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11.2 Barriers forOral Mucosal Drug Delivery
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7. Useful for patients who have difculty swallowing (e.g., in the case of nausea
and vomiting)
8. Possibility of sustained delivery, depending on the characteristics of the drug and
formulation
9. Local delivery to treat diseases specic to the mouth (e.g., ulcers, periodontal
disease)
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11.2 Barriers forOral Mucosal Drug Delivery
11.2.1 Oral Mucosal Membrane Barriers
Though all surfaces of the mouth except for the teeth can be considered permeable
to some extent, the permeability of the oral tissue differs depending upon its location and function in the mouth (Fig.11.1). The hard palate and gums are covered by
a highly lipidic, keratinized epithelium that is similar in structure to the skin, while
the upper (dorsal) surface of the tongue is covered by a partially keratinized epithelium. In contrast, the epithelium of the sublingual and buccal regions of the mouth
is non-keratinized and thus more permeable to drug diffusion. The sublingual
mucosa is thinner (100–200μm thick) compared to the buccal mucosa (500–800μm
thick) and thus provides a lower diffusional barrier to drug permeation according to
Fick’s law of diffusion (see Chaps. 3 and 10).
Similar to the skin, the barrier function of the oral mucosa is derived from the
lipid content of the supercial epithelium, which prevents uid loss from the underlying tissue and limits entry of exogenous substances into the body. However, the
oral mucosa in the buccal and sublingual areas is comparatively more permeable to
water and hydrophilic drugs compared to the skin. Drugs can permeate the oral
mucosa via the transcellular or paracellular routes (Fig. 11.2). The transcellular
route involves passive diffusion of drugs through the cells from the apical (oral
cavity-facing) to the basolateral (blood-facing) membranes, which means drugs
must permeate the cell’s lipid bilayer. Low molecular weight, lipophilic (nonionized) drugs are more likely to permeate through cells due to their afnity for the
lipid bilayer of cell membranes. The pH of the oral mucosa is close to neutral, with
buffering agents in saliva playing an important role in stabilizing the pH.Choosing
drugs with favorable pKa values (i.e., below or above 7) can facilitate the transport
of drugs through the buccal and sublingual mucosa, as these drugs tend to remain
predominantly nonionized in the oral environment. Though increased lipophilicity
can enhance the transcellular diffusion rate, this must be balanced with aqueous
solubility to ensure dissolution of the dosage form in the saliva of the oral cavity.
The paracellular route involves passage of drugs around cells through tight junc-
tions. Tight junctions are specialized protein structures forming a barrier between
cells, offering a selective permeability to small ions and water but preventing the
passing of larger molecules. Low molecular weight hydrophilic drugs are more
likely to move through tight junctions. Passive diffusion of large molecular weight
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Fig. 11.2 Examples of buccal and sublingual placement of a dosage form intended for buccal
administration
drugs (e.g., proteins) through the oral mucosa is limited. Some sublingual vaccines
and immunotherapy have been developed and are approved by FDA.
11 Oral Transmucosal Delivery
11.2.2 Residence Time andDilution
An additional barrier of the oral mucosa is its smaller surface area compared to the
epithelium of the GI tract and skin. This requires that drugs being delivered by the
oral mucosal route (i.e., buccal and sublingual) are relatively potent and that sufcient contact time is maintained between the dosage form and the oral mucosa for
the drug to be absorbed. Patients must be counseled to use dosage forms appropriately to ensure contact with the oral mucosa and reduce inadvertent swallowing.
Saliva secretion, swallowing, and tongue movements can signicantly affect
dosage forms placed in the sublingual area. Excipients with mucoadhesive properties can also be incorporated to prolong residence time in the oral cavity.
11.2.3 Other Barriers andConsiderations
Other considerations for developing an oral mucosal delivery system include how
mastication and speech can inuence drug release from the dosage form and its
intended residence time in the mouth. In addition, the organoleptic properties of the
drug, excipients, and the need for taste-masking agents can be critical. Saliva also
contains a signicant amount of enzymes that can degrade certain types of drugs,
including carbohydrates (amylase) and lipids (lipase). In designing oral transmucosal drug delivery systems, one must also consider the risk of choking and the effects
11.3 Methods ofOral Transmucosal Administration
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of swallowing the dosage form in different patient groups (e.g., pediatric or elderly
patients).
