9

Gastrointestinal Bioadhesive Drug

Delivery Systems and Their Applications
Olufunke D. Akin-Ajani and Oluwatoyin A. Odeku*

Department of Pharmaceutics & Industrial Pharmacy, University of Ibadan,

Ibadan, Nigeria

Abstract
There are many routes of drug delivery but the gastrointestinal route is the oldest
and most used due to ease of administration and patient compliance. However,
this route has shortcomings such as hepatic first-pass metabolism and enzymatic
degradation in the gastrointestinal tract (GIT), which is a hindrance to the absorp-
tion of most groups of drugs. The mucosa of the GIT can be optimized for drug
delivery by the use of adhesive dosage forms since the mucosa has a rich blood
supply and it is relatively permeable. In the design of drug delivery systems, bio-
adhesion infers attachment of a drug carrier system to a specific epithelial tissue.
A bioadhesive drug delivery system prolongs the retention time of the dosage
form at the site of absorption, facilitates intimate contact of the dosage form with
the absorption surface, and leads to better therapeutic outcomes of the drug. This
chapter is on gastrointestinal drug delivery systems and their applications.

Keywords:  Bioadhesives, gastrointestinal bioadhesive drug delivery systems,

mucous membrane, mucoadhesive polymers, bioadhesive formulations

Abbreviations
DDS Drug delivery system
GI Gastrointestinal
GI-MAPS Gastrointestinal mucoadhesive patch system
GIT Gastrointestinal tract
HPC Hydroxypropyl cellulose

*Corresponding author: pejuodeku@yahoo.com

K.L. Mittal, I. S. Bakshi and J. K. Narang (eds.) Bioadhesives in Drug Delivery, (245–258) © 2020
Scrivener Publishing LLC

245
246  Bioadhesives in Drug Delivery

HPMC Hydroxypropyl methyl cellulose

MC Methyl cellulose
PAA Poly (acrylic acid)
PEG Poly (ethylene glycol)
PVP Polyvinylpyrrolidone
SCMC Sodium carboxy methyl cellulose

9.1 Introduction
Adhesion has been defined as the molecular force of attraction in the area
of contact between dissimilar bodies that acts to hold them together, which
becomes bioadhesion when one or both of the adherends are of a biolog-
ical nature [1]. Bioadhesion, therefore, is an interfacial phenomenon in
which two materials, at least one of which is biological, are held together by
means of interfacial forces [2]. A bioadhesive drug delivery system utilises
excipients, either natural or synthetic polymer, with bioadhesive property
that would adhere to biological tissues, in this case, soft tissues of the gas-
trointestinal mucosa. When adhesion is formed with the mucous mem-
brane of the GI tract the term mucoadhesion may be used [3, 4].
Generally, oral drug administration has been the predominant route for
drug delivery. Over the past three decades, numerous oral delivery systems
have been developed to act as drug reservoirs from which the active phar-
maceutical ingredient can be released at a predetermined and controlled
rate over a defined period of time [5]. However, the challenge with sus-
tained release dosage forms is the inability to increase the residence time
of the dosage form in the gastrointestinal tract, which is a continuous mus-
cular tube, extending from the mouth to the anus, particularly the stomach
and proximal portion of the small intestine [3]. The gastrointestinal tract
has been the subject of intense study for the use of bioadhesive formula-
tions to improve drug bioavailability [6]. Therefore, developing a formu-
lation that remains at the absorption site for an extended period would
be highly beneficial. The mucous membrane is the main administration
site for bioadhesive systems [7]. For mucoadhesion to occur there must be
intimate contact between the bioadhesive and the membrane, penetration
of the bioadhesive into the crevice of the tissue surface and mechanical
interlocking between mucin and the bioadhesive polymer [8].
The target sites for bioadhesion in the GIT are:

■■ The mucosal tissue.

■■ The mucosal gel layer.
 Gastrointestinal Bioadhesive Drug Delivery Systems  247

The thickness of the mucosal gel layer varies regionally throughout the
GIT. There is a continuous renewal of the mucosal layer by a turnover pro-
cess, which limits the duration of mucoadhesion.

9.2 The Mucus Layer

Mucus is a translucent and viscid secretion, which forms a thin, continu-
ous gel blanket capable of adhering to the mucosal epithelial surface. The
mean thickness of this layer varies from about 50-450 μm in humans [9,
10]. It is secreted by the goblet cells lining the epithelia or by special exo-
crine glands with mucus cells acini. The composition of the mucus layer is
highly dependent on the anatomical location, the species, and the patho-
logical state. However, it has a general composition of water 95%, glyco-
proteins and lipids 0.5 – 5%, mineral salts 1% and free proteins 0.5 – 1%
[3, 11]. The primary functions of the mucus layer are [12]:

i. Lubrication: - An important role of the mucus layer is to

keep the mucosal membrane moist.
ii. Adhesion: - Mucus has strong adhesion property and
firmly binds to the epithelial cells surface as a continuous
gel layer.
iii. Protective: - This is due to its hydrophobic nature.
iv. Barrier: - The role of the mucus layer as a barrier in tissue
absorption of drugs and other substances influences the
bioavailability of the drugs.

