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222 S. Vanukuru et al.
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10.2.2.4 Rectum
The rectum is the terminal part of the large intestine characterised by being highly
vascular and is a temporary storage site of faecal matter. As the chyme moves
through the colon, due to water reabsorption and the presence of mucus, the
formation of faeces begins. When the peristaltic wave moves this faecal matter
into the rectum, the expansion causes the stretch receptors present in the rectal
wall to signal for defecation to take place. The rectal mucosa is comprised of
one-cell thick epithelia. It has a constant environment with a neutral pH between
7 and 8. The rectum mucosa is the innermost cell lining and is in constant contact
with faecal matter. As it is an extension of the large intestine, the rectum does not
have villi or microvilli, thus drug absorption is lower than other parts of the GIT.
Furthermore, as water is mostly reabsorbed in the large intestines, the consistency of
faeces is due to mucus which is produced by the goblet cells present in the rectal
mucosa. The mucus protects the rectal epithelium and is a target for drug delivery
(Hua 2019).
Drug delivery via the rectum is an alternative for unconscious patients and is also
used for localised drug delivery which, due to rich blood supply, can be particularly
useful for rapid systemic absorption (Prasanna and Rao
is commonly used in end-of-life patients because compared to other transmucosal
routes it does not induce vomiting and is not affected by vomiting. The main
mechanisms for drug absorption are via the transcellular and paracellular routes.
Even though the rectum has a smaller surface area, due to its lower enzymatic
activity combined with its rich blood supply, this route is often associated with
better drug absorption. Rectal drug delivery dosage forms such as suppositories are
common vehicles for antipyretic drugs (drugs that lower the body temperature). The
disadvantage of rectal drug delivery other than lack of patient acceptance is the
possibility of expulsion of dosage form (Purohit et al.
Bioavailability can also vary depending on conditions such as constipation or
diarrhoea.
2012). Rectal drug delivery
2018; Lam et al. 2020).
10.2.3 Ocular Drug Delivery
The eye is a very complex and specialised sensory organ (Fig. 10.7). Eyes are well
protected within the skull along with the eyelids which provide additional protection
from environmental hazards as well as from dryness. The outermost layer (tunica
fibrosa oculi) consists of the sclera and the cornea. The cornea is the most accessible
part of eye for drug delivery, however, only 5% of the topically applied drugs can
penetrate through the cornea (Moiseev et al. 2019
the eye, the cornea is regularly flushed with aqueous humour from within the eye.
The anterior chamber is present behind the cornea. The aqueous humour maintains
the pressure within the eye. The iris, at the front of the eye, controls the intensity of
). To maintain homeostasis of
10 Transmucosal Drug Delivery: Main Physiological Features and Modern Approaches 223
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Fig. 10.7 Anatomy of
the eye: 1—cornea; 2—
meibomian glands; 3—
palpebral conjunctiva; 4—
bulbar conjunctiva; 5—
conjunctival fornix; 6—
sclera; 7—iris; 8—anterior
chamber; 9—iridocorneal
angle; 10—ciliary body;
11—lens; 12—posterior
chamber; 13—suspensory
ligament; 14—choroid;
15—retinal pigmented
epithelium; 16—retina;
17—vitreous body; 18—
optic disc; 19—optic nerve;
20—central artery and vein
of the retina; 21—fovea.
(Reprinted from Moiseev
et al.
2019)
light entering the eye. The retina is present in the vitreous humour between the
anterior and posterior chambers and is connected to the optic nerve. The lacrimal
glands in the upper eyelid produce tear fluid. The tear film acts as a buffer that
maintains the pH around pH 7 (Morrison and Khutoryanskiy
¼
2014b).
