysaccharides in colon specific drug delivery. J. Transl. Sci. 2015, 1, 3–11.
61. Wen, Y.; Oh, J.K. Recent strategies to develop polysaccharide-based nanomaterials for biomedical applications.
Macromol. Rapid. Commun. 2014, 35, 1819–1832. [CrossRef]
62. Shaikh, R.; Singh, T.R.R.; Garland, M.J.; Woolfson, A.D.; Donnelly, R.F. Mucoadhesive drug delivery systems.
J. Pharm. Bioallied. Sci. 2011, 3, 89–100.
63. Song, Q.; Jia, J.; Niu, X.; Zheng, C.; Zhao, H.; Sun, L.; Zhang, H.; Wang, L.; Zhang, Z.; Zhang, Y. An oral drug
delivery system with programmed drug release and imaging properties for orthotopic colon cancer therapy.
Nanoscale 2019, 11, 15958–15970. [CrossRef]
64. Sookkasem, A.; Chatpun, S.; Yuenyongsawad, S.; Wiwattanapatapee, R. Alginate beads for colon specific
delivery of self-emulsifying curcumin. J. Drug Deliv. Sci. Technol. 2015, 29, 159–166. [CrossRef]
65. Agarwal, T.; Narayana, S.N.; Pal, K.; Pramanik, K.; Giri, S.; Banerjee, I. Calcium alginate-carboxymethyl
cellulose beads for colon-targeted drug delivery. Int. J. Biol. Macromol. 2015, 75, 409–417. [CrossRef]
66. Sinha, P.; Udhumansha, U.; Rathnam, G.; Ganesh, M.; Jang, H.T. Capecitabine encapsulated chitosan
succinate-sodium alginate macromolecular complex beads for colon cancer targeted delivery: In vitro
evaluation. Int. J. Biol. Macromol. 2018, 117, 840–850. [CrossRef]
67. Asnani, G.P.; Bahekar, J.; Kokare, C.R. Development of novel pH–responsive dual crosslinked hydrogel
beads based on Portulaca oleracea polysaccharide-alginate-borax for colon specific delivery of 5-fluorouracil.
J. Drug Deliv. Sci. Technol. 2018, 48, 200–208. [CrossRef]
68. Yuan, Y.; Xu, X.; Gong, J.; Mu, R.; Li, Y.; Wu, C.; Pang, J. Fabrication of chitosan-coated konjac
glucomannan/sodium alginate/graphene oxide microspheres with enhanced colon-targeted delivery. Int. J.
Biol. Macromol. 2019, 131, 209–217. [CrossRef]
69. Feng, K.; Li, C.; Wei, Y.S.; Zong, M.H.; Wu, H.; Han, S.Y. Development of a polysaccharide based multi-unit
nanofiber mat for colon-targeted sustained release of salmon calcitonin. J. Colloid. Interface Sci. 2019, 552,
70. Cao, J.; Cheng, J.; Xi, S.; Qi, X.; Shen, S.; Ge, Y. Alginate/chitosan microcapsules for in-situ delivery of the
protein, interleukin-1 receptor antagonist (IL-1Ra), for the treatment of dextran sulfate sodium (DSS)-induced
colitis in a mouse model. Eur. J. Pharm. Biopharm. 2019, 137, 112–121. [CrossRef]
71. Sun, X.; Liu, C.; Omer, A.M.; Yang, L.Y.; Ouyang, X.K. Dual-layered pH-sensitive
alginate/chitosan/kappa-carrageenan microbeads for colon-targeted release of 5-fluorouracil. Int. J. Biol.
Macromol. 2019, 132, 487–494. [CrossRef]
72. Sabra, R.; Roberts, C.J.; Billa, N. Courier properties of modified citrus pectinate-chitosan nanoparticles in
colon delivery of curcumin. Colloid. Interface Sci. Commun. 2019, 32, 100192. [CrossRef]
73. Sabra, R.; Billa, N.; Roberts, C.J. Cetuximab-conjugated chitosan-pectinate (modified) composite nanoparticles
for targeting colon cancer. Int. J. Pharm. 2019, 572, 118775. [CrossRef]
74. Andishmand, H.; Tabibiazar, M.; Mohammadifar, M.A.; Hamishehkar, H. Pectin-zinc-chitosan-polyethylene