The continuous secretion of mucus from the goblet cells compensates

for the removal of the mucus layer as a result of digestion, bacterial degra-
dation, and solubilisation of mucin molecules. The mucus network (i.e. the
mucosal epithelial surface, and the cells secreting the mucus) may exhibit
a negative charge due to the presence of sialic acid and sulphate residues
at physiological pH. This high negative charge density contributes signifi-
cantly to the bioadhesion.

9.3 Gastrointestinal Bioadhesive Drug

Delivery Systems
Bioadhesive drug delivery systems are gastroretentive type dosage forms,
which effectively increase site-specific absorption of drugs after oral
248  Bioadhesives in Drug Delivery

administration [13, 14]. Bioadhesive polymeric materials are used to

achieve adhesion of dosage form to the epithelial surface in the gastric
region and to prolong gastric residence time. Bioadhesive property of dos-
age forms is achieved by different mechanisms, which are based on sim-
ple processes in which the dosage form adheres to the surface of mucous
membrane [14]. Examples of some frequently used polymeric materials
for bioadhesive purposes are chitosan, cholestyramine, sodium alginate,
poly(acrylic acid), hydroxypropyl methyl cellulose, sucralfate, tragacanth,
dextrin, and poly(lactic acid) etc [13, 15, 16].

9.3.1 Solid Bioadhesive Formulations

9.3.1.1 Tablets
In general, mucoadhesive tablets have the potential to be used for con-
trolled release drug delivery; however, coupling of mucoadhesive prop-
erty to tablet has additional advantages, such as efficient absorption and
enhanced bioavailability of the drugs due to a high surface to volume ratio,
and a much more intimate contact with the mucus layer [11] as shown
in Figure 9.1. Mucoadhesive tablets offer the possibilities of localized as
well as systemic controlled release of drugs since they can be tailored to
adhere to any mucosal tissue including the stomach [3]. The application of
mucoadhesive tablets to the mucosal tissues of gastric epithelium produces
localized action of drugs. Mucoadhesive tablets have the following advan-
tages: prolonged release of the drug, reduced frequency of drug adminis-
tration and improved patient compliance [17, 18].

Figure 9.1  Example of mucoadhesive tablet [38].

 Gastrointestinal Bioadhesive Drug Delivery Systems  249

Different researchers have formulated various mucoadhesive tablets

with the aid of polymers such as carbopol, HPMC, Eudragit, sodium car-
boxymethyl cellulose, sodium alginate, xanthan and karaya gum. These
polymers have been used for mucoadhesive single layer tablets [19-21],
bilayered tablets [22], mucoadhesive trilayered tablets [23], and mini-
tablets [24].

9.3.1.2 Bioadhesive Microparticles/Nanoparticles

Bioadhesive microspheres constitute an efficient and relevant drug release
systems, since they combine the advantages of conventional microspheres
with those of mucoadhesive systems [25]. They are composed entirely of
a bioadhesive polymer or are polymer coated. Despite the limited drug
loading capacity of bioadhesive micro-and/or nanoparticles, they have
been widely investigated for three major features [18]:

1. Immobilization of particles on the mucosal surface by adhe-

sion after modification of surface properties via bioadhesive
polymers.
2. Very large specific surface between the dosage forms and the
mucosa.
3. Sustained release of entrapped drug, leading to higher
absorption.

Micro/nanoparticles are attached to the mucosal layer through specific

or non-specific interactions.

a. Specific Bioadhesion
Specific bioadhesion signifies adhesion directly to surface of the cells of the
mucosa. This involves specific ligand-receptor interactions between comple-
mentary structures (i.e. the use of polymers or drugs as ligands, which have
specific affinity for the target structures within the GIT). The adhesion takes
place when the dosage form reaches the desired site. Based on the pharma-
ceutical application, different targets identified within the GIT include muco-
sal glycoprotein, M-cells, epithelial cells, Payer’s patches or gut-­associated
lymphoid tissue. However, the limitations of specific bioadhesion are:

i. In vivo, the capacity of the particles to diffuse through the

mucous layer before reaching cell surfaces is limited.
ii. The search for ligands exhibiting a sufficient specificity
and lack of toxicity may be a crucial task.
250  Bioadhesives in Drug Delivery

iii. The immunogenicity of the ligand, and possible change or

an obstruction of the cell membrane functions should be
considered.