Conventional dosage forms for ocular drug delivery include eye drops, topical
gels and intravitreal injections. Intravitreal injectio ns are delivered via an invasive
procedure with low patient acceptance; therefore, topical administration of drops and
gels is the most common route accounting for approximately 90% of aqueous
ophthalmic formulations. Its advantage being ease of administration and patient
compliance. The disadvantage of ocular drug delivery with particular focus on
topical administration is the inherent barrier function of the eye. When eye drops
or gels are applied to the cornea, they are diluted due to the tear fluid and eliminated
quickly due to blinking and nasolacrimal drainage. Furthermore, the cornea is
composed of five layers of which the mucosal epithelium layer is the outermost
and is known to be poorly permeable to foreign particles and drug molecules
entering the eye. Due to this poor permeability of the cornea, only about 1% of
any topical formulations will be able to cross the corneal layer effectively (Morrison
and Khutoryanskiy
2014a, b). To achieve longer residence times and higher drug
bioavailability, mucoadhesive polymers have been commonly used in ophthalmic
formulations. Furthermore, thermosensitive polymeric in situ gelling systems for
chloramphenicol have been shown to exhibit better retention in the conjunctiva
allowing sustained release of the drug (Ali Allah and Abd-Al Hammid 2012).
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10.2.4 Respiratory System
10.2.4.1 Pulmonary Drug Delivery
The respirato ry system is comprised of two regions known as the upper and lower
respiratory tracts comprising of 23 generations of dichotomous branching, extending
from trachea (generation 0) to the last order of terminal bronchioles. The upper
respiratory tract consists of nasal cavity, oral cavity, pharynx and larynxes. The
lower respiratory tract starts at the trachea and ends with the alveoli where gas
exchange takes place. Each generation splits into two daughter branches to give rise
to a new generation with different structures and functions. The 23 generations are
further divided into two zones called the conducting and respiratory. The conducting
zone includes generation 0 to 16 comprising of structures from upper respiratory
tract to the bronchioles. Air moves into trachea from the upper respiratory tract and
moves into either the left or right lung via the bronchi (Ward et al. 2010). The left
lung is composed of two lobes while the right lung has three lobes. The respiratory
zone includes structures from generation 17 to 23, these include the alveolar sacs and
alveoli where gas exchange occurs (Al-Obaidi et al.
epithelia, therefore gas exchange by diffusion does occur quickly. There are two
types of alveolar cells with the ratio of type 1 to 2 being 1:2. Type 1 epithelial cells
are where gas exchange occurs; type 2 cells produce and secrete the surfactant. The
surfactant helps to make sure the alveoli do not coll apse during the expiration
process (Knudsen and Ochs
cells some of which are ciliated. It is also interspersed with goblet cells which
produce mucus. The lung mucosa also c ontains two distinct macrophages which
reside in the alveoli and interstitial spaces to break down pathogens (Mercer et al.
2006).
Before the first metered dose inhaler was introduced in 1956, common respiratory
conditions such as asthma were significa ntly more fatal. For example, asthma life
expectancy improved with developing inhaler and aerosol technologies (O’Byrne
2019). However, even when a metered dose inhaler is used with an appropriate
et al.
technique, only about 10% of the drug reaches the airways below the larynx (upper
respiratory tract). The rest of the drug is swallowed and absorbed from the gastrointestinal tract. Even with nebulisers, only 12% of the drugs enter the lungs (Rees
2005; Stein and Thiel
drugs are delivered to the site of action. However, the low drug availability remains
the main challenge with drug delivery to the lungs. The difficulty is that lung
deposition is dependent on various physiological and human factors. The respiratory
system is lined with ciliated epithelium and goblet cells which trap the drug in the
mucus and allow it to be broken down. Mucoadhesive polymers can improve the
retention on the respiratory mucosa which can increase drug bioavailability. For
example, spray-dried chitosan with salbutamol microparticles provide rapid drug
release and have potential for pulmonary delivery (Corrigan et al.
2018). Respiratory mucosa consists of varied epithelial
2017
). The advantage of using inhalers and nebulisers is that
2021). Alveoli have single-cell
).