glycol colloidal nano-suspension as a food grade carrier for colon targeted delivery of resveratrol. Int. J. Biol.
Macromol. 2017, 97, 16–22. [CrossRef]
75. Castangia, I.; Nácher, A.; Caddeo, C.; Merino, V.; Díez-Sales, O.; Catalán-Latorre, A.; Fernàndez-Busquets, X.;
Fadda, A.M.; Manconi, M. Therapeutic efficacy of quercetin enzyme-responsive nanovesicles for the treatment
of experimental colitis in rats. Acta Biomater. 2015, 13, 216–227. [CrossRef]
76. Ansari, M.; Sadarani, B.; Majumdar, A. Colon targeted beads loaded with pterostilbene: Formulation,
optimization, characterization and in vivo evaluation. Saudi Pharm. J. 2019, 27, 71–81. [CrossRef]
77. Gautam, M.; Santhiya, D. In-situ mineralization of calcium carbonate in pectin based edible hydrogel for the
delivery of protein at colon. J. Drug Deliv. Sci. Technol. 2019, 53, 101137. [CrossRef]
78. Kumar, B.; Kulanthaivel, S.; Mondal, A.; Mishra, S.; Banerjee, B.; Bhaumik, A.; Banerjee, I.; Giri, S. Mesoporous
silica nanoparticle based enzyme responsive system for colon specific drug delivery through guar gum
capping. Colloids Surf. B 2017, 150, 352–361. [CrossRef]
79. Seeli, D.S.; Prabaharan, M. Guar gum oleate-graft-poly(methacrylic acid) hydrogel as a colon-specific
controlled drug delivery carrier. Carbohydr. Polym. 2017, 158, 51–57. [CrossRef]
80. López-Molina, D.; Chazarra, S.; How, C.W.; Pruidze, N.; Navarro-Perán, E.; García-Cánovas, F.;
García-Ruiz, P.A.; Rojas-Melgarejo, F.; Rodríguez-López, J.N. Cinnamate of inulin as a vehicle for delivery of
colonic drugs. Int. J. Pharm. 2015, 479, 96–102. [CrossRef]
81. Ranmal, S.R.; Yadav, V.; Basit, A.W. Targeting the end goal: Opportunities & innovations in colonic drug
delivery. ONdrugDelivery Mag. 2017, 77, 22–26.
82. D’Haens, G.R.; Snadborn, W.J.; Zou, G.; Stitt, L.W.; Rutgeerts, P.J.; Giilgen, D.; Jairath, V.; Hindryckx, P.;
Shackelton, L.M.; Vandervoort, M.K.; et al. Randomised non-inferiority trial: 1600 mg versus 400 mg tablets
of mesalazine for the treatment of mild-to-moderate ulcerative colitis. Aliment. Pharmacol. Ther. 2017, 46,
83. Dodoo, C.C.; Wang, J.; Basit, A.W.; Stapleton, P.; Gaisford, S. Targeted delivery of probiotics to enhance
gastrointestinal stability and intestinal colonisation. Int. J. Pharm. 2017, 530, 224–229. [CrossRef]
84. Allegretti, J.R.; Fischer, M.; Sagi, S.V.; Bohm, M.E.; Fadda, H.M.; Ranmal, S.R.; Budree, S.; Basit, A.W.;
Glettig, D.L.; de la Serna, E.L.; et al. Fecal microbiota transplantation capsules with targeted colonic versus
gastric delivery in recurrent clostridium difficile infection: A comparative cohort analysis of high and lose
dose. Dig. Dis. Sci. 2019, 64, 1672–1678. [CrossRef]
85. Si, X.Y.; Merlin, D.; Xiao, B. Recent advances in orally administered cell-specific nanotherapeutics for
inflammatory bowel disease. World J. Gastroenterol. 2016, 22, 7718–7726. [CrossRef]
86. Harel, E.; Rubinstein, A.; Nissan, A.; Khazanov, E.; Nadler Milbauer, M.; Barenholz, Y.; Tirosh, B. Enhanced
transferrin receptor expression by proinflammatory cytokines in enterocytes as a means for local delivery of
drugs to inflamed gut mucosa. PLoS ONE 2011, 6, e24202. [CrossRef]
87. Xiao, B.; Laroui, H.; Viennois, E.; Ayyadurai, S.; Charania, M.A.; Zhang, Y.; Zhang, Z.; Baker, M.T.; Zhang, B.;
Gewirtz, A.T.; et al. Nanoparticles with surface antibody against CD98 and carrying CD98 small interfering
RNA reduce colitis in mice. Gastroenterology 2014, 146, 1289–1300. [CrossRef]