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11.3 Methods ofOral Transmucosal Administration
Several dosage forms can deliver drugs across the oral mucosa, including tablets,
lozenges, troches, lm, spray, and chewing gum.
11.3.1 Tablets, Lozenges, andTroches
Tablets, lozenges, and troches are examples of solid dosage forms for oral transmucosal drug delivery. These dosage forms can be avored, colored, and prepared in
various sizes and shapes to enhance patient acceptability. Disintegration and/or dissolution of the dosage form occurs upon contact with the saliva; thus, the entire
surface of the oral cavity can be utilized for absorption. A disadvantage, however, is
that inter-patient variability in saliva production can result in variability of drug
release. Patients must also be counseled to avoid chewing or swallowing the dosage
form, as this can result in drug loss if the drug has low oral bioavailability (e.g., the
drug is acid-labile or undergoes extensive rst-pass metabolism). Several low
molecular weight drugs have been developed into commercial tablet, lozenge, or
troche products for systemic absorption via the oral transmucosal routes including
nitroglycerin, fentanyl, buprenorphine, and lorazepam. The Fentora® buccal tablet
contains fentanyl and is indicated for the management of breakthrough pain in cancer patients who are already receiving and who are tolerant to around-the-clock
opioid therapy. As described on the product label, delivery of fentanyl through the
oral transmucosal route is achieved using the OraVescent® drug delivery technology, which is based on effervescence.
Apart from transmucosal delivery, tablets, lozenges, and troches can also be used
for topical treatment of oral diseases. An example is the use of over-the-counter
lozenges to relieve sore throat or the Mycelex® troche, which contains clotrimazole,
an antifungal drug for topical treatment of oropharyngeal candidiasis.
11.3.2 Films andPatches
The US Pharmacopeia (USP) nomenclature describes oral lms as thin sheets that
are placed in the oral cavity and are composed of one or more layers that can or cannot contain a drug substance. In the literature, patches are also used to describe a
similar transmucosal dosage form, although it is not included in the preferred USP
nomenclature. This chapter will refer to both delivery systems as lms.
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Buccal and sublingual lms are typically designed to be thin and exible, and
can also incorporate a bioadhesive to retain the dosage form on the oral mucosa.
These dosage forms can be designed to be rapidly dissolving (< 30seconds) and fast
acting, which is useful for the acute treatment of conditions such as migraines or
nausea. Conversely, the dosage form can incorporate a slowly dissolving matrix or
matrix that does not completely dissolve and must instead be removed from the site
of administration in the mouth. These delivery systems can be useful for sustained
local or systemic drug delivery.
Bunavail® buccal lm is an example of a buccal lm approved by the FDA.It
contains buprenorphine and naloxone in a citrus-avored transmucosal lm intended
for patients requiring maintenance treatment of opioid dependence. This buccal lm
is composed of, among other excipients, the polymers carboxymethylcellulose
sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, and polycarbophil, which
may function to enhance the adhesion of the buccal lm to the oral mucosa.
Bunavail® must be placed against the inside of the cheek, where it adheres and completely dissolves after a period of time. Onsolis® buccal soluble lm contains fentanyl and is indicated for breakthrough pain in patients with cancer. This buccal lm
contains the polymers carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and polycarbophil, along with other excipients. Lastly, Belbuca®
buccal lm, which contains buprenorphine, is described as a bilayered lm. In this
product, a backing layer and a drug/adhesive layer are distinguished by color, and
the entire product dissolves after about 30 min. Typical recommendations for
patients include the following: (1) press and hold in the cheek for a few seconds, (2)
avoid eating or drinking until the lm dissolves, and (3) wait about an hour before
brushing their teeth.
