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Chapter 10
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Transmucosal Drug Delivery: Main
Physiological Features and Modern
Approaches
Shiva Vanukuru, Hisham Al-Obaidi, and Vitaliy V. Khutoryanskiy
10.1 Introduction
Mucosal membranes enclose the moist surfaces in the human body and are comprised of one or more layers of epithelial cells. The primary funct ion of these
membranes is to protect the epithelial tissues which are directly beneath them.
Mucosal membranes are predominantly found in the nose, lungs, eyes and eyelids,
mouth, gastrointestinal tract, urethra and vagina (Hall and Hall 2020).
Transmucosal drug delivery (TDD) refers to drug molecules diffusion to their site
of action across the mucosal membranes. Currently, about 90% of the medicines are
formulated as oral dosage forms due to the convenience of their use and ease of mass
production (Indurkhya et al. 2018). However, gastric emptying, absorption rate and
bioavailability affect the duration of action of orally administered drugs (Sato et al.
2014). Table 10.1 lists all the major TDD routes, including some examples of current
medicines available on the market. Even though all these routes have different
anatomical and physiological features they have some common characteristics of
mucosal membranes (Lam et al.
Even though the oral route is the often preferred, its main drawback is that it does
not provide a rapid onset of action. On the other hand, TDD has been shown to be
effective for treating life-threating situations such as angina using sublingual glyceryl trinitrate spray (Jensen and Mikkelsen
There are many advantages of transmucosal drug delivery, including increased
time of residency at the site of action. Furthermore, localised action of the drug can
reduce systemic side effects which can be beneficial. The main limitation of
transmucosal delivery is the mucus layer which reduces drug absorption (Laffleur
2020).
1997).
S. Vanukuru · H. Al-Obaidi · V. V. Khutoryanskiy (*)
Reading School of Pharmacy, University of Reading, Reading, UK
e-mail: v.khutoryanskiy@reading.ac.uk
© The Editor(s) (if applicable) and The Author(s), under exclusive license to
Springer Nature Switzerland AG 2024
I. F. Uchegbu et al. (eds.), Fundamentals of Pharmaceutical Nanoscience,
https://doi.org/10.1007/978-3-031-59478-6_10
213
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Table 10.1 Examples of medicines administered via different transmucosal routes
Current drugs
Transmucosal
route
Buccal Oro mucosal Prochlorperazine Nausea
Gingival Lidocaine gel Desensitisation/pain relief
Sublingual Glyceryl
Gastrointestinal Oesophageal Gaviscon Acid reflux
Rectal Gastrointestinal Bisacodyl Constipation
Nasal Respiratory Mometasone
Inhalation Salbutamol Asthma
Ocular Visual system Chloramphenicol Bacterial conjunctivitis
Vaginal Genitourinary Oestradiol Vaginal atrophy
Intravesical Mitomycin Chemotherapy
Table 10.2 Advantages and disadvantages of transmucosal drug delivery (TDD)
Advantages Disadvantages
Increased time of residency at
the site of action
Ease of administration Mucosal membranes are often very sensitive, and some dosage
Localisation of drug action Some TDD routes have small surface area for drug absorption
Reduced first-pass metabolism Some TDD routes can only accept low volumes which is not
Reduced dose-related side
effects
Various routes of drug deliv-
ery are available
Different dosage forms are
available
Organ system
available on
market
trinitrate spray
spray
Barrier properties of the mucus layer
forms may cause irritation
ideal if drugs need high volume
Therapeutic application/conditions
being treated (Joint Formulary
Committee 2020)
Angina
Allergic rhinitis
and Bernkop-Schnürch 2013). This can be improved by permeability enhancers.
Table 10.2 lists some advantages and disadvantages of transmucosal drug delivery.
The term mucoadhesion, defined as interfacial force interactions between synthetic or natural polymeric materials serving as a dosage form and a mucus layer that
covers a mucosal tissue, has emerged following pioneering studies by Nagai and
co-workers in the 1980s (Ishida et al. 1983; Nagai and Konishi 1987) and Peppas
and co-workers (Gurny et al. 1982; Peppas and Sahlin 1996). Adhesion of dosage
forms to mucosal surfaces provides improved retention, which facilitates drug
penetration and improves bioavailability.