The concept of cytoadhesion is specifically based on certain materials

that can reversibly bind to cell surfaces in the GIT. This next generation of
mucoadhesives function with greater specificity because they are based on
receptor-ligand-like interactions in which the molecules bind strongly and
rapidly directly onto the mucosal cell surface rather than on the mucus.
One such class of compounds that has these unique requirements are the
lectins.
Lectins have been used extensively for oral delivery in recent years
because of their inherent property to provide specific binding to biological
surfaces. They are resistant to acidic pH and enzymatic degradation. The
binding of lectins is only possible if corresponding sugar moieties are avail-
able on the mucosal surface. Thus, lectin-based drug delivery systems have
applicability in targeting epithelial cells, intestinal M cells, and enterocytes.
Lectins favour binding at neutral pH. Therefore, it is likely that they will
be suited for drug targeting to the small intestine. Lectins, however, can
be toxic at certain levels. Thus, toxicity is an important factor to consider.
Examples of micro/nanoparticles that have been used as drug carriers
are the stomach-specific controlled release clarithromycin microspheres
[26], amoxicillin-loaded mucoadhesive gliadin nanoparticles [27] and the
positively charged biodegradable gelatine microspheres [28].

b. Non–Specific Bioadhesion
Non-specific bioadhesion with the intestinal membrane occurs through
physicochemical interactions. In the GIT, the micro/nanoparticles directly
mixes with liquid materials in the stomach, which then decreases the
adhesiveness of the polymers due to premature hydration of the polymer.
This occurs before the particles make contact with mucosal surface. Non-
swellable hydrophobic polymers are often used and adhesion is mainly due
to inherent tendency of these small particles to develop intimate contact
with large mucosal surfaces. However, the limitations of non-specific bio-
adhesion are:

i. Only a fraction of the drug in the administered dos-

age form is absorbed while the remainder is eliminated
through the faecal route as shown in Figure 9.2.
ii. Targeting to specialized areas of the mucosa is unrealistic
due to the non-specificity of the interactions.
 Gastrointestinal Bioadhesive Drug Delivery Systems  251

Lumen Mucous layer

Epithelium
Administration of the colloidal particulate system, Step-1

Adsorption of particles and Mucoadhesion, Step 2

Particulate detachment & faecal elimination, Step 3

Figure 9.2  Non-specific mucoadhesion and elimination of micro/nanoparticles [39].

9.3.1.3 Bioadhesive Patches

These are the systems which prolong the intestinal transit time by remain-
ing in the intestinal region for several hours. The prolonged transit time
improves bioavailability, minimizes drug waste and enhances solubility of
drugs that are less soluble in a high pH environment. These have applica-
tions also for local drug delivery to proximal small intestine [3].
A multilayered patch system is one of the approaches for inducing
greater levels of absorption and stability at the intestinal epithelium. The
patches are made up of layers of thin, flexible membranes; an impermeable
backing; a drug reservoir; a rate-controlling membrane, and an adhesive
[3]. On application of the patch, the drug flows through the intestinal epi-
thelium into the bloodstream at a pre-programmed rate regulated by the
patch’s membrane to keep the drug at an effective level. GI patch systems
have three key attributes:

i. Bioadhesive property for retention of the dosage form

ii. Controlled drug release
iii. Unidirectional release towards the intestinal epithelium

9.3.1.3.1 Types of Patches for GI Mucoadhesive Drug Delivery

i. Gastrointestinal-mucoadhesive patch system: This con-
sists of four layers: a backing layer made of a hydrophobic
252  Bioadhesives in Drug Delivery