88. Shia, J.; Klimstra, D.S.; Nitzkorski, J.R.; Low, P.S.; Gonen, M.; Landmann, R.; Weiser, M.R.; Franklin, W.A.;
Prendergast, F.G.; Murphy, L.; et al. Immunohistochemical expression of folate receptor alpha in colorectal
carcinoma: Patterns and biological significance. Hum. Pathol. 2008, 39, 498–505. [CrossRef]
89. Xiong, S.; Yu, B.; Wu, J.; Li, H.; Lee, R.J. Preparation, therapeutic efficacy and intratumoral localization
of targeted daunorubicin liposomes conjugating folate-PEG-CHEMS. Biomed. Pharmacother. 2011, 65, 2–8.
[CrossRef]
90. Handali, S.; Moghimipour, E.; Rezaei, M.; Ramezani, Z.; Kouchak, M.; Amini, M.; Angali, K.A.; Saremy, S.;
Dorkoosh, F.A. A novel 5-Fluorouracil targeted delivery to colon cancer using folic acid conjugated liposomes.
Biomed. Pharmacother. 2018, 108, 1259–1273. [CrossRef]
91. Yu, M.; Jambhrunkar, S.; Thorn, P.; Chen, J.; Gu, W.; Yu, C. Hyaluronic acid modified mesoporous silica
nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells. Nanoscale 2013, 5, 178–183.
[CrossRef]
92. Liu, K.; Wang, Z.Q.; Wang, S.J.; Liu, P.; Qin, Y.H.; Ma, Y.; Li, X.C.; Huo, Z.J. Hyaluronic acid-tagged silica
nanoparticles in colon cancer therapy: Therapeutic efficacy evaluation. Int. J. Nanomed. 2015, 10, 6445–6454.
93. Vafaei, S.Y.; Esmaeili, M.; Amini, M.; Atyabi, F.; Ostad, S.N.; Dinarvand, R. Self assembled hyaluronic acid
nanoparticles as a potential carrier for targeting the inflamed intestinal mucosa. Carbohydr. Polym. 2016, 144,
94. Xiao, B.; Han, M.K.; Viennois, E.; Wang, L.; Zhang, M.; Si, X.; Merlin, D. Hyaluronic acid-functionalized
polymeric nanoparticles for colon cancer-targeted combination chemotherapy. Nanoscale 2015, 7, 17745–17755.
[CrossRef]
95. Xiao, B.; Zhang, Z.; Viennois, E.; Kang, Y.; Zhang, M.; Han, M.K.; Chen, J.; Merlin, D. Combination therapy
for ulcerative colitis: Orally targeted nanoparticles prevent mucosal damage and relieve inflammation.
Theranostics 2016, 6, 2250–2266. [CrossRef]
96. Prajapati, S.K.; Jain, A.; Shrivastava, C.; Jain, A.K. Hyaluronic acid conjugated multi-walled carbon nanotubes
for colon cancer targeting. Int. J. Biol. Macromol. 2019, 123, 691–703. [CrossRef]
97. Tesauro, D.; Accardo, A.; Diaferia, C.; Milano, V.; Guillon, J.; Ronga, L.; Rossi, F. Peptide-based drug-delivery
systems in biotechnological applications: Recent advances and perspectives. Molecules 2019, 24, 351.
[CrossRef]
98. Ghosh, D.; Peng, X.; Leal, J.; Mohanty, R. Peptides as drug delivery vehicles across biological barriers.
J. Pharm. Investig. 2018, 48, 89–111. [CrossRef]
99. Jiang, Z.; Guan, J.; Qian, J.; Zhan, C. Peptide ligand-mediated targeted drug delivery of nanomedicines.
Biomater. Sci. 2019, 7, 461–471. [CrossRef]
100. Al-azzawi, S.; Masheta, D. Designing a drug delivery system for improved tumor treatment and targeting by
functionalization of a cell-penetrating peptide. J. Pharm. Investig. 2019, 49, 643–654. [CrossRef]
101. Ren, Y.; Mu, Y.; Song, Y.; Xie, J.; Yu, H.; Gao, S.; Li, S.; Peng, H.; Zhou, Y.; Lu, W. A new peptide ligand for
colon cancer targeted delivery of micelles. Drug Deliv. 2016, 23, 1763–1772. [CrossRef] [PubMed]
102. Guo, F.; Ouyang, T.; Peng, T.; Zhang, X.; Xie, B.; Yang, X.; Liang, D.; Zhong, H. Enhanced oral absorption
of insulin using colon-specific nanoparticles co-modified with amphiphilic chitosan derivatives and
cell-penetrating peptides. Biomater. Sci. 2019, 7, 1493–1506. [CrossRef] [PubMed]
103. Grifantini, R.; Taranta, M.; Gherardini, L.; Naldi, I.; Parri, M.; Grandi, A.; Giannetti, A.; Tombelli, S.;
