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Drug Delivery to the Gastrointestinal Tract: Challenges and Opportunities 289
connective tissue, blood vessels, lymphatics, and submucosal glands
that secrete digestive enzymes, and a network of nerve fibers known
as the submucosal plexus or Meissner’s plexus [
16].
The muscularis layer, which is the third layer of the alimentary
canal, consists of two layers of smooth muscle, except at the most
proximal and distal ends where it is composed of skeletal muscle
providing voluntary control. The inner circular layer of smooth
muscle and the outer longitudinal layer together form the muscularis layer [
17]. The primary function of this layer is to facilitate
mechanical digestion, reduce particle size for enzymatic action, and
propel food through the alimentary canal via peristaltic movement.
The serosa is the outermost layer of the gastrointestinal tract
(GIT) found within the abdominal cavity. It is composed of a layer
of visceral peritoneum and loose connective tissue that provides
structural support and anchors the GIT in place. Drugs administered via the enteral route pass through the following segments of
the GIT.
2.1 Mouth and Esophagus
2.2 Stomach
When drugs are taken orally, they initially enter the mouth where
they mix with saliva. Saliva, which typically has a pH range of
6.2–7.6 with an average pH of 6.7, plays a crucial role in oral
drug administration. Firstly, saliva aids in breaking down carbohydrates and helps eliminate acids produced by bacteria. Secondly, it
neutralizes acidity from beverages and food, thus providing a buffering effect that protects the oral cavity and the drug itself. After
mixing with saliva in the mouth, drugs then pass through the
esophagus. In this part of the digestive tract, they undergo further
mechanical and enzymatic digestion processes. Despite the relatively short transit time in the esophagus, these initial stages of
digestion are important as they prepare the drug for absorption
and subsequent distribution throughout the body. Understanding
how drugs interact with saliva and the esophagus is essential for
optimizing oral drug delivery. Researchers continue to explore
these processes to enhance drug effectiveness and ensure predictable absorption rates [
18].
The stomach acts as a reservoir for digesting ingested food, maintaining a highly acidic environment (pH 1.5–3.5) through the
secretion of gastric acid. This acidity facilitates food digestion and
helps in eliminating bacteria [
11]. While the stomach provides a
limited area for the absorption of acidic drugs, its acidic conditions
can also degrade acid-labile or basic drugs, thereby reducing their
solubility and effectiveness. This dual role underscores the stomach’s critical influence on both digestion and drug behavior
within the body.
290 Milindmitra K. Lonare et al.
2.3 Small Intestine
2.4 Ruminant Digestive System
The small intestine is composed of three main parts: the duodenum, jejunum, and ileum, serving as the primary location for drug
absorption. The jejunum and ileum, especially due to their extensive microvilli, provide a large surface area, totaling approximately
200 m
2
in adult humans [6]. This feature greatly enhances the
absorption of many weakly basic drugs, facilitated by the pH gradient ranging from around 6 in the duodenum to 7.4 in the terminal
ileum. Conversely, the small intestine plays a crucial role in the
ionization of weakly acidic drugs, thereby regulating their absorp-
19]. It plays a major role in absorption of water and salts from
tion [
the digesta.
The digestive system of ruminant animals is uniquely structured to
efficiently utilize high-fiber feed. Unlike monogastric animals,
ruminants possess a four-compartment stomach consisting of the
rumen, reticulum, omasum, and abomasum, in addition to other
common digestive organs (Fig.
2). Feed and forage are mixed with
saliva in the mouth and transported through the esophagus to the
reticulum [20]. The pH of saliva varies among different ruminant
species: buffalo 8.8, sheep 8.12–8.32, goats 8.2–8.8, calves
8.1–8.23, and cattle 8.55–8.90 [21–23]. Saliva serves essential
roles in chewing and swallowing, containing enzymes that aid in
the initial breakdown of food. One of its crucial functions is to
regulate pH levels in the reticulum and rumen, facilitating the
digestion of fats and starches [
24]. Muscle contractions and pres-
sure differentials propel these substances down the esophagus into
the reticulum.
The r
eticulum f
eatures a honeycomb-like structure designed to
trap and collect dense objects that ruminants inadvertently consume, such as nails or wires. The rumen, commonly known as the
“paunch,” features a lining of papillae that significantly boosts
nutrient absorption. It is segmented into sacs by muscular pillars,
serving as the main site for microbial fermentation, especially of
complex, high-fiber foods. W ithin this chamber, anaerobic conditions prevail, facilitating the breakdown of cellulose and complex
starches. Additionally, it supports the synthesis of proteins from
non-protein nitrogen (NPN) and the production of essential vitamins like B and K. The pH of the rumen generally ranges between
6.5 and 6.8.