polymer to protect protein drugs from enzymatic hydro-

lysis; a surface layer made of a pH-sensitive polymer; a
drug-loaded middle layer; and an adhesive layer between
the middle and surface layers to create a high concentra-
tion gradient between the patch and intestinal entero-
cytes (Figure 9.3). An example of this patch system is the
GI-MAPS developed by Eaimtrakarn et al. [29].
ii. Drug-in-adhesive patch: This was designed primarily to
increase the drug-loading capacity of the patch [30]. The
reworked system was composed of three layers: a back-
ing layer of ethyl cellulose, an enteric polymer, and a new
drug-carrying layer.
iii. Microsphere patch: This also consisted of three layers and
was fabricated by Shen and Mitragotri [31]. The prepared
microspheres were spread uniformly and partially pressed
into a thick mucoadhesive layer made of Carbopol and
pectin, which was then covered with an ethyl cellulose
layer. The three-layered film was cut into smaller squares
and circles after drying (Figure 9.4).
iv. Insulin patch for oral delivery: This is a bilayered intes-
tinal patch fabricated using a mucoadhesive matrix of
Carbopol, pectin and sodium CMC (Figure 9.5) and
loaded with bovine insulin (0.25–2.50 U/mg) as a model
drug for oral delivery [32].
v. Gated hydrogel patch: This is a drug delivery system that
provides controlled release using a bilayered self-folding
pH-sensitive hydrogel gate. The device consists of two
parts- a poly (hydroxyl ethyl methacrylate) p(HEMA)
based drug reservoir with targeting function and a hydro-
gel gate. Drug release from the device was controlled
by the pH-dependent swelling property of the bilayered
gate. In pH 3 medium, both hydrogels used showed
similar response, thus the gate remained closed and sta-
ble. However, on increasing the pH of the medium to
7.3, swelling of the poly (methacrylic acid-grafted-poly
(ethylene glycol) p(MAA-g-EG) increased significantly
while the swelling of the p(HEMA) layer remained con-
stant [33].
vi. Micropatches: These may be fabricated to be small
enough to travel between intestinal villi, for increas-
ing the effective surface area for absorption along with
 Gastrointestinal Bioadhesive Drug Delivery Systems  253

Figure 9.3  GI mucoadhesive patches in a capsule [3].

Figure 9.4  A microsphere patch [3].

(a) (b)

2 mm
(c) (d)

2 mm

2 mm

Figure 9.5  (a) GI insulin patches in capsule, (b) insulin patches in the GIT, (c, d) Patches
attached to the mucosa [32].
254  Bioadhesives in Drug Delivery

possible avoidance of phagocytosis by macrophages. The

process of fabricating micropatches involves standard
microelectromechanical techniques, such as photoli-
thography, etching and thin film deposition on three dif-
ferent substrates (silicon oxide, porous silicon and poly
(methyl methacrylate) PMMA [3].
vii. Bilayered patches: These are bilayered stomach-specific
patches, which are for drug delivery [34]. The patch sys-
tem consists of a drug release rate controlling film using
a combination of Eudragit RSPO and RLPO; and muco-
adhesive film using a combination of various hydrophilic
polymers. In vivo bioavailability results indicate that the
gastroretentive patch system provides a novel way to retain
the drug matrix for a longer period of time in the stomach,
enhances drug absorption and thereby offers a promising
strategy for gastroretentive mucoadhesive drug delivery
for the lercanidipine HCl [34].

9.3.2 Semisolid Bioadhesive Formulations

The absorption capacity of hydrogels for aqueous solutions and biologi-
cal fluids has made them useful with novel characteristics resulting in
increased compatibility with biological activity [35]. Ramadan et al. [36]
used a rectal mucoadhesive hydrogel to deliver a non-steroidal anti-
inflammatory drug based on the absorptive ability of the hydrogel.
Hydrogel systems may be formulated into tablets, films, patches, gels, and
ointments. The possibility of co-formulating hydrogels as nanoparticles
extends the limits of their formulation and application [35]. Mucoadhesive
suppositories for the local treatment of diseases such as haemorrhoids and
rectal cancer have also been developed.

9.3.3 Liquid Bioadhesive Formulations

9.3.3.1 Suspensions
The adhesion of sucralfate suspension directly to mucosal surfaces within
the GIT is due to the acidification of the insoluble powder leading to
the formation of an adhesive paste and not as a result of bioadhesive
polymer. Incorporation of a bioadhesive agent, however, has demon-
strated enhanced in vitro adhesion of sucralfate formulation within the
 Gastrointestinal Bioadhesive Drug Delivery Systems  255

oesophagus. Nanosuspension technology and the mucoadhesive princi-

ple have also been combined to develop formulations for poorly soluble
drugs [37].

9.3.3.2 Bioadhesive Liquids

Bioadhesive liquids that coat the oesophagus after oral administration may
be used to protect oesophageal tissue from damage due to gastric reflux of
acidic materials from the stomach. These adhesive liquids may be used to
deliver drugs for the treatment of local disorders including motility dys-
function, fungal infections and oesophageal cancer, since they coat the
oesophagus.

9.4 Summary
The idea of gastrointestinal bioadhesive drug delivery systems began with
the clear need to localize a drug at a certain site in the GI tract. The muco-
adhesive dosage form offers prolonged contact at the site of administration,
low enzymatic activity, and high patient compliance. The formulation of a
mucoadhesive drug delivery system depends on the selection of suitable
polymer with excellent mucosal adhesive property and biocompatibility.
With improvements in bioadhesive-based drug delivery and, in particu-
lar, the delivery of novel highly-effective and mucosa-compatible polymers
such as the lectins and thiols, new commercial and clinical opportunities
for delivering drugs with narrow absorption window at the target sites to
maximise their usefulness will be created.

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