2006
10 Transmucosal Drug Delivery: Main Physiological Features and Modern Approaches 225
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10.2.4.2 Nasal Drug Delivery
The nasal cavity is divided into two canals by the septum. The mucosa is divided into
the respiratory and the olfactory regions. In the nasal cavity, the posterior two-thirds
of epithelial cells are ciliated. Figure 10.8 shows the different areas of respiratory and
olfactory mucosa within the nasal cavity (Selvaraj et al.
2018).
The respiratory mucosa consists of the ciliated epithelial cells dispersed with the
goblet cells which produce the mucus. The respiratory region has a high degree of
vascularity and is primarily responsible for systemic drug absorp tion (Minn et al.
2002; Dhakar et al. 2011). The olfactory region which is above the superior turbinate
is vital for drug transportation to brain and the central nervous system (CNS). Drugs
can cross the epithelial cells in the olfactory mucosa between the interstitial space by
passive diffusion or across the cell membrane by endocytosis. The olfactory neurons
terminate at the apical surface of the epithelium and have direct contact with the
environment in the nasal cavity. Drugs can be transported through the olfactory bulb
through the axonal channels and distributed in the CNS (Minn et al. 2002 ; Bourganis
et al. 2018).
Nasal drug delivery has received increased interest as a drug delivery pathway
for the treatment of neurodegenerative diseases (NDD). This is because in comparison to the conventional drug formulations for NDD, it has a faster onset with higher
bioavailability at the site of action (Lile et al.
2011; Erdő et al. 2018). Other
advantage of nasal delivery is that first-pass metabolism can be avoided. However,
the main disadvantage of nasal drug delivery is that absorption is an issue due to
mucociliary clearance and the short retention time in the nasal pathway. The nasal
mucosal membrane is sensitive and can become easily irritable. Common conditions
such as cold and rhinitis can affect the mucosal membranes in the nasal cavity;
increased production of mucus will reduce the absorption of the drug (Arora et al.
Fig. 10.8 Anatomy of nasal
cavity. (Adapted from
K. Selvaraj et al.
2018)
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2002). Mucoadhesive polymers such as chitosan have been shown to improve nasal
retention of drugs. Chitosan rivastigmine nanoparticles have been shown to have
better efficacy for drug delivery to the brain compa red to other formulations (Fazil
et al.
2012; Illum 2012).
10.2.5 Genitourinary System: Vaginal and Intravesical
10.2.5.1 Vaginal Drug Delivery
The human vagina has not been commonly used for drug delivery except for treating
local problems associated with infections or menopause-loca lised symptoms. The
pH in the vagina is typically varied from 3.8 to 4.5 and the vaginal mucosa is highly
vascularised with a large surface area making it an ideal candidate for localised as
well as systemic drug delivery (Acarturk 2009). The vaginal wall consists of three
layers: the epithelial layer, the muscular coat and tunica adventitia. The epithelial
layer is a few layers thick and is the innermost layer. The vaginal surface has
elasticity which makes it fold; this increases the surface area of vagina which is
advantageous. The vaginal epithelium is composed of stratified squamous epithelium and its thickness is dependent on age and stage in menstrual cycle.
In comparison with the common drug delivery methods, the advantage of vaginal
drug delivery is the ability to avoid first-pass metabolism, ease of administration and
high permeability. The vagina secretes a large volume of fluid due to various factors
and mechanisms due to the action of the hormone oestrogen. The vaginal fluid is
composed of enzymes, other proteins and most importantly cervical mucus. The
fluids can dilute the drug within the vagina or decrease its residence time (De Araújo
Pereira and Bruschi
and hormonal levels within the vagina keep changing throughout the month which
can be detrimental to drug delivery. Unfortunately, the stigma and cultural beliefs
associated with this route and organ make it a barrier to drug delivery (Srikrishna and
Cardozo 2013). Mucoadhesive polym ers such as carboxy methylcellulose and
hydroxyethylcellulose have been formulated as gels with benzydamine with carboxymethylcellulose gel having better adhesion to the vaginal mucosa in the ex vivo
studies (Perioli et al. 2009).