The omasum
is spherical and connects to the reticulum
through a short tunnel. It is nicknamed the “many piles” or the
“butcher’s bible” due to its numerous folds, resembling pages of a
book. These folds significantly increase surface area, enhancing
nutrient and water absorption from the feed. Water absorption
specifically occurs in the omasum, which is well-developed and
large in cattle.
Drug Delivery to the Gastrointestinal Tract: Challenges and Opportunities 291
Fig. 2 Illustration showing the gastrointestinal tract of ruminants and different parts of the compound stomach
The abomasum functions as the ruminant’s “true stomach,”
analogous to the stomach in non-ruminants. It produces hydrochloric acid and digestive enzymes like pepsin (for protein breakdown) and receives enzymes from the pancreas such as pancreatic
lipase (for fat breakdown). These secretions prepare proteins for
absorption in the intestines. The abomasum maintains a pH typically ranging from 3.5 to 4.0 and secretes mucus to protect its
lining from acid damage.
Following the
abomasum, the small and large intestines serve as
additional sites for nutrient absorption. The small intestine, up to
150 feet long in a mature cow with a 20-gallon capacity, receives
292 Milindmitra K. Lonare et al.
digesta mixed with pancreatic and liver secretions. These secretions
raise the pH from about 2.5 to a range between 7 and 8, optimizing
conditions for digestion and absorption.
Immature ruminants, such as very young ones from bir th to
approximately 2–3 months old, functionally operate as
non-ruminants. During this stage, a specialized structure called
the reticular (esophageal) groove, formed by muscular folds of
the reticulum, directs milk directly to the omasum and then to
the abomasum, bypassing the reticulorumen. Thus, when drugs
are administered orally to calf, they may enter the abomasum
directly instead of the rumen, where they bypass microbial degradation or inactivation. Conversely, if drugs used in these adult
animals are excreted in manure, may degraded by microflora, or
alters the microflora, it can potentially alter their efficacy. Immature
ruminants should not be given access to feeds containing
non-protein nitrogen (urea). They are also more sensitive to gossypol and dietary fat levels compared to mature ruminants. When
designing nutritional programs for ruminants, it is crucial to consider the age of the animals.
3 Blood Supply
4 Nerve Supply
The gastrointestinal system receives blood supply from both intramural and extramural components. Intramurally, there are welldeveloped vascular distributions with plexuses present in different
layers of the bowel wall. These plexuses are specialized in organs
such as the liver, small intestine, and gastroesophageal junction,
tailored to their respective functions.
Extramurally, the arterial supply to the esophagus originates
from the thoracic aorta or its major branches. Abdominal organs
are supplied by three principal unpaired vessels arising from the
abdominal aorta: the coeliac trunk, and the superior and inferior
mesenteric arteries. Branches from these vessels form
interconnected networks (anastomoses), ensuring a robust blood
supply to the adjacent organs [
The gastrointestinal (GI) tract is innervated by intrinsic neurons of
the enteric nervous system (ENS) and by axons from extrinsic
sympathetic, parasympathetic, and visceral afferent neurons. Both
intrinsic and extrinsic innervation are influenced by age [
Extrinsic inner
prevertebral ganglia, the brainstem, and peripheral afferent ganglia.
Noradrenergic fibers within the GI tract wall originate from cell
bodies in the prevertebral sympathetic ganglia.
vation of the gut comes from neurons located in
25, 26].
27].
Drug Delivery to the Gastrointestinal Tract: Challenges and Opportunities 293
The myenteric plexus (MP), situated between the muscle layers
of the GI tract, is the outer of the two major ENS plexuses. It plays
a primary role in initiating and regulating smooth muscle motor
patterns such as peristalsis [
ganglia supply fibers to the stomach, small intestine, and partially to
the proximal large intestine. The inferior mesenteric ganglia provide fibers to the large intestine, while noradrenergic fibers to the
rectum originate from the pelvic ganglia [
The vagus nerve serves dual roles in the gastrointestinal system,
providing both sensory (afferent fibers) and motor (efferent fibers)
functions. Vagal afferent fibers extend into extensive networks,
forming endings in the smooth muscle, mesenteric plexus, and
mucosa. Within the smooth muscle, these endings are referred to
as intramuscular arrays, while within the myenteric ganglia, they are
termed intraganglionic laminar endings [
work allows the vagus nerve to play a crucial role in sensing and
regulating various gastrointestinal functions.
