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Chapter 13
Drug Delivery to the Gastrointestinal Tract: Challenges
and Opportunities
Milindmitra K. Lonare, Afroz Jahan, Manjinder Sharma,
and Sivaraman Ramanarayanan
Abstract
The effective oral drug delivery in animals and humans requires an understanding of their unique gastrointestinal tract (GIT) physiology and biochemical regulators. Oral drugs rely on how effectively absorbed
through the intestinal wall and come into systemic circulation. Absorption is hindered by various factors
within the enteric epithelium, such as efflux transporters, enzymatic degradation, tight junctions in addition
to intestinal linings, and first-pass hepatic metabolism. Factor related to the drugs are hydrophilicity or
lipophilicity, high molecular weight, or substrates of efflux transporters, another challenging limiting factor.
Thus, careful designing of oral delivery systems is required in order to improve the systemic availability of
drug by taking into various factors. The majority of drugs are taken orally, as this route is more convenient
and practical, except in emergency and hospitalized conditions. Despite advancements in the pharmaceutical industry, orally administered drugs many times fail to produce the desired effect due to limiting factors
of GIT. Here, we discussed the physiological and pharmacological aspects of the GIT. We also tried to
discuss the challenges underlying in oral drug delivery and future strategy for improvement of drug delivery
via the gastrointestinal tract.
Key words Drug deliver, Gastrointestinal-tract, First-pass metabolism, Efflux transporter, Metabolizing enzyme
1 Introduction
The gastrointestinal tract presents an appealing option for drug
administration because of its accessible entry point, extensive surface area for absorption, and efficient blood circulation that aids in
widespread distribution throughout the body. Furthermore, this
route is favored for its ease of use, cost-effectiveness (allowing
patients to self-administer, thus reducing therapy expenses), and
effective therapeutic outcomes. Consequently, these advantages
contribute to improved patient adherence to treatment
protocols [
1].
285
286 Milindmitra K. Lonare et al.
Despite its widespread use, drug delivery through the gastrointestinal tract remains challenging due to the complex anatomical
structure and physiological regulatory mechanisms. One significant
obstacle is the acidic environment of the stomach, which can
degrade or deactivate many drugs [
the presence of various digestive enzymes in the gastrointestinal
tract that can metabolize drugs before they are absorbed into the
bloodstream. Additionally, the permeability of the intestinal
mucosa can limit the absorption of certain drugs, particularly
those with large or hydrophilic molecules. Factors influencing this
include the disintegration and dissolution characteristics of drug
preparations, lipid solubility, particle size, and the drug’s pKa
[
3, 4].
Various factors such as disease conditions and surgical procedures affecting gastrointestinal anatomy and physiology can also
affect drug absorption through the GIT. To improve drug bioavailability, technologies such as nano carriers and permeation enhancers have been developed to enhance transport across the mucosal
barrier. Strategies to mitigate these challenges also include the use
of enzyme inhibitors or prodrugs that enhance drug activity and
reduce drug inactivation due to enzymatic metabolism in the GIT
. R
5]
ecent advancements in oral drug delivery systems have tack-
[
led challenges associated with anatomical barriers in the GIT, such
as the mucosal barrier that impedes drug absorption, along with
physiological factors like delayed absorption, taste concerns, gastric
irritation, first-pass metabolism, and the influence of the gastrointestinal environment on drug effectiveness [
Additionally,
ruminant species presents a significant challenge for the scientific
community. Ruminants such as cows, sheep, and goats have a
complex stomach structure consisting of four compartments: the
rumen, reticulum, omasum, and abomasum. This multi-chambered
system necessitates specialized drug delivery strategies to ensure
effective drug absorption during treatment. The rumen, which
houses a large microbial population, can metabolize drugs before
they reach absorption sites, thereby reducing bioavailability or
potentially disrupting normal microflora [
consider is the diet of ruminants, which can impact drug absorption. High-fiber diets may slow gastrointestinal transit time and
enhance drug absorption, whereas high-grain diets can expedite
passage through the GIT, reducing contact time with absorptive
surfaces [
bypass the rumen or release drugs at a controlled rate that aligns
with the animal’s digestive kinetics. Formulations needed for ruminants often provide protective coatings or encapsulation that prevent microbial drug degradation and premature drug release in the
rumen [
intact to the lower GI tract where absorption is more favorable.