Lucarini, G.; Ricotti, L.; et al. Magnetically driven drug delivery systems improving targeted immunotherapy
for colon-rectal cancer. J. Control. Release 2018, 280, 76–86. [CrossRef] [PubMed]
104. Teruel, A.H.; Pérez-Esteve, É.; González-Álvarez, I.; González-Álvarez, M.; Costero, A.M.; Ferri, D.; Parra, M.;
Gaviña, P.; Merino, V.; Martínez-Mañez, R.; et al. Smart gated magnetic silica mesoporous particles for
targeted colon drug delivery: New approaches for inflammatory bowel diseases treatment. J. Control. Release
2018, 281, 58–69. [CrossRef] [PubMed]
105. Kono, Y.; Gogatsubo, S.; Ohba, T.; Fujita, T. Enhanced macrophage delivery to the colon using magnetic
lipoplexes with a magnetic field. Drug Deliv. 2019, 26, 935–943. [CrossRef] [PubMed]
106. Metwally, A.A.; Hathout, R.M. Computer-assisted drug formulation design: Novel approach in drug delivery.
Mol. Pharm. 2015, 12, 2800–2810. [CrossRef]
107. Ramezanpour, M.; Leung, S.S.; Delgado-Magnero, K.H.; Bashe, B.Y.; Thewalt, J.; Tieleman, D.P. Computational
and experimental approaches for investigating nanoparticle-based drug delivery systems. Biochim. Biophys.
Acta 2016, 1858, 1688–1709. [CrossRef]
108. Patra, P.; Seesala, V.S.; Soni, S.R.; Roy, R.K.; Dhara, S.; Ghosh, A.; Patra, N.; Pal, S. Biopolymeric pH-responsive
fluorescent gel for in-vitro and in-vivo colon specific delivery of metronidazole and ciprofloxacin. Eur. Polym.
J. 2019, 114, 255–264. [CrossRef]
109. Markovic, M.; Dahan, A.; Keinan, S.; Kurnikov, I.; Aponick, A.; Zimmermann, E.M.; Ben-Shabat, S.
Phospholipid-based prodrugs for colon-targeted drug delivery: Experimental study and in-silico simulations.
Pharmaceutics 2019, 11, 186. [CrossRef]
110. Barroso, E.; Cueva, C.; Peláez, C.; Martínez-Cuesta, M.C.; Requena, T. The computer-controlled
multicompartmental dynamic model of the gastrointestinal system SIMGI. In The Impact of Food Bioactives
on Health: In Vitro and Ex Vivo Models; Verhoeckx, K., Cotter, P., López-Expósito, I., Kleiveland, C., Lea, T.,
Mackie, A., Requena, T., Swiatecka, D., Wichers, H., Eds.; Springer: Cham, Switzerland, 2015; pp. 319–327.
111. Vadlapatla, R.; Wong, E.Y.; Gayakwad, S.G. Electronic drug delivery systems: An overview. J. Drug Deliv.
Sci. Technol. 2017, 41, 359–366. [CrossRef]
112. Yadav, K.S.; Kapse-Mistry, S.; Peters, G.J.; Mayur, Y.C. E-drug delivery: A futuristic approach. Drug Discov.
Today 2019, 24, 1023–1030. [CrossRef] [PubMed]
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article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Pharmaceutics 2020, 12, 68; doi:10.3390/pharmaceutics12010068 www.mdpi.com/journal/pharmaceutics

2. Formulation Approaches for Colon Targeted Drug Delivery

2.1. pH-Dependent Drug Delivery Systems

2.1.1. Polymer-Based Nano-/Micro-Particles

2.1.2. Lipid-Based Formulations

2.1.3. Tablets and Capsules

2.2.1. Polysaccharide-Based Systems

Table 1. Selected examples of polysaccharides-based colonic delivery system.

Polysaccharide Delivery System API Mechanism Ref

2.2.2. Phloral® Technology

2.3. Ligand/Receptor-Mediated Drug Delivery System

2.3.2. Folic Acid

2.3.3. Hyaluronic Acid

2.4. Magnetically-Driven Drug Delivery System

3.1. Computer-Assisted Formulation Design

3.2. Electronic Device-Assisted Formulation Design

74. Andishmand, H.; Tabibiazar, M.; Mohammadifar, M.A.; Hamishehkar, H. Pectin-zinc-chitosan-polyethylene

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