There are numerous therapeutic
opportunities and possibilities that the colon provides. Although the colon has a low surface
area and viscous luminal fluid which provides considerable challenges in drug
delivery, the colon’s enriched microbiota, variable pH, and enzymes present can
be utilized to aid the delivery and maximize the bioavailability of drugs. The presence of efflux transporters and metabolic enzymes such as
cytochrome P450 are often lower in the colon. Cytochrome P450 enzymes can
metabolize drug molecules, which consequently lowers the bioavailability of
drugs. Thus, CSDDS improves the bioavailability of drugs by reducing
drug metabolism (1). Because the intended site of action is not reached by the
drugs in the right concentrations, the majority of the current drug delivery
systems for treating colonic ailments are not a substantial success (2). Colon targeting offers
several clinical advantages for drugs that are destroyed by stomach acid or
metabolized by pancreatic enzymes. It enhances patient compliance by reducing
dose and frequency and allows more effective localized treatment for conditions
like colorectal cancer, ulcerative colitis, and Crohn’s disease. However,
pH-dependent systems, which can protect formulations in the upper GI tract, may
release drugs prematurely in the lower intestine due to pH changes,
particularly in diseases like inflammatory bowel disease where colon pH
decreases. Additionally, the colon's lower fluid content compared to the small
intestine can hinder the dissolution of poorly water-soluble drugs,
necessitating their use in presolubilized forms and targeting the more
fluid-rich proximal colon (3, 4, 5).
In
order to provide safe and effective therapy for some colonic diseases, CSDDS
can be utilized to target the colon (2). CSDDS
protects the drug entering into the colon i.e. inhibits premature drug release
into the GIT. In this drug delivery system, absorption does not occur in any
part of the gut other than the colon. Thereby, the degradation of
bioactive agents does not occur in either the stomach or the small intestine;
instead, the drug is released and absorbed only when the system reaches the
colon (6). Technologies such as CODESTM, Pulsincap® system, prodrug
approach, nanoparticle drug delivery systems, etc, provide such protection and
site-specific drug release. Although the intrarectal route is one of the
possible routes for CSDDS, the oral route is the most practical and recommended
one (). Hirchsprung's disease, angiodysplasia, salmonellosis, ulcerative
colitis, and other inflammatory bowel disorders can all benefit from CSDDS. For
example, Budesonide, a drug used for the treatment of CD, is coated with
azo-polymer to transform it into a prodrug (, ). Phloral™ technology offers an advanced drug
delivery method, particularly beneficial for the treatment of inflammatory
bowel disease (IBD) and similar conditions (). This review is focused
on the anatomy, physiology, diseases of the colon, and also the factors that
affect drug delivery in the colon. Most importantly, it discusses various old and novel colon-specific drug delivery
approaches, while encouraging further exploration. Reviewing the topic of
colon-specific drug delivery systems (CSDDS) is crucial due to ongoing
advancements in drug delivery technologies and the increasing prevalence of
colonic diseases like Crohn's disease, ulcerative colitis, and colorectal
cancer. Previous reviews may not encompass the latest innovations such as 3D
printed drug devices, and advanced coating technologies like OPTICORE and
Phloral™. This review is urgent because it highlights cutting-edge approaches
that significantly improve drug bioavailability, reduce systemic side effects,
and offer more precise targeting of colonic regions, providing new insights
into overcoming existing delivery challenges and optimizing therapeutic
outcomes.
An orally administered dosage form must traverse the
entirety of the digestive system to reach the colon, facing several obstacles.
These obstacles impede the development of an optimal colon-specific drug
delivery system (CSDDS). The gastrointestinal tract (GIT) has a complex
physiology with varying fluid quantities, differing transit times, multiple
metabolic enzymes, and other factors that hinder effective and consistent drug
delivery to the colon (3). Developing a suitable in vitro dissolution method
that accurately predicts in vivo performance remains a significant challenge
(10). Additionally, the colon's intestinal fluid volume is low, the fluid is
highly viscous, and the pH is neutral around 7, all of which can limit drug
solubilization and absorption rates (3). The colon has a smaller surface area
compared to the small intestine which results in BCS class III and IV drugs to
have limited colonic permeabilities and low bioavailability of less than 50%. A
double layer of mucus, that acts as a physical barrier between the microbiota
and the colonic epithelium, covers the whole colonic epithelium. This layer
also facilitates the transit of chyme into the lumen. The mucosal layer can
hinder the crossing of drugs across the epithelium and absorption, posing a
serious obstacle to systemic bioavailability (11).
There are several reasons why colon-specific drug delivery
systems (CSDDS) are necessary: they ensure smaller dosages, reduced frequency
of dosing, reduced systemic side effects, and precise treatment at the disease
site through local delivery (3, 12). They improve the bioavailability of orally
administered proteins and peptide drugs, which are not readily absorbed into
the bloodstream from the gastrointestinal tract due to the colon's long transit
and residence time, and its natural absorptive characteristics (13). CSDDSs are
effective in treating colon diseases and inflammatory bowel diseases (IBD) like
Crohn's disease (CD) and ulcerative colitis (UC) (14, 15). Moreover, they can
minimize first-pass metabolism, making them suitable for drugs that are polar,
prone to breakdown by enzymes, or affected by the acidic environment in the
upper GI tract, as well as those significantly impacted by hepatic metabolism
(15).
Anatomical Features and Physiology of Colon
The large intestine, which is a cylindrical closed receptacle, comprises the caecum, colon, and anus. The colon, which is approximately 1.5 meters in length, can be divided into two main parts: the proximal and distal colon. The proximal colon consists of the caecum, ascending colon, and transverse colon. The distal colon, on the other hand, is further divided into four parts: the descending colon, sigmoid colon, rectum, and anus (11). An important feature of the colon is the hepatic flexure, a 90° bend that connects the ascending colon to the transverse colon. Conversely, the descending colon and transverse colon are linked by the splenic flexure. The colon is lined with a soft, pink mucosa (11, 16). The diameter of the colon measures approximately 2-3 inches (3), with some variations observed between genders (11). These variations pertain to both the length and diameter of different colonic regions. The summarized measurements are presented in Table 1 (16).
Table 1. Length and diameter of different colonic regions.
Segment
Length (cm)
Diameter (cm)
Caecum
6-9
8
Ascending colon
20-25
6
Descending colon
10-15
5
Transverse colon
40-45
5
Sigmoid colon
35-40
5
Rectum
12
4
The blood supply around the
absorptive section of the epithelium is essential for the absorption of drugs
from the colon. Arterial blood is supplied through the mesenteric and inferior
mesenteric artery to the proximal and distal colon respectively. Blood flow is
higher in the proximal portion of the colon compared to the distal portion. The
colon has an intestinal surface area of 1300 cm2 and is capable of
absorbing large volumes of water, electrolytes, and also short-chain fatty
acids. The key roles of the colon are storage and removal of fecal content and
absorption of sodium and water thus concentrating fecal content (17).
Colon Diseases and Their Impact on Colon
Characteristics Changes
Different colonic diseases include
IBD (UC, Crohn's disease), Hirchsprung’s disease, salmonellosis,
angiodysplasia, colorectal cancer, amebiasis, diarrhea, and colorectal polyps,
etc. The following table summarizes different colonic diseases, changes of
colon characteristics and drugs in the treatment.
Table 2. Different colonic diseases, characteristics and drugs used in the treatment of colonic disorders.
Disease Name
Affected Region
Characteristic changes
Drug Used
Ulcerative Colitis
Inflammation starts in the lower portion of
the colon and the rectum, although it can affect the whole colon (18).
Ulcerative colitis is a form of IBD (19).
Inflammation and damage to
the mucosal surface of large intestine occur, leading to issues with
motility and secretion (18, 20).
Condition
causes patients to have a tender mass
in the right lower quadrant, thickened bowel loops, thickened mesentery, or
an abscess. Chronic localized, transmural, discontinuous, patchy, and
inflamatory perianal fistulas or abscesses may also be present (21).
Amoebic invasion occurs through the mucosa,
penetrating into the submucosal tissues. The distinctive flask-shaped ulcer
which is characteristic of amoebiasis is caused by lateral extension through
submucosal tissues (25).