5 Challenges in GIT Drug Delivery
There are various factors that play a critical role in modulating the
effect of drugs. They may interfere in the activity of the drugs; make
them inactive, increase metabolism or increase elimination; and
limit their pharmacological activity (Fig.
28]. Specifically, the celiac-mesenteric
29].
30]. This intricate net-
3).
5.1 Acidic Environment of the Stomach
The highly acidic environment of the stomach can degrade drugs
that are sensitive to low pH. Some examples include penicillin,
erythromycin, tetracycline, omeprazole, esomeprazole, insulin,
aspirin, and morphine (some formulations of morphine). Hence,
the development of enteric coatings preparation or other protective
mechanisms is necessary to ensure that the drug reaches the intestine intact.
Metabolizing
pH of
intestine
Digestive
enzymes
enzymes
Challenges in
Gut
microflora
GIT drug
delivery
GI transit
pH of
stomach
Efflux
transporters
times
Fig. 3 Factors that interfere in pharmacological activity of drugs
294 Milindmitra K. Lonare et al.
5.2 Alkaline pH of the Intestine
5.3 Variable GI Transit Times
Drugs can degrade under alkaline pH conditions due to various
chemical reactions. Some common degradation mechanisms
include: hydrolysis (many drugs contain ester, amide, or other
functional groups may undergo hydrolysis); oxidation (some
drugs under go oxidation reactions lead to the formation of inactive
or potentially toxic by-products); isomerization (isomerization of
drugs, altering their chemical structure and potentially affecting
their therapeutic activity); decarboxylation (drugs with carboxylic
acid groups may undergo decarboxylation). Here are some examples of drugs that may degrade under alkaline conditions are barbiturates, epinephrine, erythromycin, chlorpromazine, protease
inhibitors, etc.
The transit time through different segments of the gastrointestinal
(GI) tract follows a normal range: gastric emptying typically takes
2–5 h, small bowel transit 2–6 h, colonic transit 10–59 h, and
whole gut transit 10–73 h. This timing can vary significantly
between individuals and within the same person at different times
31], impacting drug absorption and bioavailability.
[
For orally administered drugs, it generally takes around 3 h to
pass through the small intestine to the beginning of the colon.
While designing formulations must consider the specific characteristics of the colon, which influence development strategies. The
total transit time through the colon varies widely due to factors
like diet, mobility, stress, diseases, and concurrent medications
32]. The colon serves as a site for both local and systemic drug
[
delivery, offering significant therapeutic advantages. Traditionally,
immediate-release formulations release drugs in the upper GI tract,
where the small intestine maximizes absorption due to its extensive
surface area and abundant transporter proteins. However, controlled-release formulations are now designed to release drugs
over 12–24 h [
20], targeting specific therapeutic benefits in the
colon and has some significance in colonic diseases.
5.4 Presence of
Digestive Enzymes and
Gut Microflora
Digestive enzymes present in the stomach and intestine can
degrade certain drugs before they are absorbed, thereby diminishing their effectiveness. Additionally, oral digestive enzymes may
experience reduced efficacy when taken alongside antacids containing calcium or magnesium. For instance, amylase or other
carbohydrate-digesting enzymes can potentially decrease the effectiveness of alpha-glucosidase inhibitors like acarbose or miglitol.
Pharmaceutical formulations are meticulously crafted with consideration for digestive enzymes. Enteric-coated formulations, for
example, are specifically designed to withstand degradation by
stomach acid and enzymes. This design ensures that the drug
reaches targeted sites in the gastrointestinal tract intact, optimizing
its absorption and therapeutic benefit.
Drug Delivery to the Gastrointestinal Tract: Challenges and Opportunities 295
Disintegration of dosage form and dissolution of drug can be
controlled by formulation but can be affected by peristaltic movement, luminal pH, and the release of bile salts and the presence of
food. For most of the drugs (excluding some sustained release
formulations), absorption occurs from duodenum and jejunum.
Transcellular absorption predominates for most of the lipophilic
drugs, whereas the polar, hydrophilic compounds are taken up via
paracellular [
33, 34].