2012). Furthermore, the physiological conditions such as pH
10.2.5.2 Intravesical Drug Delivery
Intravesical drug delivery focuses on drug deli very to the bladder via the use of a
catheter. The urinary bladder wall consists of four layers, the adventitia, which
covers the surface of the bladder, muscularis consisting of detrusor muscles, submucosa and mucosa. The epithelial cells within mucosa are called uroepithelium and
is composed of three layers. The apical layer is the innermost layer which is one cell
thick called umbrella cells, followed by intermediate and basal layers. The
10 Transmucosal Drug Delivery: Main Physiological Features and Modern Approaches 227
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Fig. 10.9 Histology of
urinary bladder mucosa
uroepithelium acts as a barrier between the urine and the underlying tissue (Fry and
Vahabi 2016). The epithelium is covered by mucopolysaccharide glycocalyx which
protects it from
urine, which has a pH range of 4.5–8. The bladder wall is composed
of detrusor smooth muscle layer which when contracted releases the urine. Furthermore, direct administration into the bladder reduces systemic side effects and gives a
higher drug concentration at the site of action. However, repeated catheterisation can
cause damage to the bladder often associated with the risk of ex
(GuhaSarkar and Banerjee 2010).
mycin C showed that
chitosan formulations had better uroepithelial mucoadhesive
properties compared to free mitom ycin (Kolawole et al.
An in vitro release study of chitosan with mito-
2019a). This allows for high
travasation
concentrations of the cytotoxic drug to be administered to the bladder without
penetration into the surrounding tissues and systemic circulation (Fig. 10.9).
10.3 Drug Delivery Approaches
Except intravesical drug delivery, other routes of administration for TDD are
manageable by patients without difficulties. Furthermore, all the routes are used
for localised conditions. The physiological conditions vary widely in different
organs of the body leading to each route needing different drug delivery approaches
even though the target mucosal site is similar. The composition of mucus, enzymes,
macrophages and blood supply can have a huge impact on the bioavailability of
drugs. Mucoadhesion plays a crucial role in drug delivery via mucosal surface as
228 S. Vanukuru et al.
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poor retention within the mucosa is a problem to overcome for successful drug
delivery.
10.3.1 Mucoadhesive Dosage Forms
10.3.1.1 Solids
The site of the mucosa plays a role in determining the suitable dosage for
transmucosal drug administration. Solid dosage forms such as tablets can be used
for buccal and vaginal drug delivery, while suppositories are commonly used in
rectal drug delivery.
10.3.1.1.1 Tablets
Tablet formulations are widely accepted and used due to their ease of administration
and lower production costs involved. Tablet formulations are commonly used for
drug delivery via oral or vaginal routes. It is the most explored formulation for
buccal drug delivery. There are several tablet formulations currently available on the
market to treat different conditions by buccal delivery (Buccastem M) and Vagifem
tablets for vaginal delivery (Shaikh et al. 2011). However, their retention within oral
and vaginal mucosa can be improved by the incorporation of mucoadhesive polymers. Carbomers, chitosan and some derivatives of cellulose are mucoadhesive
polymers used for formulating mucoadhesive buccal dosage forms (de Sá et al.
2018). For buccal drug delivery, adhesive tablets have distinct advantage over
conventional tablets as they allow for drinking and speaking without too much
inconvenience to the patient. Increased retention of drug within the mucosa by
addition of mucoadhesive polymers can be achieved through several mechanisms
of mucoadhesion. The physicochemical properties of the polymer such as charge and
molecular weight influence the drug stability and adhesion. A disadvantage of
mucoadhesive tablets that increased retention can cause localised irritation of
mucosa. Furthermore, if tablet is formulated for buccal delivery but is swallowed
by mistake, it can adhere to the oesophageal mucosa causing issues with swallowing
(Chinna Reddy et al. 2011; Kaul 2021).