22% of all colorectal cancers occur in the
distal colon, 28% involve the rectum and approximately 41% occur in the
proximal colon (27).
Colorectal
cancer development is attributed to mutated genes that regulate tumor growth
(tumor suppressor genes) and genes that promote tumor formation (oncogenes)
(28). Most colorectal cancers arise from adenomas. Frequently, one or more
synchronous adenomas are found in operative specimens of colon cancer (29).
Presence of palpable mass is common in right colon cancer. The most common
association between malignant blockage of the large bowel and sigmoid
carcinoma is this (30).
The rectosigmoid portion of the colon and
the entirety of the colon is affected (32).
Functional colonic obstruction is caused due
to various lengths of distal colon not being able to relax and distension of proximal
segments (megacolon) (33). Hirschsprung disease results from absence of ganglion cells in the
distal hindgut(32, 34). Larger neural trunks take the place of ganglion cells
(34).
Distal ileum and proximal colon are affected
(36).
Salmonellosis is caused as a result of
ingestion of food contaminated with Salmonella (a gram-positive bacteria).
(36). Salmonella releases high level of inflammatory cytokines,
enhances proliferation activity, and promotes tumorigenesis. Salmonella
infection can also induce colitis that is similar to UC. It causes serious colitis with
severe emaciation and diarrhea, erosion of the colonic epithelium, and
increases inflammation substantially increased (37)
Pathogenic
microorganisms cause epithelial damage thus, reducing the absorptive area and
function; leading to unabsorbed solutes drawing water into the intestinal
lumen. Enterotoxins from bacteria
stimulate cAMP or cGMP, leading to significant water secretion and
dehydration (40).
Affects upper gastrointestinal tract, small
intestine, colon (42).
Angiodysplasias of the colon refers to the
presence of abnormally enlarged and delicate blood vessels within the colon,
which can occasionally lead to bleeding in the lower portion of the
gastrointestinal tract (43). Angiodysplasia can be characterized as the
observation of abnormal, dilated, ectatic, tortuous and mostly tiny (less
than 10 mm) blood vessels that can be seen in the mucosal and submucosal
layers of the GIT. Diseased blood vessels are lined solely by the endothelium
and barely have any smooth muscle (42).
Upon
oral administration, the primary factors influencing drug distribution to the
colon are gastric emptying and bowel transit time. The dosage form, the
peristaltic phase, and the presence or absence of food are factors that affect
this time (3, 11).
Gastric
emptying time is observed to be longer in the fasted state and is significantly
delayed by the intake of high-fat food. Females of reproductive age exhibit a
notably longer gastric emptying time compared to males and post-menopausal
females (11). Diseased states such as UC and Crohn’s disease also change
gastric transit time (3). Patients suffering from diarrhea have shorter transit
times than those suffering from constipation (47). Patients having type 2
diabetes mellitus are reported to have a gastric transit time of up to 300%
times longer than healthy individuals (11).
Large
variability of gastric emptying time is observed between and within
individuals. Under typical circumstances, the colon
transit time ranges from 5 to 7 h. However, this transit time changes
according to the gastrointestinal tract’s fed and fasting states. In the fasted
condition, transit time ranges from 3 to 5 h and in the fed condition, it
varies between 6 to 10 h. The Table 3 summarizes the transit time of
different segments of GIT (48)
Table 3. Lists the transit times of various segments of the GIT.
Segment of GIT
Transit time
Stomach
Fasted
condition: 10 min – 2 h
Fed
condition: >2 h
Small
intestine
3-4
h
Colon
20-35
h
pH of Colon
Variation
of pH is observed between individuals. Consumption of food, diseased state,
etc, can affect the pH levels of the GIT (47). The pH of luminal fluid does not
remain the same along the GI tract. While the pH of gastric fluid varies with
fed and fasted state and gender, the ascending colon typically has a lower pH
than the ileocaecal area. The
pH of the ascending colon is about 6.4±0.6 while the pH of the traverse colon
ranges around 6.6±0.8 (49). This is caused by the colonic bacteria
producing lactate and short-chain fatty acids (SCFAs). Meanwhile, pH of distal
colon is comparatively higher, around
7.0±0.7 (11, 49). The pH
of the sigmoid colon is also comparatively higher at about 7.4 ± 0.6 (11). Colonic
pH may be altered by polysaccharide-based drugs and laxative drugs, e.g.
lactulose. Diseased states such as ulcerative colitis (UC) also affect pH of
the colon. In UC patients, the
pH of proximal regions of the colon ranges from 2.3-4.7 (49). Pharmacokinetics
and pharmacodynamics of CSDDS are affected by colonic pH, as the solubility of
drugs is being influenced (3).
Colonic Microbiota
and Enzymes
Enzymes
in the gastrointestinal tract, including bacterial enzymes like azoreductase,
nitrate reductase, nitroreductase, and sulfatase abundant in the colon,
significantly influence drug bioavailability and digestion efficiency. These
enzymes play pivotal roles in drug metabolism and the breakdown of mucosal
glycans, impacting the absorption of orally administered protein drugs and
other pharmaceuticals within the gastrointestinal environment (50). Over 400
distinct bacterial species inhabit the colon, such as Escherichia coli and
Clostridium, which produce enzymes that can increase the rate of metabolism of
drugs and other biological molecules (3, 50, 51). Some bacterial enzymes
include azoreductase, involved in the metabolism of azo dyes, nitro-aromatic,
and azoic drugs, resulting in the formation of amine (52, 53); nitrate
reductase, which biotransforms nitrate to nitrite (52); nitroreductase,
facilitating the conversion of nitroaromatic compounds into aromatic amines,
changing nitro groups into hydroxylamine or amino groups in the presence of
nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide
phosphate (NADP) (54); and sulfatase, which plays a role in breaking down
mucosal glycans, including those found in colonic mucins (52). Other than bacteria, the colon also consist of fungi,
viruses, archaea, free DNA,
metabolites, etc (11).
According to histochemical staining reports in a study, in general, high
expression of CYP P450 enzymes was observed in UC and CD patients compared to
normal (55). In a study done by Carrette et
al, it was observed that the activity of β-D-Galactosidase and Azoreductase
was significantly low in patients with CD compared to normal (56).
Volume and
Viscosity of Colonic Fluid
The
composition of the colonic fluid varies depending on factors like the amount of
food and/or water consumed. Usually, colonic fluids are constituted of water,
chyme, microbiota, electrolytes, proteins, bile acids, short-chain fatty acids
(SCFAs), and other different metabolites (11). The colon has a propensity to
absorb higher amounts of water, thus it is capable of absorbing 90% of the
water that enters it. However, colonic fluid volume is quite low, ranging from
1 - 44 mL, which can make the dissolution of drugs difficult (3). The colon's
strong propensity to absorb water results in its viscous contents, thereby
resulting in reduced availability for absorption of most drugs through the
colon’s membrane (16). After a meal, the colonic fluid increases due to the
intake of liquid and food. As it travels along the colon, the fluid volume
gradually decreases due to the colonic absorption of water (11).
Pharmaceutical
Factors
Several
factors influence the development of colon-specific drug delivery systems and
the bioavailability of drugs in the colon. These factors, both intrinsic and
extrinsic, play vital roles in formulation considerations. Intrinsic factors
such as intestinal colonic transit time, fluid volume, pH levels, colonic
microflora, enzymatic metabolism, drug absorption, and colonic luminal content
viscosity, significantly impact drug delivery efficacy. For instance, the
transit time of dosage forms in the colon varies based on factors like diet,
mobility, and colonic disease, affecting drug retention and release. Meanwhile,
extrinsic factors like the nature of the drug candidate and the choice of
polymeric drug carriers are equally important. The selection of drugs depends
on their chemical properties, solubility, and intended therapeutic targets,
with drugs treating conditions like inflammatory bowel disease and colon cancer
being particularly suitable for localized colon delivery. Polymeric carriers,
whether synthetic or natural, offer versatile options for formulation
development, providing favorable physicochemical properties for drug release
and targeting. These factors collectively underscore the complexity and
importance of optimizing colon-specific drug delivery systems for enhanced
therapeutic outcomes (57).