Intestinal microbial metabolism of drugs involves the synthesis
of reductase enzymes by gut microbiota, leading to azo reduction
or nitro-reduction of certain drugs. A notable example of this
process includes prodrugs like prontosil, neoprontosil, sulfasalazine, balsalazide, and olsalazine, which undergo reduction by
reductase enzymes produced by gut microflora. Additionally, intestinal microflora produce nitro-reductase enzymes that catalyze the
nitroreduction of drugs such as nitrazepam, clonazepam, bromazepam, metronidazole, misonidazole, chloramphenicol, and
digoxin [
the reduction of digoxin [
35]. Erythromycin and tetracycline are known to inhibit
36]. Additionally, certain drugs undergo
hydrolysis by intestinal microflora, including methotrexate, sodium
picosulfate, irinotecan, and sorivudine.
Intestinal microflora
are
also involved in various other metabolic processes such as oxidation (e.g., levamisole), deamination
(e.g., 5-fluorocytosine), denitration (e.g., glyceryl trinitrate, isosorbide dinitrate), deacetylation (e.g., phenacetin), and decarboxylation (e.g., L-Dopa) [
37–40]. These interactions underscore the
complex role of intestinal microflora in drug metabolism, influencing drug effectiveness, toxicity, and overall therapeutic outcomes.
Understanding these processes is crucial for optimizing drug therapies and managing their interactions with gut microbiota.
5.5 Metabolizing
Enzymes and Efflux
Transporters
Drug-metabolizing enzymes in the gut mucosa serve a crucial role
in limiting the systemic exposure of drugs absorbed from the
gastrointestinal tract, a feature believed to have evolved in herbivorous or omnivorous animals. The proximal small intestine, particularly the villi, represents the optimal site for drug absorption. The
columnar epithelial cells lining the gastrointestinal surface are rich
in oxidative, conjugative, and hydrolytic drug-metabolizing
enzymes.
When foreign molecules penetrate the intestinal capillary
bed via diffusion or transport across the luminal plasma membrane
of mature enterocytes, they encounter this enzymatic barrier. High
enzyme activity levels can result in near-complete extraction efficiency during first-pass metabolism at the mucosal epithelium
[
33, 41].
Once drugs move into the villous epithelium, they are
poised for intracellular enzymatic metabolism. In the case of peptide or peptide-based drugs, degradation by extracellular enzymes
can also take place within the epithelial brush border and the
unstirred water layer [
34].
296 Milindmitra K. Lonare et al.
Efflux transporters like P-glycoprotein and metabolic enzymes
such as cytochrome P450 present in the intestinal epithelium play a
crucial role in limiting drug absorption. These transporters can
actively pump drugs back into the intestinal lumen, while metabolic
enzymes can metabolize drugs before they have a chance to enter
systemic circulation [
42]. This intricate interplay underscores how
the physiological barriers within the gastrointestinal tract impact
the bioavailability and effectiveness of drugs, influencing their
pharmacokinetics and therapeutic outcomes.
6 Future Opportunities in GIT Drug Delivery
Advanced drug formulation techniques such as nanoparticle-based
delivery systems, liposomes, solid lipid nanoparticles, control
release system, etc. are employed to safeguard drugs from degradation, enhance their solubility, and augment their release and
absorption (Fig.
4).
6.1 NanoparticleBased Delivery
Systems
Nanoparticles have emerged as a promising strategy to enhance
drug delivery in the gastrointestinal (GI) tract. These particles,
typically ranging from 1 to 1000 nm, are designed to enhance
drug solubility, stability, and bioavailability. Engineered nanoparticles can shield drugs from the acidic environment of the stomach
Nanoparticle
-based
delivery
systems
Future
opportunities
in GIT drug
delivery
Fig. 4 Future opportunity for the effective GIT drug delivery development
Drug Delivery to the Gastrointestinal Tract: Challenges and Opportunities 297
and facilitate their transport across the intestinal epithelium. For
instance, polymeric nanoparticles can encapsulate drugs, offering a
protective shield against degradation and enhancing drug stability
within the GI tract. Moreover, nanoparticles can be functionalized
with specific ligands to target precise cells or tissues, thereby optimizing drug delivery accuracy.
6.1.1 Targeted Delivery Systems
Targeted delivery systems like prodrugs and ligand-conjugated
nanoparticles offer the capability to deliver drugs precisely to
selected regions of the gastrointestinal tract or specific cell types.