2]. Another challenge involves
6].
drug delivery to the gastrointestinal tract (GIT) in
7].
Another factor to
8, 9]. Thus, targeted delivery systems are needed to
10].
These approaches aim to deliver the active ingredient
Drug Delivery to the Gastrointestinal Tract: Challenges and Opportunities 287
Therefore, targeted delivery systems are essential to bypass the
rumen or release dr ugs at a controlled rate that matches the digestive kinetics of the animal. Formulations designed for ruminants
often incorporate protective coatings or encapsulation to safeguard
against microbial drug degradation and premature release in the
rumen [
10]. These strategies aim to deliver the active ingredients
intact to the lower gastrointestinal tract where absorption is more
efficient.
2 Anatomy and Physiology of GIT
The gastrointestinal tract (GIT), or alimentary canal, is a fundamental component of the digestive system, comprising the mouth,
pharynx, esophagus, stomach, small intestine, and large intestine
1). It also includes accessory digestive organs such as the
(Fig.
salivary glands, liver, pancreas, and gallbladder. Functions of the
digestive system encompass ingestion, propulsion, mechanical and
chemical digestion, absorption, and defecation. Each organ plays a
critical role in breaking down food, releasing nutrients, and facilitating their absorption into the body [
segment exhibits unique anatomical, physiological, and biochemical characteristics that profoundly influence drug delivery, absorption, metabolism, and elimination.
11]. Importantly, each
Fig. 1 Illustration showing the gastrointestinal tract and different parts of the simple stomach
288 Milindmitra K. Lonare et al.
The alimentary canal is composed of four tissue layers, each
tailored to fulfill specific functions in different parts. These layers,
arranged from the lumen outward, include the mucosa, submucosa, muscularis, and serosa [
or mucous membrane, is responsible for mucus production. In
segments like the mouth, pharynx, esophagus, and anal canal, the
mucosa consists of non-keratinized, stratified squamous epithelium. In contrast, it comprises columnar epithelium in the stomach
and intestines. Goblet cells, which secrete mucus and fluid into the
lumen, and enteroendocrine cells, which release hormones into the
spaces between cells, are dispersed among the epithelial cells.
Intestinal epithelial cells play a crucial role in maintaining gut
balance by forming mucosal barriers that separate gut microbes
from the host immune system. These barriers encompass physical
defenses like the mucus layer and chemical defenses such as antimicrobial peptides (AMPs) produced by Paneth cells. Dysfunction of
these barriers can lead to intestinal inflammation, as observed in
conditions like inflammatory bowel diseases (IBD), characterized
by reduced mucus production and AMP levels. Moreover, intestinal
epithelial cells facilitate communication between gut microbes and
host immunity by generating cytokines, chemokines, and antimicrobial substances in response to environmental factors within the
gut. This interaction helps regulate immune responses and uphold
a symbiotic relationship between gut microbes and the host. The
critical role of gut epithelial cells in supporting immune function
and overall health is well recognized [
ing research aims to elucidate how epithelial cells precisely modulate immunity, produce antimicrobial peptides, and maintain gut
equilibrium.
The l
of loose connective tissue, blood vessels, and lymphatics that transport absorbed nutrients from the lumen to various parts of the
body. Additionally, the lamina propria serves as an immunomodulatory center, housing clusters of lymphocytes in the mucosaassociated lymphoid tissue (MALT). Particularly well-defined in
the ileum, these are known as “Peyer’s patches” and are distributed
throughout the small intestine, primarily on the antimesenteric
side. They include components such as high endothelial venules,
T cells, B cells, and follicular dendritic cells, organized into germinal centers, follicular areas, parafollicular areas, and dome areas,
each with distinct cellular compositions and functions [
The outer
mucosae, is a thin layer of smooth muscle that contributes to the
formation of folds in the mucosa, significantly increasing the surface area available for absorption. Directly beneath this layer, the
submucosa is histologically positioned and lies beneath the muscularis mucosae and muscularis layers. It comprises a broad array of
12]. The innermost layer, the mucosa
13, 14]. Nevertheless, ongo-
amina p
ropria, surrounding the epithelium, is composed
most layer of the mucosa, known as the muscularis
15]
.