Conventional
Approaches for Colon Targeted Drug Delivery System
Prodrug
Prodrug
is an inactive compound that encloses the original drug. It undergoes enzymatic
and biotransformation in the body to enable drug release at its designated
site. This design is intended to improve pharmacological and physicochemical
drug properties while reducing toxicity (58). Azo-polymers have been used to
coat drugs like 5-amino salicylic acid (5-ASA), Budesonide, etc, to evaluate
their potential as CSDDS. Azo-polymers can undergo degradation by azoreductase
which is found in the large intestine. Therefore, the drug product will neither
be broken down in the stomach nor the small intestine; resulting in
colon-specific delivery (7). Glycosidic prodrugs can be used as a strategy for
colon targeting since they are minimally absorbed from the stomach and small
intestine but are cleaved by bacterial glycosidase which is present in the
large intestine (59). In an experiment by Yang et al, metoclopramide (MCP) was
azo-linked with 5-ASA and tested on a rat model. The result of the experiment
showed that a significant amount of both MCP and 5-ASA reached the large
intestine (60). The
therapeutic availability of a colon-specific prodrug and a parent drug is
dependent on its availability at the target site. If the parent drug is
metabolically stable, its level primarily depends on the prodrug's conversion
rate. On the other hand, if the parent drug is not stable, its level is
determined by the difference between the prodrug conversion rate and the parent
drug metabolism rate in the target organ. It can be challenging to modify drugs
into such a suitable prodrug. Moreover, a suitable functional group is required
for conjugation to occur with a colon-specific promoiety. The covalent bond
should only cleave in the large intestine. Additionally, polymeric prodrugs cannot
be formulated using hydrophobic or low efficacy drugs (61).
Coating with
pH-Sensitive Polymers
The
colonic pH is high, therefore, a CSDDS can be devised where the release of
drugs from the drug product occurs at a high pH (50, 62). The formulation can
be coated with polymers that are pH sensitive such as cellulose, acrylic acid
derivatives, and Eudragit®; or be incorporated into pH-sensitive materials. The
polymer used must disintegrate at a pH that is present in the colon and should
have a narrow pH release range so that premature release does not occur.
Mesalazine formulations, such as Salofalk® and Claversal®, depend on pH and are
coated with Eudragit-L. They disintegrate when the pH is greater than or equal
to 6, leading to the drug release in the middle to the distal portion of the
ileum as well as the colon. If Eudragit-S is used as a coating, as in Asacol®,
the drug product disintegrates at a pH less than or equal to 7, which causes
drug release in the terminal portion of the ileum and colon (51).
pH-sensitive
hydrogels are 3-dimensional structures made up of a polymer framework, water,
and crosslinking agents. They can expand significantly in water without
dissolving. They shrink in acidic environments and swell in alkaline
environments. When the drug product comes in contact with the high pH of the
colon, it swells and bursts, releasing the drug. Colonic disorders like UC and
CD can be treated locally with it (62). However, only small amount of drug can be incorporated in matrices and
hydrogels, so it cannot be used when a greater amount of drug is needed. Drug
loading is also a problem of using hydrogels. A high drug yield can be achieved
by loading the hydrogel during polymerization, though this risks intolerable
levels of residual monomers or initiators, whereas loading drugs after hydrogel
formation results in a lower drug level. Moreover, intestinal pH varies with
numerous factors such as food, diseased states, etc. Therefore, it is extremely
difficult to predict the pH of the colon when formulating a dosage form (63).
Time-Based Formulations
In
time-based formulations, once a predetermined amount of time has passed, the
drug is liberated. Therefore, it can be
used to target particular regions of the body. An example of such a formulation
is Pentasa®, an ethylcellulose-coated mesalazine tablet that gradually releases
the drug from the duodenum to the rectum. Mechanisms of some time-dependent
formulations include swelling and/or osmosis (41). The Time Clock® system is a
type of reservoir device characterized by a tablet core encased within a layer
of natural waxes and surfactants. It is then coated with an enteric film. In
the small intestine, dissolution of the film would occur which would then
initiate the dissolution of the inner layer; resulting in the release of the
active pharmaceutical ingredient (API) into the colon (64). Although
time-dependent releases do not depend on pH, it is affected by variations in
gastric emptying time, gastric transit time, presence of food, and many other
factors (7). Moreover, gradual release throughout the GIT can result in higher
systemic side effects (51). The
gastric retention time has significant variability which makes it challenging
to predict the exact drug release location using this method. Limitations of
time-dependent formulations include limited in-vivo evaluation and its
usefulness only in diseases which particularly depend on circadian rhythm (62).
Pressure-Dependent Systems
Due
to strong peristalsis, the colonic content faces greater luminal pressure compared to the small
intestine (7, 59). The viscosity of the contents in the colonic lumen is high
due to water reabsorption and feces formation (59). Based on the high pressure
in the colon which can reach as high as 110 mmHg for 14 s, Takaya et al.
developed a capsule formulation that is pressure-controlled and disintegrates
in the colon (7, 51, 62). The capsule shells are made using a hydrophobic
polymer called ethyl-cellulose (65). Due to the pressure inside the colon, the
capsule bursts and the drug is released. The thickness of the shell can be
modified to withstand different levels of pressure while the size of the
capsule and its density can also affect the system (7). Very limited data can be obtained regarding how the
luminal pressure varies across different regions of the GIT, and how food
affects luminal pressure is also yet to be documented. It is also unclear if
pressure in the lumen varies across subjects (62).
CODES Technology
CODES is a distinctive and special
CSDDS. It uses a combination of colonic microflora and pH-sensitive polymer for
drug release. Generally in tablets manufactured by the CODES configuration,
three layers of polymer coat the main tablet. The simple tablet core contains
the active ingredient mixed with excipients such as lactulose (7). The three
layers of the coating are: the first layer, encompassing the core, is a polymer
that is acid-soluble combined with a degradable polysaccharide (lactulose), the
second is a layer of enteric polymer, such as Eudragit E and the third is a
layer composed of Eudragit L (66, 67). The idea behind this technology is that
the tablet in the stomach is protected by an enteric coating Eudragit L, and it
dissolves soon after gastric emptying. After gastric emptying, the tablet
travels to the small intestine where the Eudragit L layer undergoes dissolution
due to the high pH environment (pH 6) (65, 67). Thus, the Eudragit E coating is
revealed and the small intestine does not break down this layer. Rather, this
coat allows the lactulose to be released close to the tablet (67). Upon
reaching the colon, polysaccharide (lactulose) is broken down into organic acid
by the colonic microflora (59). Thus, pH is lowered, which facilitates the
breakdown of the acid-soluble coating and ensue the release of the drug (67). The release of drugs via this
approach may be influenced by inter and intra-subject variability. Moreover,
the drug release can also be impacted by pH similarity between the colon and
the small intestine. In diseased conditions, there might be changes in the gut
microbiota which can also contribute to variation in drug release (62).
Nanoparticle Drug
Delivery System
The nano drug delivery system
contains several variations including size-dependent delivery, charge-mediated
delivery, redox-responsive delivery, and ligand receptor-mediated delivery.
Size-Dependent Nanodelivery
System
In this formulation, the size of the
drug particles is reduced to nanoscales (51). Penetration of nanosized
particles is increased in inflamed regions due to enhanced permeability and
retention (EPR) (68). Boloqui et al discussed
in a study, conducted on mice that had been induced with colitis, that
elimination of Budesonide-loaded nanostructured lipid carriers is slow even in
the case of diarrhea which frequently occurs in IBD (69). Reduced particle size
not only allows for increased residence time but also enhances preferential
absorption of the drug by immune cells which are abundant in areas of
inflammation (70). The smaller
the particle, the more likely it is to be absorbed systemically which can
result in systemic side effects (68).
Charge-Mediated Nano Drug
Delivery
It is possible to regulate how the
nanoparticles interact with the mucosa of the colon by modifying their surface
charge. The colonic mucosa contains carbohydrates, sialic acid, sulfates, and
colonic mucin which are negatively charged (68). Therefore, positively charged
nanoparticles attracted to these molecules can be used for targeted delivery
(51). Niebel et al conducted an experiment where nanoparticles loaded with
clodronate were modified by positively charged polymethacrylate and tested on
mice with induced Crohn’s disease and UC (71). Mucoadhesion could be a
promising approach towards targeting Crohn’s disease due to higher levels of
mucus production associated with this disease (51).