11 Oral Transmucosal Delivery
11.3.3 Other Oral Transmucosal Dosage Forms
Oral sprays and aerosols deliver drugs as ne droplets onto the buccal or sublingual
mucosa, allowing for absorption upon contact. These dosage forms can offer rapid
drug delivery and are particularly useful for drugs with a short half-life or for
patients who have difculty swallowing. Nitrolingual pumpspray® (nitroglycerin) is
an example of a solution for sublingual administration to treat or prevent angina in
coronary artery disease. The metered dose spray contains nitroglycerin and delivers
400 mcg per spray and can be dispensed as 60 or 200 metered sprays. The inactive
ingredients include medium-chain triglycerides, dehydrated alcohol, medium-chain
partial glycerides, peppermint oil, sodium lactate, and lactic acid.
Gel and ointment dosage forms can be applied directly to the mucous membranes of the mouth. They can offer somewhat sustained drug release and are often
used for localized effects, such as treating oral mucosal lesions or periodontal disease. These preparations can adhere to the mucosa, providing a longer contact time
and are targeted to local tissues in the oral cavity.
11.4 Excipients Used inOral Transmucosal Formulations
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Chewing gums formulated with a drug offer another method of oral transmucosal drug delivery. As the patient chews the gum, the drug is released and becomes
available to be absorbed through the oral mucosa in addition to being swallowed.
Chewing gums can be suitable for drugs requiring sustained release, such as nicotine replacement therapy in Nicorette® gum.
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11.4 Excipients Used inOral Transmucosal Formulations
Oral transmucosal delivery systems require different types of excipients, typically
including taste-masking agents such as sweeteners (e.g., sucralose and sugar alcohols like mannitol, sorbitol, and xylitol). Mannitol can be used in oral formulations
like sublingual and buccal tablets since it imparts good taste and a cooling sensation. Because of these desirable properties, sugar alcohols are also used as diluents
in sublingual and buccal tablets. Depending on the pharmaceutical form, formulations can include effervescent agents and disintegrants for immediate release tablets, bioadhesives for lms, and gum base for chewing gums. Table11.1 describes
examples of excipients used in approved sublingual and buccal products for transmucosal delivery. Excipients that have been described in this book for use in other
dosage forms for other routes of administration can also be used in oral transmucosal dosage forms.
Water-soluble cellulose-derivative polymers, including carboxymethyl, hydroxyethyl, hydroxypropyl, and hydroxypropylmethyl cellulose, can be used in bioerodable lms. Colorants and inks can be used for aesthetic and identication purposes,
helping identify the proper orientation that the lm should be placed on the mucosa.
For example, Belbuca® is a buccal bilayered lm with a backing layer (prevents
release into the oral cavity) and a mucoadhesive layer that contains the drug and the
mucoadhesive excipients (carboxymethyl cellulose and polycarbophil). Fentora®
buccal tablet is designed for oral transmucosal administration after disintegration. A
combination of effervescent excipients and disintegrants allows for the absorption
of fentanyl through the buccal mucosa. Nicorette® chewing gum is a medicated
chewing gum that reduces withdrawal symptoms in patients who quit smoking and
contains nicotine polacrilex, in which the nicotine is bound to an ion-exchange resin
(i.e., polymethacrylic acid) to stabilize it from volatilization. Nicotine gum is not
chewed like ordinary gum, but it is intermittently chewed and held in the mouth over
about 30minutes to release the nicotine. Chewing gums use gum base as the main
constituent, which can contain a mixture of water-insoluble synthetic polymers
(e.g., polyvinyl acetate), plasticizers, llers, and other ingredients. Gum base is generally a proprietary formulation.
Acronyms: HPMC: hydroxypropyl methylcellulose; CMC Na: carboxymethyl
cellulose sodium; HEC: hydroxyethyl cellulose; HPC: hydroxypropyl cellulose;
NaOH: Sodium hydroxide; PEO: polyethylene oxide.