Generally, mucoadhesive materials are hydrophilic polymers with the ability to
form hydrogen bonds or to interact electrostatically with mucins. For example,
chitosan is a well-known cationic polymer that is highly mucoadhesive. It binds to
negatively charged mucins on the mucosal membranes (Robinson et al.
1987). There
10 Transmucosal Drug Delivery: Main Physiological Features and Modern Approaches 215
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have been different theories to explain mechanisms involved in mucoadhesion by
which electronic, absorption, wetting and diffusion seemed the main mechanisms
(Khutoryanskiy 2011).
10.2 Mucosal Routes of Drug Administration and Their
Physiological Features
10.2.1 Oral Cavity: Buccal, Gingival and Sublingual
The oral cavity refers to the mouth, it starts at the lips and ends at the start of
oesophagus. The mouth is a sensory organ and is regarded as the first part of the
digestive tract. Figure 10.1 shows the distinctive features of the oral cavity comprising of gingival and buccal tissue, hard palate and the tongue. The mucosal membranes in the mouth are comprised of stratified squamous epithelium which covers
the connective tissue beneath. Histologically, the oral mucosa can be divided into
three categories: lining, masticatory and specialised. The thickness of the epithelial
mucosa and the level of keratinisation determine the physiological functions which
Fig. 10.1 The positioning of mucosal surfaces in the oral cavity adapted from NIH oral cavity
(https://www.cancer.gov/publications/dictionaries/cancer-terms/def/oral-cavity)
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Fig. 10.2 Permeation profile of nicotine through various oral mucosae. (Reprinted from Chen et al.
1999)
can occur effectively at specific locations wi thin the cavity. First, the hard palate and
the gingiva are covered by a keratinised mucosal layer, and these structures along
with the teeth and tongue form the masticatory mucosa. These structures break down
the ingested food and form a bolus that is swallowed allowing maximum exposure to
digestive enzymes. The tongue is covered by papillae (test buds) which contain the
taste buds (Travers et al. 2010).
A large part of the oral cavity has non-keratinised mucosa. This non-keratinised
mucosa covers the lining of the lips, cheeks (buccal) and floor of the mouth
(sublingual). Salivary glands are located within the submucosa of the buccal and
sublingual linings and are connected to the oral cavity. There are three main salivary
glands: parotid which is located near the ear, sublingual which is located under the
tongue and submandibular which is in the jaw. There are other minor glands situated
within the buccal and labial linings. Saliva produced in these glands covers the
linings of the oral mucosa. Saliva is composed of 99% water, proteins, enzymes and
electrolytes and is slightly acidic with a pH range of 6.2–7.4 with an average of 6.7
(Humphrey and Williamson
2001). One of the important roles of saliva is to act as a
barrier layer for the mucosa. It is known to have antibacterial activity; antimicrobial
lysosomes and immunoglobulins A, G and M are present which can eradicate
pathogens. Furthermore, enzymes such as amylases and lipases start to break
down starch and fats, respectively, within the oral cavity. Finally, it acts as a buffer
system to adjust the pH and protect the environment within the oral cavity (Humphrey and Williamson 2001; Baliga et al. 2013).
The oral cavity offers three distinct opportunities for TDD such as buccal,
sublingual and gingival. The key differences between buccal, sublingual and gingival routes of drug administration other than their location within the oral cavity, are
the thicknesses of epithelia, their permeability and levels of irrigation by the saliva.
10 Transmucosal Drug Delivery: Main Physiological Features and Modern Approaches 217
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Figure 10.2 presents the experimental data on permeability of nicotine through three
mucosal membranes present in the oral cavity as reported by Chen et al. (1999).
These results clearly illustrate greater permeability of sublingual and gingival
membranes compared to the buccal tissue. Compared to the buccal cell layer, the
sublingual cell layer is thinner and more vascularised leading to higher permeability
and faster onset of action. However, the sublingual area is more affected by
excessive salivation. Therefore, the sublingual route is more useful for drugs with
short delivery period requirements and infrequent dosing.
The buccal route is more effective when extended drug release is desired. This
route often benefits from the use of mucoadhesive formulations that facilitate longer
dosage form retention on the buccal mucosa and extended periods for drug absorption. Buccal formulations include lozenges, gels, films, patches and tablets.