Redox-Responsive Nano Drug
Delivery System
Overproduction of reactive oxygen
species (ROS) is evident in inflammatory diseases like UC and CD. Therefore, a
delivery system that is redox-dependent might be a promising approach for IBD
treatment. Nano-drug formulations that are broken down by ROS could be used to
target the colon (72). Vong and his team developed a novel redox nanoparticle
that consists of a center containing nitroxide radicals, which work as ROS
scavengers in the treatment of colon cancer (73). Redox-mediated drug delivery systems face challenges due to
their susceptibility to volatility in acidic environments, exposure to high
enzyme concentrations, and rapid release of drug (68).
Ligand Receptor Mediating Nano
Drug Delivery
Expression of some receptors and
ligands increases during inflammation. These can be target sites for the
attachment of nanodrug particles (74). In an experiment, mannosylated
bioreducible nanoparticles were created which targeted mannose receptors that
are overexpressed on macrophages (75). A liposome-based nano-particles targeted at 7 integrin (7 I-tsNPs) and
loaded with siRNAs was developed by Peer
et al. It was intended to silence Cyclin D1 (CyD1) in the treatment of Dextran sulfate sodium (DSS)-induced murine
colitis. Expression of CyD1 increases in IBD, therefore, the delivery of
CyD1-siRNA using 7 I-tsNPs resulted in a significant decrease in intestinal
tissue damage and a reduction in infiltration of leukocytes into the colon.
Exosomes can also be used to target inflammatory sites since they have certain
proteins on their membrane that are highly selective and thus, allow them to
target specific sites (74). This
approach shows potential as CSDDS, but there are concerns involving the
instability of ligands in the GIT (68).
Bacterial Degradable Polymer Coatings
The colon is home to an extensive
range of bacteria, most of which are anaerobes, such as Bacteriocides,
Enterobacteria, Bifidobacteria, Eubacteria, etc. The bacterial population in
the colon ranges between 1011-1012 CFU/mL. The majority of the microflora
obtain energy by fermenting certain substrates like di-saccharides, and
polysaccharides, using enzymes such as xylosidase, arabinosidase,
galactosidase, azoreductase, urea de-hydroxylase, glucuronidase, nitroreductase
and deaminase (7, 59). Using this mechanism, natural polymers, e.g. inulin,
guar gum, amylose, etc, can be used to coat the drug. These compounds are able
to resist degradation in the upper GIT but can act as substrates for the
colon's anaerobic bacteria, causing delivery that is site-specific. However,
these polymers have poor film-forming properties and can produce toxic
by-products (76). Qiyan Chen et al. devised a drug delivery system for UC that
consisted of hyaluronic acid, polyethyleneimine, yeast cell wall microparticles (HA/PEI-RH NYPs), and modified rhein. The
yeast cell wall provided protection to the drug from the gastric environment,
but it could be broken down by β-glucanase that is formed by the bacteria
present in the colon. The results from the in vivo studies suggested that this
could be a great oral drug delivery system for colon-targeted drug delivery
(50). The bacterial
enzyme-mediated conversion rate of colon-specific prodrug to its active parent
drug primarily depends on the susceptibility of the linkage between the drug and
its promoiety to colonic metabolic processes. The degree of susceptibility may
vary based on nature of the promoieties and the drug, even when the linkage is
of the same type. This can prove to be a challenge when designing a drug with
bancterial degradable polymer (61).
Chitosan-Based Drug Delivery Systems
Chitosan (CS) is an alkaline
polysaccharide that can be derived from chitin which is a naturally occurring
compound found in the exoskeleton of crustaceans (77, 78). It exhibits a wide
array of pharmacological as well as biological functions such as antioxidant,
anticoagulant, anti-tumor, anti-diabetic, etc.
Moreover, due to its non)-toxic, stable, antibacterial, and biocompatible
nature, it is a valuable and high-demand resource (78).
Alhakamy et al
conducted a study where simvastatin (SMV), which has shown anticancer
properties, was formulated in chitosan and then coated with Eudragit S100
(ES100). The formulation showed significant release in the colonic pH and
adhesion to the colonic tissues (77). In another study by Zhou et al, Escherichia coli Nissle 1917 (ECN),
which is a probiotic that is administered orally, was genetically modified with
the intention of treating IBD. The active material was coated with a biofilm of
sodium alginate and chitosan using the Layer-by-Layer Self Assembly technique.
This formulation exhibited better protection of the drug compared to regular
enteric coating (79). However, chitosan has weak mechanical
characteristics and is susceptible to degradation. It is also thermally
unstable, highly hydrophilic, swellable and poorly water-soluble. To prevent
rapid degradation of Chitosan, it is usually cross-linked with other polymers.
It is also necessary to improve solubility of Chitosan (80).
Pulsatile Drug Delivery System
(PDDS)
Pulsatile
drug release systems show sustained release as the drug is released within a
therapeutic window for an extended duration. These systems have advantages such
as reduced dose size, dosing frequency, side effects, and adaptation of drugs
to the circadian rhythm of body functions and diseases (81). Pulsatile drug delivery systems are
primarily controlled by time with a lag phase. The pH, motility, and enzymes in
the GIT does not influence drug delivery in this approach. It has the
capability to deliver drugs in cases where dosage is required during sleep. It
can also be used in the case of drugs that are extensively metabolized in the
liver and have site-specific absorption. However, this approach does not show
consistent reproducible results in terms of therapeutic efficacy and
manufacturing. Moreover, it is expensive to manufacture since it requires
advanced technology and expert personnel. Additionally, large amounts of drugs
cannot be loaded in this formulation, and in vivo-in vitro correlation is also
not predictable (82).
Pulsincap® System
Variations in gastric emptying time
and gastrointestinal transit caused by peristalsis or disorders of the
gastrointestinal tract often make time-dependent systems unideal for drug
delivery in the colon (18). This is where a Pulsincap system comes into work.
Pulsincap system is a formulation that combines the advantages of both the
timed-release systems and the pH-dependent systems (83). Most of these systems
are created as capsules, consisting of a water-soluble cap and a
water-insoluble body treated with formaldehyde. Within the body of the capsule,
a mixture of drug, osmogen, and swelling agent is inserted (81, 83). At the open
end of the water-insoluble body a hydrogel plug is placed which is then covered
by the water-soluble cap (84). The capsule is enteric coated with an
acid-insoluble film. Thus, preventing drug release in the stomach and
preventing variable gastric emptying. After the dissolution of the enteric
coating, the hydrogel plug swells when the capsule comes in contact with the
dissolving fluid, and the drug is released as the plug pushes itself out. The
drug releases with a lag time caused by the plug swelling, and the release
relies on the length of the plug and how deeply it is inserted (3, 81, 83).
Osmotic Controlled-Release
Oral Delivery System
An Osmotic Controlled-Release Oral
Delivery System (OROS-CT) is a system regulated by osmotic pressure (3). It was
adopted for drugs with low water solubility (81). The formulation consists of
5-6 push-pull units, each having a diameter of 4mm, contained within a hard
gelatin capsule. A drug-impermeable enteric coating surrounds each unit within
which there is a semipermeable coating that surrounds an osmotic push layer and
a drug layer (3, 7). The drug layer is composed of poorly soluble drugs, osmotic
agents, and suspending agents (84). The enteric coating protects the drug in
the acidic pH of the stomach and dissolves in the high pH state (pH>7) of
the small intestine, causing water to enter the unit. When water permeates the
unit, the osmotic push compartment undergoes swelling, leading to the formation
of a gel that is flowable (3, 7). The gel is pushed through the membrane
adjacent to the drug compartment through an aperture. The rate at which water
enters the units determines the drug's flow rate (3). Each push-pull unit is
made with a 3-4 h post-gastric delay to prevent drug distribution in the
small intestine during the treatment of UC. The drug is released when the unit
reaches the colon. Drugs can be released using OROS-CT units at a consistent pace
for up to 24 h or over a brief period of 4 h (7).