10.3.1.1.2 Suppositories
Suppositories are commonly used in rectal and vaginal drug delivery. Even though
the vaginal and rectal routes are primarily used to treat localised diseases, they can
also be used for delivering drugs to the systemic circulation as both regions are
highly vascularised. Most drugs delivered vaginally and rectally are available as
suppositories (Khan and Saha
2015). Suppositories are often formulated with either
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a lipophilic or a hydrophilic base. The lipophilic-based suppositories melt at body
temperature to release the drug which is more suitable for rectal delivery due to less
fluid being present. In comparison, the hydrophilic-based formulation is not affected
by body temperature but requires the presence of aqueous media for it to dissolve
and release the drug; therefore vaginal application is ideal due to more fluid present
in the vagina in contrast to the rectum (Caramella
The major drawback
can release the drug close to the superior hemorrhoidal vein which is connected to
the hepatic portal vein, thus first-pass meta bolism is possible. To increase retention
time within the mucosa, a common strategy is to incorporat e mucoadhesive polymer
into the suppository. One or more mucoadhesive polymers such as sodium carboxymethylcellulose, carbomers or others can be mixed wi
hydroph
polymers within the formulation are present to prolong the presence of drug at the
application site without affecting the release of the drug (Ham and Buckheit
10.3.1.2 Semi-solid Dosage Forms
Semi-solid preparation s constitute a significant percentage of pharmaceutical dosage
forms. These dosage forms are primarily used in topical drug delivery. Creams,
ointments, gels and patches are the most common semi-solid preparations. Creams
and ointments are generally used for transdermal drug delivery while gels and
patches are more common in transmucosal drug delivery.
ilic
base
of rectal delivery is that if the suppository is inserted deeper, it
and
the drug to form a mucoadhesive suppository. Mucoadhesive
et al. 2015; Al-Joufi et al. 2021).
th e
ither a lipophilic base or
2017).
10.3.1.2.1 Gels
Gel formulations can be used in various mucosal drug delivery systems such as
ocular, oral and nasal (Bernkop-Schnürch
hydrophilic polymers acting as a gelling agent (Santanu et al. 2012
tions are easily dispersed throughout the mucosa and may provide fast er onset of
drug action compared to tablets. There are many physiological features that can
affect drug delivery for nasal or ocular mucosa for either local or systemic action.
Gel formulations with suitable mucoadhesive properties increase the retention time
within the mucosa, thus increasing the bioavailability of drug at the site of action.
The drawback of gels is the difficulty to deliver an accurately measured dose of
drugs (Fini et al.
Carbopol are known to undergo a phase change from liquid to semi-solid, enhancing
their viscosity and resulting in sustained and controlled release of drugs. Hydrogels
are formed when polymers are hydrated and physically entrap drug molecules for
drug to be released over a long time (Boddupalli et al. 2010).
2011; Bora et al.
2005). Gels are usually formulated using
). Gel formula-
2014). Some mucoadhesive polymers such as
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10.3.1.2.2 Patches
Compared to creams, ointments and gels, patches have an advantage of delivering
accurate drug dose to site of action (Chinna Reddy et al.
include ease of drug administration and in case patients develop undesirable effects,
then removal of the patch terminates drug release (Jacob et al.
transmucosal drug administration routes, oral mucosa is most suitable for drug
delivery by mucoadhesive patches due to the increased absorption allowed by its
large surface area. Furthermore, increased residence time in the mucosa allows for
more drug release. Patches can be formulated either with controlled or rapid drug
release profiles. The type of polymer and design such as matrix (bidirectional) and
reservoir (unidirectional) also play a factor in drug release from patches (Rohani
Shirvan et al.
10.3.1.3 Liquid Dosage Forms
Liquid formulations have the benefit that the drug regimen can be easily optimised
according to the weight or age of the patient (Walsh et al. 2021). Paediatric and
geriatric patient groups are more prone to developing swallowing difficulties, therefore liquids are ideal for drug delivery (Breitkreutz and Boos 2007). Regarding
mucosal drug delivery, liquid formulations are commonly used to deliver drugs
nasally. The drug solutions are administered as drops, sprays and as metered dose
nebuliser. Formulation parameters such as dose and pH of solution influence nasal
absorption. Suspensions are formulated by suspending drugs in a diluent for nasal
administration (Chaturvedi et al. 2011). Furthermore, compared to other drug formulations, liquids have faster onset as there is no dissolution required. However, the
drawback is that microbiological stability of liquid formulations is compromised
when compared with solid dosage forms, requiring the inclusion of preservatives.