These systems can be designed to release drugs in response to
specific stimuli or to target specific receptors. This precision
enhances drug efficacy and diminishes potential side effects.
6.1.2 Ligand-Conjugated Nanoparticles
Ligand-conjugated nanoparticles are designed to target specific
receptors on the surface of cells in the GI tract. By conjugating
nanoparticles with ligands that bind to these receptors, it is possible
to achieve targeted drug delivery. This approach can improve the
precision of drug delivery, enhance therapeutic efficacy, and reduce
side effects. Examples of ligands used for targeting include antibodies, peptides, and small molecules.
6.1.3 Liposomes Liposomes are spherical vesicles made of phospholipid bilayers
capable of encapsulating both hydrophilic and hydrophobic
drugs. They serve as a versatile drug delivery system, shielding
drugs from degradation and promoting enhanced absorption.
Liposomes can be tailored for controlled release, optimizing drug
pharmacokinetics. Furthermore, they can be engineered with targeting ligands to precisely direct drug delivery to specific locations
within the gastrointestinal tract, thereby boosting therapeutic
effectiveness.
6.1.4 Solid Lipid Nanoparticles
6.2 Controlled Release Systems
Solid lipid nanoparticles (SLNs) represent a promising oral delivery
system. These nanoparticles consist of biocompatible and biodegradable lipids that efficiently encapsulate drugs, thereby enhancing
their stability and bioavailability. SLNs offer several advantages,
including controlled release of drugs, superior drug protection,
and the capability to encapsulate both hydrophilic and hydrophobic
drugs. Moreover, SLNs can be engineered to circumvent efflux
transporters, thereby augmenting drug absorption in the gastrointestinal tract.
Controlled release systems are designed to deliver drugs at a predetermined rate, prolonging their therapeutic effect and reducing
the frequency of administration. These systems can be tailored to
release drugs in response to specific stimuli or over an extended
period. Controlled release formulations, such as osmotic pumps
298 Milindmitra K. Lonare et al.
and matrix systems, effectively regulate the gradual release of drugs,
thereby enhancing their bioavailability and potentially reducing the
frequency of dosing.
6.2.1 Osmotic Pumps
Osmotic pumps represent sophisticated controlled-release mechanisms harnessing osmotic pressure for precise drug delivery. These
devices feature a semipermeable membrane that allows water to
permeate, creating pressure that expels the drug through a delivery
port. This technology ensures consistent and reliable release of
medication, maintaining steady plasma concentrations regardless
of external factors. Osmotic pumps are particularly beneficial for
medications requiring exact dosing and sustained therapeutic levels
in the bloodstream.
6.2.2 Matrix Systems Matrix systems constitute a distinct category of controlled-release
formulations where the drug is uniformly dispersed within a polymer matrix. Drug release occurs either as the matrix gradually
erodes or through diffusion processes. This design enables matrix
systems to effectively extend drug release durations, thereby
enhancing patient adherence and ensuring consistent therapeutic
drug levels. These systems are highly adaptable, capable of being
customized to release drugs at specified rates and in response to
specific stimuli.
6.3 Mucoadhesive Systems
Mucoadhesive drug delivery systems are engineered to adhere to
the mucosal lining of the gastrointestinal tract, thereby extending
the drug’s residence time and enhancing its absorption. These
systems are formulated as tablets, gels, or films, utilizing polymers
that interact effectively with the mucin layer of the GI tract.
6.3.1 Mucoadhesive Polymers
6.4 Absorption Enhancers
Mucoadhesive formulations are specifically engineered to cling to
the mucosal lining of the gastrointestinal tract, thereby prolonging
the drug’s presence and facilitating improved absorption. Utilizing
mucoadhesive polymers like chitosan, carbopol, and polyvinyl alcohol, these formulations establish robust bonds with the mucosal
surface, effectively extending the drug’s retention time at the
absorption site. This prolonged interaction significantly enhances
the drug’s bioavailability and can optimize its therapeutic impact.
Mucoadhesive systems prove particularly advantageous for drugs
with low absorption rates or those requiring precise delivery within
the gastrointestinal tract.
Absorption enhancers work by temporarily disrupting tight junctions or inhibiting efflux transporters, thereby increasing the permeability of drugs across the intestinal epithelium and enhancing
their absorption. Absorption enhancers are compounds that can
temporarily increase the permeability of the intestinal epithelium,