Novel Approaches
OPTICORE
The OPTICORE (OPTImised
COlonic RElease)
is a novel drug coating technology that was devised for rapid drug delivery in
the ileocolonic area (11). It consists of a drug core which is enclosed by an
inner alkaline layer. The outer layer of OPTICORE™ makes use of a dual trigger
mechanism (enzyme and pH) and is made from a combination of Eudragit® S and
resistant starch (85). Resistant starch undergoes enzymatic degradation by
bacteria in the colon while Eudragit® S is affected by the pH of the colon. The
inner layer is meant to accelerate the drug release rate. It was found in a
study that in OPTICORE™, drug release starts just 1 h after reaching the
colon (86). A 1600 mg 5-ASA drug product that has been formulated using OPTICORE
has received market approval and is currently used for the treatment of UC
(85).
Phloral Technology
Accurately targeting the colon plays
a significant role in treating inflammatory bowel diseases. The recent
approaches of stimulating drug release target three variations in
gastrointestinal physiology- transit time, pH, and rise in the concentration of
bacteria in the distal gut. An earlier approach makes the use of a polymer
coating that is pH-responsive, such as Eudragit® S. This coating dissolves at
an intestinal pH of around 7.0 and triggers drug release. Although this
approach yielded positive results in the treatment of UC, infrequently, whole
undissolved tablets were found in the patient’s feces. This infrequent
occurrence may be attributed to exposure to insufficient volumes of fluid in a
neutral or alkaline environment for the required time period and scarcity of
fluids in the distal small intestine and large intestine. As the colonic pH of
UC patients is reportedly lower than healthy individuals, exposure of the drug
to fluid of pH 7 is hindered. The amount of fluid in the intestinal region is generally
lower and the presence of fluid in pockets contributes to this issue more. Thus
to facilitate fail-safe drug release, Ibekwe et al suggested combining both pH
and enzymatic triggers into a single coating system, referred to as Phloral™.
The pH trigger is made up of a polymer coating (Eudragit® S) and the enzymatic
trigger is a resistant starch polysaccharide. The enzymatic trigger aids drug
release in cases where the environment is not alkaline enough for the required
time period to dissolve the enteric polymer. Resistant starch can be classified
into four types and the type RS2 is used in Phloral coating technology. The
RS2-resistant starch consists of a high amount of amylose which causes the RS2
to gelatinize at a higher temperature compared to the other starches and often
not gelatinize at all; thus making it less digestible and more suitable to be
used in drug delivery systems that specifically target the ileo-colonic region.
The microbial population gradually increases along the small intestine, but
increases by several folds beyond the ileo-colonic region.The prime source of
fermentable carbohydrates for the bacterial population in this area is
undigested polysaccharides, and they also play a key role in metabolism of oral
drug. Thus, this two-trigger mechanism provides a timely and thorough drug
release (9).
3D Printed Bicompartmental Devices
3D printing of pharmaceutical
products is rising due to the convenience it provides and how it allows us to
easily modify or control drug release kinetics, dose, appearance, and texture
(87). There is a shift towards utilizing materials that allow the development
of composite-based products, especially in technologies that depend upon Fused
Deposition Modeling (FDM) (88). FDM is a method of thermal extrusion where
molten thermoplastic filaments are deposited layer by layer onto a surface in
order to create 3D solid structures based on a computer-aided design (CAD)
model. In a recent experiment, a drug product was developed using polyvinyl
alcohol and hydroxypropyl methylcellulose acetate succinate as the polymers to
build the matrix. The latter dissolves at the colonic pH, making it suitable
for targeting the colon. The
outer compartment was cylindrical while the inside consisted of a spiral
compartment with an opening on top that allows it to communicate with the
surrounding media. The special shape of this device allows the release of large
doses of drugs in a controlled manner. The drug used was 5-ASA, which is
an anti-inflammatory drug used for IBD and CRC (89).
MMX Technology
The Multimatrix (MMX) is a drug
formulation that facilitates the release of high-concentration active drugs
into the colon. This formulation ensures uniform distribution of drugs into the
colon, especially the distal colon. In this formulation, a hydrophilic
structure disperses the lipophilic matrix. The drug and excipients are trapped
in the matrix in a net of hydrophilic and amphipathic polymeric material (90).
This matrix is coated with a pH-resistant enteric coating. The hydrophilic
excipients in the matrix swell as they come into contact with the gastric fluid
due to the disintegration of the enteric coating (91). The drug becomes more
soluble in the amphipathic polymeric matrix, which also relaxes the hydrophilic
material and makes it swell. As a result, the drug is distributed uniformly
throughout the colon (92). The swelling of the tablet forms a viscous gel mass,
which causes slow diffusion of the drug into the colonic lumen from the tablet
core. The gel mass that surrounds the tablet core gradually breaks off as it
moves through the colon. Lipophilic excipients limit the rate at which drugs
dissolve by preventing digestive fluids from penetrating the tablet core. This
prolongs drug release (91). This formulation provides effective delivery of
active molecules to the site of action due to low systemic absorption and
reduced adverse events. MMX®
mesalamine and budesonide have gained worldwide registration for treating
ulcerative colitis (90).
Authors Perspective
The
unique colonic environments can act as a base for developing different CSDDS.
It is important to develop a drug delivery system that maximizes the release
and activity of drugs in the colon while minimizing side effects. Most conventional approaches rely on a single
trigger system while most novel approaches are based on multiple trigger
systems such as OPTICORE and Phloral™. The prevalence of colonic diseases is
increasing daily. We’ve noticed that although there are quite a few CSDDS,
there is a gap in the personalized treatment of colon diseases. Characteristics
of different colonic diseases and the environment of the colon can vary amongst
individuals. Therefore, in order to provide a treatment tailored to individual
patients, it is crucial that more studies regarding the correlation amongst
each colonic diseases, CSDDS and other factors (food, gender, body weight,
history of other diseases, etc) are conducted. We believe 3D printing
technology could aid in the advancement of personalized treatment and allow
vast customization. Moreover, the integration of nano-drug particles in 3D
printing technology could also be used to develop newer CSDDS. Although CSDDS is used in an array of colonic diseases,
in case of a few diseases, there are not enough drug treatments available and
hence no delivery system can treat the disease. For example, no effective
preventive treatment currently exists for gastrointestinal angiodysplasia
(GIADs). Studies on pharmacological agents like lanreotide have shown promising
results in a significant number of patients, but these studies involved small,
non-comparative samples. Octreotide and lanreotide have been more effective
than endoscopic therapy in reducing recurrent bleeding and have fewer adverse
effects. Reduced bleeding episodes were also observed in studies with
thalidomide, but significant side effects were observed. While somatostatin
analogs and thalidomide show potential, more prospective, controlled, and
randomized studies, as well as cost-benefit analyses, are needed.
Conclusion
Studying colon-specific drug delivery systems (CSDDS) is a
vital area in pharmaceutical research since it offers many potential treatments
for various diseases that affect the colon, which is a crucial part of the
digestive system. The pH environment, fluid content, microbiota, enzymes
present, pressure, etc, varies across different regions of the colon. This
unique feature of the colon imposes challenges in drug delivery. Although it is
a challenge, these characteristics of the colon can be utilized using CSDDS to
precisely target the drug in different areas of the colon while enhancing drug
bioavailability, reducing systemic side effects, and thereby optimizing
therapeutic outcomes.Conventional approaches such as prodrugs, pH-sensitive
coatings, and time-based formulations have led to innovative technologies like
3D-printed devices, OPTICORE, Phloral™, MMX technology; offering promising
solutions to the advancement of colon-specific drug delivery. The novel systems
have many advantages over the previous approaches, including drug release site
specificity, varied release kinetics and more. Many conventional approaches act
as bases for some novel approaches. The novel approaches could be combined
(such as, 3D printing of an oral dosage form using nanoparticles and coating
with pH sensitive, biodegradable polymers) to design an even better CSDDS that
is safe, highly accurate, specific with minimal side effects. However, there
are more areas to explore regarding the variabilities in the colonic
environment and more research to be done on some of the novel approaches, so
that they do not remain just as treatment possibilities and can become viable
treatment options.