For oromucosal routes, once the drug has overcome the mucus and epithelium
barriers through either paracellular or transcellular diffusion, it enters the systemic
circulation via venous drainage bypassing first-pass metabolism and gastrointestinal
drug degradation (Bruschi and De Freitas
of the oromucosal route is that patients who suffer from xerostomia (dry mouth) can
be affected as saliva is needed for dissolution of the drug. Furthermore, it is not
suitable for people who suffer from nausea and vomiting. The small surface area
within the oral cavity and the taste of the drug also can play a major role in whether
patients prefer this route to other routes (Lam et al.
biological aspects of the oral cavity have a significant effect on drug dissolution,
including pH, fluid (saliva) volume, enzyme activity and the permeability of oral
mucosa.
2005; Patel et al. 2011). The disadvantage
2020). Cer tain physiological and
10.2.2 Gastrointestinal System: Oesophagus, Stomach,
Intestine and Rectum
10.2.2.1 Oesophageal Drug Delivery
The oesophagus is a muscular tube that is lined with stratified squamous epithelium.
It connects the mouth to the stomach and its function is to transport food and water
into the gastrointestinal tract (GIT). At either end of oesophagus, there is sphincter
muscle. The upper sphincter muscle opens just when swallowing is required. The
lower sphincter muscle is closed to stop the acid from the stomach from rising into
the oesophagus. Saliva is swallowed from the oral cavity, and it contains mucins
which form the lining over the epithelium. The pH of the fluids irrigating the
oesophagus is around pH ¼ 7 and the typical transit time for food and water through
this organ is 10–14 s (Cook et al. 2012).
The problems with the oesophagus may arise when people have swallowing
difficulties. These are commonly observed in young and geriatric populations. The
oesophageal epithelium is poorly permeable for many types of drug molecules.
About 20% of solid dosage forms adhere to the oesophagus which can potentially
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Fig. 10.3 Anatomy of
gastrointestinal tract with
pH ranges in different
organs. (Reprinted from
Cook et al.
2012)
lead to injury. Gastro-oesophageal reflux disease (GORD) can also damag e the
oesophageal tissue. Therefore, mucoadhesive formulations which have increased
residence time within the oesophagus are often required. Oesophageal motor disorder (Achalasia) is treated by calcium channel blockers and nitrates which relax the
smooth muscle. Using these therapeutic agents may cause systemic side effects,
hence liquid formulations which adhere to the oesophagus will be
oesophageal diseases
(Batchelor
2005; Schiele et al. 2013; Liu et
ideal to treat
al. 2014). Furthermore, Gaviscon liquid formulation is used to treat GORD in all ages. Compared to
proton pump inhibitors which reduce the production of acid, Gaviscon has alginate
which forms a gel raft at the top of the stomach and stops the chyme and stomach
acid from entering the oesophagus. Also, alginate is a mucoadhesive polymer that
increases the residence time within the stomach and oesophageal mucosa. Calcium
carbonate and sodium bicarbonate present in the formulatio
excess acid and also
release carbon dioxide that is entrapped in the gel raft. This gel
n help neutralise the
is formed by the reaction of alginate with calcium ions released from calcium
carbonate. The carbon dioxide bubbles help keep the gel raft on the surface of the
gastric juice in the stomach. A meta-analysis by Leiman et al. showed that alginate
2017) (
therapy is effective for GORD symp toms (Leiman et al.
Fig. 10.3).
10.2.2.2 Stomach
The stomach is located in the upper left-hand region of abdomen cavity and is
connected to the oesophagus and intestines. The stomach is a muscular organ
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characterised by regular contractions and relaxations that occur to help with the
breakdown of food into chyme and the movement of chyme towards the intestine.
The lower oesophageal sphincter relaxes to allow the food content of the oesophagus
to move towards the stomach. The pH levels within the stomach are around 1 to 2
during the fasting state and can typically increase to around 3 to 6 in the fed state
(Mudie et al.
The cardia
2010). There are four main parts to the stomach, as seen in Fig.
is at the top, close to oesophagus; this is where the lower oesophageal
10.4.
sphincter muscle is located. The fundus and corpus are the main sections; this is
where the food is broken down by enzymes (Hsu et al.