Thus, the reduced stability and short retention time within the nasal cavity are other
major disadvantages. The deposition site, device and mode of administration are also
important parameters for absorption within nasal cavity. To overcome the
mucociliary clearance within the nasal cavity, mucoadhesive polymers could be
used. Some polymers such as derivatives of polyacrylic acid and others also contribute to enzyme inhibitory activities in the nasal cavity which can contribute
towards better bioavailability of the drugs (Ugwoke et al. 2005; Morita and
Yamahara 2016).
2019).
2011). Other advantages
2021). Of all the
10.3.2 First-Generation Mucoadhesives
All water-soluble and weakly cross-linked hydrophilic polym ers have some ability
to adhere to mucosal membranes due to hydrogen bonding, electrostatic attraction,
interpenetration, chain entanglements and other factors. These polymers are
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classified as first-generation mucoadhesives commonly used in various formulations
for TDD. These polymers could be either of synthetic origin (e.g. Carbomers) or they
could be derived from natural sources (e.g. chitosan, alginates and cellulose ethers).
These polymers are further categorised into four classes: cationic, anionic,
amphoteric and non-ionic. Polymers with ionisable groups (cationic and anionic)
are expected to exhibit greater mucoadhesive properties compared to non-ionic
macromolecules (Khutoryanskiy
mucoadhesive properties.
Chitosan is an example of biodegradable cationic mucoadhesive polysaccharide
which is formed when chitin from crustaceans is treated under alkaline conditions. It
is often considered excellent mucoadhesive due to its excellent adhesivity to mucosal tissues. This is mainly due to electrostatic interactions between positively
charged amino groups on chitosan and mucins which are negatively charged.
Furthermore, the hydroxyl groups present in chitosan may also form hydrogen
bonds with mucins (Sogias et al. 2008). However, despite the superior
mucoadhesive properties of chitosan over many other water-soluble polymers, it is
rarely used in commercial pharmaceutical formulations. One of the reasons for this is
its animal origin and possible contamination with proteins that could cause allergic
reactions.
Carbomers are weakly cross-linked derivatives of polyacrylic acid along with
alginates and carboxymethylcellulose are examples of negatively charged
mucoadhesives. Hydrogen bonding, van der Waal forces and hydrophobic interactions are often responsible for their mucoadhesive properties. Some cellulose derivatives such as hydroxy propyl methylcellulose, hydroxyethyl cellulose and methyl
cellulose are non-ionic polymers, which have weaker mucoadhesive properties
compared to charged polymers (Carvalho et al. 2010).
2011). Amphoteric polymers tend to exhibit poorer
10.3.3 Second-Generation Mucoadhesives
Second-generation mucoadhesives have been developed with improved
mucoadhesive properties. Compared to the non-specific first generation, these
synthesised polymers adhere specifically to structures on the surface of mucous or
cells. The advantage of the second-generation mucoadhesives is that they exhibit
stronger adhesion to the mucosal membranes (Bernkop-Schnürch 2005; Carvalho
et al. 2010; Hauptstein et al. 2014). One of the examples of naturally derived secondgeneration mucoadhesives are lectins. Lectins are a diverse group of glycoproteins
that recognise and bind to carbohydrate molecules non-covalently. Cytoadhering is
the process by which lectins specifically bind to the glycosylated features on the cell
membrane unlike the first generation which bind to the mucus membrane in general
(Lehr
2000; Bernkop-Schnürch
Thiolated polymers were first proposed by Bernkop-Schnurch et al. (BernkopSchnürch 2005) as the synthetic or semi-synthetic mucoadhesives of the second
generation. These are commonly synthesised by conjugation of water-soluble
2005; Gavrovic-Jankulovic and Prodanovic 2011).
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