Prevalence of colonic diseases such as inflammatory bowel disease, colorectal cancer, angiodysplasia, salmonellosis, etc, are increasing daily and are reducing the quality of life of the patients. These diseases can be difficult to treat due to their ability to alter the normal environment of the colon such as the pH, microbiota, enzymes, and more. Anatomy and physiology of the colon also pose difficulty in case of targeted drug administration. Additionally, there are variations in how each colonic disease influences the colon, making it essential to design a Colon-Specific-Drug-Delivery System (CSDDS) that would ensure proper targeting and delivery of the drugs. To reduce systemic side effects and achieve desired therapeutic effects, the dosage form should be designed in such a way that allows for direct and precise targeting of drugs into the colon, while also preventing premature gastrointestinal drug release. In this review, we discuss the conventional (for example, prodrug, CODES, pulsatile drug delivery) and novel (OPTICORE, Phloral, MMX technology, 3D bicompartmental device) approaches aimed at ensuring drug release and absorption within the colon, as well as examine the factors that affect drug delivery targeted at the colon. Despite considerable progress, significant challenges and gaps remain, including the need for a deeper understanding of colonic environmental variability, the development of advanced biocompatible materials, and the implementation of personalized treatment strategies are highly required.
McConnell, E. L., Liu, F., & Basit, A. W.
(2009). Colonic treatments and targets: Issues and opportunities. Journal of
Drug Targeting, 17(5), 335–363. https://doi.org/10.1080/10611860902839502
Gupta, V. K., Gnanarajan, G., & Kothiyal,
P. (2012). A Review Article on Colonic Targeted Drug Delivery System. The
Pharma Innovation, 1(7).
Bansal, Vipin et al. “Novel prospective in
colon specific drug delivery system.” Polimery w medycynie vol. 44,2 (2014):
109-18.
Chaurasia M.K., Jain S.K.: Pharmaceutical
Approach to Colon Targeted Drug Delivery Systems. J. Pharm. Pharm. Sci. 2003,
6, 33–66.
Asghar L.F.A., Chandran S.: Multiparticulate
Formulation Approach to Colon Specific Drug Delivery: Current Prospective. J.
Pharm. Pharm. Sci. 2006, 9, 327–338
Akala, E. O., Elekwachi, O., Chase, V.,
Johnson, H., Lazarre, M., & Scott, K. (2003). Organic redox-initiated
polymerization process for the fabrication of hydrogels for colon-specific drug
delivery. Drug Development and Industrial Pharmacy, 29(4), 375–386. https://doi.org/10.1081/ddc-120018373
Philip, A. K., & Philip, B. (2010). Colon
Targeted Drug Delivery Systems: A Review on Primary and Novel Approaches. Oman
Medical Journal, 25(2), 79–87. https://doi.org/10.5001/omj.2010.24
Wright, E. K., Ding, N. S., &
Niewiadomski, O. (2018). Management of inflammatory bowel disease. Medical
Journal of Australia, 209(7), 318–323. https://doi.org/10.5694/mja17.01001
Varum,
F., Freire, A. C., Fadda, H. M., Bravo, R., & Basit, A. W. (2020). A dual
pH and microbiota-triggered coating (Phloral™) for fail-safe colonic drug
release. International Journal of Pharmaceutics, 583, 119379.
Kumar,
K. V., Sivakumar, T., & Mani, T. T. (2011). Colon targeting drug delivery
system: A review on recent approaches. Int J Pharm Biomed Sci, 2(1), 11-19.
McCoubrey, L. E., Favaron, A., Awad, A., Orlu,
M., Gaisford, S., & Basit, A. W. (2023). Colonic drug delivery: Formulating
the next generation of colon-targeted therapeutics. Journal of Controlled
Release, 353, 1107–1126.
https://doi.org/10.1016/j.jconrel.2022.12.029
Malik, K., Goswami, L., Kothiyal, P., &
Mukhopadhyay, S. (2012). A review on colon targeting drug delivery system:
Novel approaches, anatomy and evaluation. The pharma innovation, 1(9, Part A),
1.
Sarasija, S., & Hota, A. (2000).
Colon-specific drug delivery systems. Indian Journal of Pharmaceutical Sciences,
62, 1–8.
Balvir,
S., Patel, D. M., Patel, D. K., & Patel, D. N. (2013). A Review on colon
targeted drug delivery system. International Journal of Universal Pharmacy and
Bio Sciences, 2(1), 20-34
Amidon,
S., Brown, J. E., & Dave, V. S. (2015). Colon-targeted oral drug delivery
systems: design trends and approaches. Aaps Pharmscitech, 16, 731-741.
Vadlamudi,
H. C., Raju, Y. P., Yasmeen, B. R., & Vulava, J. (2012). Anatomical,
biochemical and physiological considerations of the colon in design and
development of novel drug delivery systems. Current Drug Delivery, 9(6),
556–565. https://doi.org/10.2174/156720112803529774
Gulbake,
A., & Jain, S. K. (2012). Chitosan: a potential polymer for colon-specific
drug delivery system. Expert opinion on drug delivery, 9(6), 713-729.
Xu,
C.-T., Meng, S.-Y., & Pan, B.-R. (2004). Drug therapy for ulcerative
colitis. World Journal of Gastroenterology, 10(16), 2311–2317. https://doi.org/10.3748/wjg.v10.i16.2311
Seyedian,
S. S., Nokhostin, F., & Malamir, M. D. (2019). A review of the diagnosis,
prevention, and treatment methods of inflammatory bowel disease. Journal of
medicine and life, 12(2), 113.
Ordás,
I., Eckmann, L., Talamini, M., Baumgart, D. C., & Sandborn, W. J. (2012).
Ulcerative Colitis. The Lancet, 380(9853), 1606–1619. https://doi.org/10.1016/s0140-6736(12)60150-0
Torres, J., Mehandru, S., Colombel, J.-F.,
& Peyrin-Biroulet, L. (2017). Crohn’s Disease. The Lancet, 389(10080),
1741–1755. https://doi.org/10.1016/s0140-6736(16)31711-1
Mills,
S. C., von Roon, A. C., Tekkis, P. P., & Orchard, T. R. (2011). Crohn's
disease. BMJ clinical evidence, 2011.
Kiran
Kumar, G. B., Annangi, V. K., Ahamed, D. M. G., & Kumar, G. P. (2013).
Preparation and evaluation of kollidon SR matrix tablets of tinidazole for
colon specific drug delivery. IJSIT, 2(1), 97-106.
Morán,
P., Serrano-Vázquez, A., Rojas-Velázquez, L., González, E., Pérez-Juárez, H.,
Hernández, E. G., ... & Ximénez, C. (2023). Amoebiasis: Advances in
Diagnosis, Treatment, Immunology Features and the Interaction with the
Intestinal Ecosystem. International Journal of Molecular Sciences, 24(14),
11755.
Stanley,
S. L. (2003). Amoebiasis. The lancet, 361(9362), 1025-1034
Carrero,
J. C., Reyes-López, M., Serrano-Luna, J., Shibayama, M., Unzueta, J.,
León-Sicairos, N., & de la Garza, M. (2020). Intestinal amoebiasis: 160
years of its first detection and still remains as a health problem in
developing countries. International Journal of Medical Microbiology, 310(1),
151358.
Thanikachalam,
K., & Khan, G. (2019). Colorectal cancer and nutrition. Nutrients, 11(1),
164.
Kumar,
V., Verma, S., Mishra, D. N., & Singh, S. K. (2012). Novel approaches in
colon targeted drug delivery systems. Bulletin of Pharmaceutical Research, 2(1),
26-33.
Cappell, M. S. (2008). Pathophysiology,
Clinical Presentation, and Management of Colon Cancer. Gastroenterology Clinics
of North America, 37(1), 1–24. https://doi.org/10.1016/j.gtc.2007.12.002
Labianca, R., Beretta, G. D., Kildani, B.,
Milesi, L., Merlin, F., Mosconi, S., Pessi, M. A., Prochilo, T., Quadri, A.,
Gatta, G., de Braud, F., & Wils, J. (2010). Colon cancer. Critical Reviews
in Oncology/Hematology, 74(2), 106–133. https://doi.org/10.1016/j.critrevonc.2010.01.010
Drugs
Approved for Colon and Rectal Cancer—NCI (nciglobal,ncienterprise). (2011, May
4). [cgvArticle]. https://www.cancer.gov/about-cancer/treatment/drugs/colorectal
Kessmann,
J. (2006). Hirschsprung’s disease: Diagnosis and management. American Family
Physician, 74(8), 1319–1322
Butler Tjaden, N. E., & Trainor, P. A.