2022). The pylorus is the final
part of the stomach; this is closest to the small intestine. The food is stored here until
the sphincter muscle relaxes to move the chyme into small intestine. Expansion of
the stomach is known to occur with ingestion of food; this is because the inner
surface of the stomach has rugae present which increases the surface area (Laurent
2012). The movement of food through the GIT occurs due to muscle contrac-
et al.
tions, called peris
talsis.
There are four different tissue layers present in the stomach. The mucosal layer is
the inner surface layer of the stomach. Foveolar cells present produce mucus which
lines the stomach walls and protects it from hydrochloric acid. The hydrochloric acid
is produced and secreted by parietal cells. The chief cells secrete pepsinogen which
is a precursor for the enzyme pepsin to break down proteins. The stomach mucus
system is two-layered; one layer is attached to the walls while the other is unbound.
The inner layer of the mucus on the walls acts as a diffusion barrier for the stomach
acid. Dru gs that have a short half-life or are absorbed quickly are eliminated quickly
Fig. 10.4 Anatomy of stomach. (Adapted from Laurent et al. 2012)
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from the systemic circulation and therefore need frequent dosing. Gastric emptying
can limit the absorption and bioavailability of some drugs as the residence time
within the stomach is shortened (Nikalje et al. 2012; Johansson et al. 2013). For
example, furosemide is known to be absorbed in the stomach, however gastric
emptying can cause a problem as the drug will be forced to leave the absorption
site before it is fully absorbed; therefore, retention in the gastric mucosa will be
2010)
beneficial in such situations (Terao et al.
Gastric residence time and gastric emptying are affected by different factors. The
size of the meal, gastric contents, dosage form and frequency of feeding determine
how long the food stays in the stomach and how long the gastric emptying occurs
(Fiebrig et al.
when treating localised problems such as peptic ulcers. A common application is gel
raft-forming systems such as Gaviscon™ which stops the acid from rising into the
oesophagus are becoming more common. Another example is Madopar™ which
uses a floating drug delivery system where the granules have lower density compared to gastric juice. Hence they float and resist gastric emptying and the drug can
release slowly (Shashank et al. 2013).
10.2.2.3 Small and Large Intestine
The difference between small and large intestine is that the large intestine is much
broader compared to the small intestine (Fig. 10.5).
Furthermore, the small intestine has small finger-like projections on the mucosal
surface called microvilli (Fig. 10.6).
Microvilli increase the surface area for absorption, therefore the small intestine is
where most of the absorption takes place (Korelitz and Janowitz 1957). The chyme
moves from the stomach into small intestine, later from small intestine it moves into
large intestine. There are three different sections which are the duodenum, jejunum
and ileum. The average pH of duodenum is 5–6 compared to jejunum and ileum
where it is 7–8. Pancreatic enzymes enter duodenum and breakdown the chyme
further. The jejunum and ileum have higher pH levels thanks to bicarbonates
released into duodenum to increase the pH of chyme. Jejunum is where most of
the absorption of sugars, amino acids and fatty acids takes place within small
intestine, with the ileum absorbing any other remaining nutrients (Yuen
Dahlgren and Lennernäs 2019; Stillhart et al. 2020). Drug physicochemical properties such as pKa and log P determine in which part of small intestine, the absorption
will take place. For example, paracetamol is absorbed throughout the small intestine,
while pseudoephedrine is absorbed best at the ileum (Murakami 2017). Furthermore,
the small intestine is highly vascularised for the effective absorption of nutrients
(Peled et al. 2016).
The large intestine is regarded as the final section of the GIT. Its function is to
absorb water and salts from undigested materials and get them ready for elimination.
The large intestine is divided into caecum, colon and rectum (Nigam et al.
chyme passes through the large intestine, the reabsorption of water leads to the
1989; Shashank et al. 2013). Improved gastric retention is beneficial
.
2010;
2019). As
10 Transmucosal Drug Delivery: Main Physiological Features and Modern Approaches 221
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Fig. 10.5 Intestinal anatomy
Fig. 1
0.6 Cross section of
microvilli. (Adapted from
Shukla et al. 2010)
formation of faeces which are stored in the rectum. The gastric emptying transit time
are key variables that affect the bioavailability and absorption process. Increasing the
gastric transit time through the small intestine will be beneficial (Müller et al. 2018).
To increase the residency time within the intestines, mucoadhesive formulations can
bind to the mucosal layer.
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