(2013). The developmental etiology and pathogenesis of Hirschsprung disease. Translational
Research, 162(1), 1–15. https://doi.org/10.1016/j.trsl.2013.03.001
Wester,
T., & Granström, A. L. (2017). Hirschsprung disease—Bowel function beyond
childhood. Seminars in Pediatric Surgery, 26(5), 322–327.
https://doi.org/10.1053/j.sempedsurg.2017.09.008
Gosain,
A., Frykman, P. K., Cowles, R. A., Horton, J., Levitt, M., Rothstein, D. H.,
Langer, J. C., & Goldstein, A. M. (2017). Guidelines for the Diagnosis and
Management of Hirschsprung-Associated Enterocolitis. Pediatric Surgery
International, 33(5), 517–521. https://doi.org/10.1007/s00383-017-4065-8
Cianflone,
N. F. C. (2008). Salmonellosis and the GI Tract: More than Just Peanut Butter. Current
Gastroenterology Reports, 10(4), 424–431
Wu, H., Ye, L., Xiao, L., Xie, S., Yang, Q.,
& Yu, Q. (2018). Lactobacillus acidophilusAlleviatedSalmonella-Induced
Goblet Cells Loss and Colitis by Notch Pathway. Molecular Nutrition & Food
Research, 62(22), 1800552–1800552. https://doi.org/10.1002/mnfr.201800552
Gut,
A., Vasiljevic, T., Yeager, T., & Donkor, O. (2018). Salmonella infection –
prevention and treatment by antibiotics and probiotic yeasts: A review. Microbiology,
164. https://doi.org/10.1099/mic.0.000709
Surawicz,
C. M. (2010). Mechanisms of diarrhea. Current Gastroenterology Reports, 12(4),
236–241. https://doi.org/10.1007/s11894-010-0113-4
Guarino, A., Buccigrossi, V., & Armellino,
C. (2009). Colon in Acute Intestinal Infection. Journal of Pediatric
Gastroenterology & Nutrition, 48(Suppl 2), S58–S62.
https://doi.org/10.1097/mpg.0b013e3181a1188b
Paredes-Paredes, M., Flores-Figueroa, J., & DuPont, H. L. (2011).
Advances in the Treatment of Travelers’ Diarrhea. Current Gastroenterology
Reports, 13(5), 402–407. https://doi.org/10.1007/s11894-011-0208-6
Sami,
S. S., Al-Araji, S. A., & Ragunath, K. (2014). Review article:
Gastrointestinal angiodysplasia - pathogenesis, diagnosis and management. Alimentary
Pharmacology & Therapeutics, 39(1), 15–34. https://doi.org/10.1111/apt.12527
Olokoba,
A., Olusegun, O., & Olatoke, S. (2012). Angiodysplasia of the colon: A
report of two cases and review of literature. Nigerian Journal of Clinical
Practice, 15, 101–103. https://doi.org/10.4103/1119-3077.94110
Sakai,
E., Ohata, K., Nakajima, A., & Matsuhashi, N. (2019). Diagnosis and
therapeutic strategies for small bowel vascular lesions. World Journal of
Gastroenterology, 25(22), 2720–2733. https://doi.org/10.3748/wjg.v25.i22.2720
Gangurde,
H. H., Chordiya, M. A., Tamizharasi, S., & Sivakumar, T. (2012). Diseases,
approaches and evaluation parameters for colon specific drug delivery: A
review. Int. J. Drug Res. Tech, 2(3), 239-262.
Long,
Q., Ao, L., Li, K., & Li, Y. (2020). The efficacy and safety of sulindac
for colorectal polyps. Medicine, 99(41), e22402. https://doi.org/10.1097/MD.0000000000022402
Challa,
T., Vynala, V., & Allam, K. V. (2011). Colon specific drug delivery
systems: a review on primary and novel approaches. International Journal of
Pharmaceutical Sciences Review and Research, 7(2), 171-181
Danda,
S., & Brahma Chandan, K. (2013). Colon targeted drug delivery-A review on
primary and novel approaches. Journal of Global Trends in Pharmaceutical
Sciences, 4(3), 1179-83.
Chowdary
Vadlamudi, H., Prasanna Raju, Y., Rubia Yasmeen, B., & Vulava, J. (2012).
Anatomical, Biochemical and Physiological Considerations of the Colon in Design
and Development of Novel Drug Delivery Systems. Current Drug Delivery, 9(6),
556–565. https://doi.org/10.2174/156720112803529774
Lou,
J., Duan, H., Qin, Q., Teng, Z., Gan, F., Zhou, X., & Zhou, X. (2023).
Advances in Oral Drug Delivery Systems: Challenges and Opportunities. Pharmaceutics,
15(2), 484–484. https://doi.org/10.3390/pharmaceutics15020484
Lemmens,
G., Van Camp, A., Kourula, S., Vanuytsel, T., & Augustijns, P. (2021). Drug
Disposition in the Lower Gastrointestinal Tract: Targeting and Monitoring. Pharmaceutics,
13(2), 161. https://doi.org/10.3390/pharmaceutics13020161
Hamer, H. M., De Preter, V., Windey, K., &
Verbeke, K. (2012). Functional analysis of colonic bacterial metabolism:
relevant to health? American Journal of Physiology-Gastrointestinal and Liver
Physiology, 302(1), G1–G9. https://doi.org/10.1152/ajpgi.00048.2011
Misal,
S. A., & Gawai, K. R. (2018). Azoreductase: a key player of xenobiotic
metabolism. Bioresources and Bioprocessing, 5(1), 1-9.
Qiao,
J., Wang, M., Cui, M., Fang, Y., Li, H., Zheng, C., ... & Li, D. (2021).
Small-molecule probes for fluorescent detection of cellular hypoxia-related
nitroreductase. Journal of Pharmaceutical and Biomedical Analysis, 203, 114199.
Plewka,
D., Plewka, A., Szczepanik, T., Morek, M., Bogunia, E., Wittek, P., &
Kijonka, C. (2014). Expression of selected cytochrome P450 isoforms and of
cooperating enzymes in colorectal tissues in selected pathological conditions. Pathology-Research
and Practice, 210(4), 242-249.
Carrette,
O., Favier, C., Mizon, C., Neut, C., Cortot, A., Colombel, J. F., & Mizon,
J. (1995). Bacterial enzymes used for colon-specific drug delivery are
decreased in active Crohn's disease. Digestive diseases and sciences, 40,
2641-2646.
Khan,
T., Aman, S., Singh, D. M., & Jain, R. Colon Specific Drug Delivery System:
Innovative Approaches to Treat Colonic Ailments.
Jornada, D. H., dos Santos Fernandes, G. F.,
Chiba, D. E., de Melo, T. R. F., dos Santos, J. L., & Chung, M. C. (2015).
The Prodrug Approach: A Successful Tool for Improving Drug Solubility. Molecules,
21(1), 42. https://doi.org/10.3390/molecules21010042
Prasanth,
V. V., & Mathew, S. T. (2012). Colon specific drug delivery systems: a
review on various pharmaceutical approaches. Journal of Applied Pharmaceutical
Science, (Issue), 163-169.
Yang,
Y., Kim, W., Kim, D., Jeong, S., Yoo, J. W., & Jung, Y. (2018). A
colon-specific prodrug of metoclopramide ameliorates colitis in an experimental
rat model. Drug Design, Development and Therapy, 231-242.
Jung,
Y., & Kim, Y. M. (2010). What should be considered on design of a
colon-specific prodrug?. Expert Opinion on Drug Delivery, 7(2), 245-258.
Kumar,
P., & Mishra, B. (2008). Colon targeted drug delivery systems-an overview. Current
drug delivery, 5(3), 186-198.
Van
den Mooter, G. (2006). Colon drug delivery. Expert opinion on drug delivery, 3(1),
111-125.
Gazzaniga,
A., Moutaharrik, S., Filippin, I., Foppoli, A., Palugan, L., Maroni, A., &
Cerea, M. (2022). Time-based formulation strategies for colon drug delivery. Pharmaceutics,
14(12), 2762.
Kothawade,
P. D., Gangurde, H. H., Surawase, R. K., Wagh, M. A., & Tamizharasi, S.
(2011). CONVENTIONAL AND NOVEL APPROACHES FOR COLON SPECIFIC DRUG DELIVERY: A
REVIEW. e-Journal of Science & Technology, 6(4)
Qelliny,
M. R., Elgarhy, O. H., Khaled, K. A., & Aly, U. F. (2019). Colon drug
delivery systems for the treatment of inflammatory bowel disease. Journal of
advanced Biomedical and Pharmaceutical Sciences, 2(4), 164-184.
Jose,
S., Dhanya, K., Cinu, T. A., Litty, J., & Chacko, A. J. (2009). Colon
targeted drug delivery: Different approaches. Journal of young pharmacists, 1(1),
13.
Yasmin,
F., Najeeb, H., Shaikh, S., Hasanain, M., Naeem, U., Moeed, A., ... &
Surani, S. (2022). Novel drug delivery systems for inflammatory bowel disease. World
Journal of Gastroenterology, 28(18), 1922.
Beloqui,
A., Coco, R., Alhouayek, M., Solinís, M. Á., Rodríguez-Gascón, A., Muccioli, G.
G., & Préat, V. (2013). Budesonide-loaded nanostructured lipid carriers
reduce inflammation in murine DSS-induced colitis. International journal of
pharmaceutics, 454(2), 775-783.
Hua,
S., Marks, E., Schneider, J. J., & Keely, S. (2015). Advances in oral
nano-delivery systems for colon targeted drug delivery in inflammatory bowel
disease: selective targeting to diseased versus healthy tissue. Nanomedicine:
nanotechnology, biology and medicine, 11(5), 1117-1132.
Niebel,
W., Walkenbach, K., Béduneau, A., Pellequer, Y., & Lamprecht, A. (2012).
Nanoparticle-based clodronate delivery mitigates murine experimental colitis. Journal
of Controlled Release: Official Journal of the Controlled Release Society, 160(3),
659–665. https://doi.org/10.1016/j.jconrel.2012.03.004
Naeem,
M., Awan, U. A., Subhan, F., Cao, J., Hlaing, S. P., Lee, J., ... & Yoo, J.
W. (2020). Advances in colon-targeted nano-drug delivery systems: challenges
and solutions. Archives of pharmacal research, 43(1), 153-169.
Vong,
L. B., Yoshitomi, T., Matsui, H., & Nagasaki, Y. (2015). Development of an
oral nanotherapeutics using redox nanoparticles for treatment of
colitis-associated colon cancer. Biomaterials, 55, 54–63. https://doi.org/10.1016/j.biomaterials.2015.03.037
Zhang, S., Langer, R., & Traverso, G.
(2017). Nanoparticulate drug delivery systems targeting inflammation for
treatment of inflammatory bowel disease. Nano Today, 16, 82-96.
Xiao,
B., Laroui, H., Ayyadurai, S., Viennois, E., Charania, M. A., Zhang, Y., &
Merlin, D. (2013). Mannosylated bioreducible nanoparticle-mediated
macrophage-specific TNF-α RNA interference for IBD therapy. Biomaterials, 34(30),
7471–7482. https://doi.org/10.1016/j.biomaterials.2013.06.008
Lin,
C., Ng, H. L. H., Pan, W., Chen, H., Zhang, G., Bian, Z., ... & Yang, Z.
(2015). Exploring different strategies for efficient delivery of colorectal
cancer therapy. International journal of molecular sciences, 16(11),
26936-26952.
Alhakamy,
N. A., Fahmy, U. A., Ahmed, O. A., Caruso, G., Caraci, F., Asfour, H. Z., ...
& Mohamed, A. I. (2020). Chitosan coated microparticles enhance simvastatin
colon targeting and pro-apoptotic activity. Marine Drugs, 18(4), 226.
Wang,
J., Zhang, C., Guo, C., & Li, X. (2019). Chitosan Ameliorates DSS-Induced
Ulcerative Colitis Mice by Enhancing Intestinal Barrier Function and Improving
Microflora. International Journal of Molecular Sciences, 20(22), 5751. https://doi.org/10.3390/ijms20225751
Zhou,
J., Li, M., Chen, Q., Li, X., Chen, L., Dong, Z., Zhu, W., Yang, Y., Liu, Z.,
& Chen, Q. (2022). Programmable probiotics modulate inflammation and gut
microbiota for inflammatory bowel disease treatment after effective oral
delivery. Nature Communications, 13, 3432. https://doi.org/10.1038/s41467-022-31171-0
Jafernik,
K., Ładniak, A., Blicharska, E., Czarnek, K., Ekiert, H., Wiącek, A. E., &
Szopa, A. (2023). Chitosan-based nanoparticles as effective drug delivery
systems—a review. Molecules, 28(4), 1963.
Maroni,
A., Zema, L., Cerea, M., & Sangalli, M. E. (2005). Oral pulsatile drug
delivery systems. Expert Opinion on Drug Delivery, 2(5), 855–871. https://doi.org/10.1517/17425247.2.5.855
Pandit,
V., Kumar, A., S Ashawat, M., P Verma, C., & Kumar, P. (2017). Recent
advancement and technological aspects of pulsatile drug delivery system-a
laconic review. Current drug targets, 18(10), 1191-1203.
Patel,
D. M., Jani, R. H., & Patel, C. N. (2011). Design and evaluation of colon
targeted modified pulsincap delivery of 5-fluorouracil according to circadian
rhythm. International journal of pharmaceutical investigation, 1(3), 172.
Jain,
D., Raturi, R., Jain, V., Bansal, P., & Singh, R. (2011). Recent
technologies in pulsatile drug delivery systems. Biomatter, 1(1), 57–65. https://doi.org/10.4161/biom.1.1.17717
Varum,
F., Freire, A. C., Bravo, R., & Basit, A. W. (2020). OPTICORETM, an
innovative and accurate colonic targeting technology. International Journal of
Pharmaceutics, 583, 119372. https://doi.org/10.1016/j.ijpharm.2020.119372
Illanes-Bordomás,
C., Landin, M., & García-González, C. A. (2023). Aerogels as Carriers for
Oral Administration of Drugs: An Approach towards Colonic Delivery. Pharmaceutics,
15(11), 2639.
Krueger,
L., Miles, J. A., & Popat, A. (2022). 3D printing hybrid materials using
fused deposition modelling for solid oral dosage forms. Journal of controlled
release, 351, 444-455.
Gogolewski,
D., Kozior, T., Zmarzły, P., & Mathia, T. G. (2021). Morphology of models
manufactured by SLM technology and the Ti6Al4V titanium alloy designed for
medical applications. Materials, 14(21), 6249.
Shojaie,
F., Ferrero, C., & Caraballo, I. (2023). Development of 3D-Printed
Bicompartmental Devices by Dual-Nozzle Fused Deposition Modeling (FDM) for
Colon-Specific Drug Delivery. Pharmaceutics, 15(9), 2362.
Nardelli,
S., Pisani, L. F., Tontini, G. E., Vecchi, M., & Pastorelli, L. (2017).
MMX® technology and its applications in gastrointestinal diseases. Therapeutic
Advances in Gastroenterology, 10(7), 545–552.
https://doi.org/10.1177/1756283X17709974
Schreiber,
S., Kamm, M. A., & Lichtenstein, G. R. (2008). Mesalamine with MMX™
technology for the treatment of ulcerative colitis. Expert review of
gastroenterology & hepatology, 2(3), 299-314.
Fiorino,
G. I. O. N. A. T. A., Fries, W., De La Rue, S. A., Malesci, A. C., Repici, A.,
& Danese, S. (2010). New drug delivery systems in inflammatory bowel
disease: MMX™ and tailored delivery to the gut. Current medicinal chemistry, 17(17),
1851-1857.