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11 Oral Transmucosal Delivery
Table 11.1
Examples of FDA-approved sublingual and buccal drug products
Proprietary
Active ingredient
Asenapine maleate Saphris
Buprenorphine HCl
name
Zubsolv
®
®
andnaloxone HCl
dihydrate
Zolpidem tartrate Edluar
Fentanyl citrate Fentora
®
®
Nitroglycerin Nitrolingual
pumpspray
Buprenorphine HCl Belbuca
Buprenorphine HCl
®
Suboxone
and naloxone HCl
dihydrate
Dexmedetomidine
Igalmi
®
HCl
Administration
site
Dosage
form Excipients
Sublingual Tablet Gelatin, mannitol, sucralose,
and black cherry avor
Sublingual Tablet Mannitol, citric acid, sodium
citrate, microcrystalline
cellulose, croscarmellose
sodium, sucralose, menthol,
silicon dioxide, sodium stearyl
fumarate, and menthol avor
Sublingual Tablet Mannitol, colloidal silicon
dioxide, silicied
microcrystalline cellulose,
croscarmellose sodium,
saccharin sodium, and
magnesium stearate
Buccal Tablet Mannitol, sodium starch
glycolate, sodium bicarbonate,
sodium carbonate, citric acid,
and magnesium stearate
Sublingual Metered
®
dose
spray
Medium-chain triglycerides,
dehydrated alcohol, mediumchain partial glycerides,
peppermint oil, sodium lactate,
and lactic acid
Buccal Film CMC Na, citric acid
anhydrous, HEC, HPC,
methylparaben, monobasic
sodium phosphate anhydrous,
peppermint oil, polycarbophil,
propylene glycol,
propylparaben, sodium
benzoate, NaOH, saccharin
sodium, titanium dioxide USP,
vitamin E acetate, yellow iron
oxide, puried water, and
TekPrint SW-9008 black ink
(shellac, black iron oxide)
®
Buccal Film PEO, HPMC, maltitol,
acesulfame potassium, lime
avor, citric acid, sodium
citrate, FD&C yellow #6, and
white ink
Buccal Film FD&C Blue #1 colorant,
HPMC, peppermint oil, PEO,
and sucralose
(continued)
Further Reading
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Table 11.1 (continued)
Active ingredient
Nicotine polacrilex Nicorette
Proprietary
name
Administration
site
®
Buccal Chewing
Dosage
form Excipients
gum
Acacia, acesulfame potassium,
carnauba wax, D&C yellow
#10 Al lake, edible ink, avors,
gum base, HPMC, magnesium
oxide, menthol, peppermint
oil, polysorbate 80, sodium
carbonate, sucralose, titanium
dioxide, and xylitol
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Further Reading
Suggested readings for the student include the following texts:
Giannola LI, Sutera FM, De Caro V.Physical methods to promote drug delivery on mucosal tissues
of the oral cavity. Expert Opin Drug Deliv. 2013;10(10):1449–62.
Montenegro-Nicolini M, Morales JO. Overview and future potential of Buccal Mucoadhesive
lms as drug delivery systems for biologics. AAPS PharmSciTech. 2017;18:3–14.
Sattar M, Sayed OM, Lane ME.Oral transmucosal drug delivery– current status and future pros-
pects. Int J Pharm. 2014;471(1–2):498–506.
Squier CA, Kremer MJ. Biology of oral mucosa and esophagus. JNCI Monographs.
2001;2001(29):7–15.
Chapter 12
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Rectal andVaginal Drug Delivery
Abstract This chapter provides an overview of dosage forms relevant to rectal and
vaginal drug delivery. Barriers to drug absorption are discussed and frequently used
excipients are covered. The manufacturing and special formulation considerations
for drug delivery using suppository formulations are also reviewed.
Keywords Rectal drug delivery · Vaginal drug delivery · Suppositories · Vaginal
dosage forms · Suppository excipients · Suppository manufacturing
Learning Objectives
1. Describe the advantages of the rectal route for systemic absorption of drugs.
2. Describe how the rectal environment and physiology affect systemic absorption
of drugs.
3. Describe the different types of rectal dosage forms.
4. Describe how the vaginal environment and physiology affect systemic absorption of drugs.
5. Describe the different types of vaginal dosage forms.
6. Describe the ideal characteristics of a suppository formulation.
7. Describe the desirable properties of a suppository base.
8. Describe the effect of the suppository base on drug release.
9. Compare and contrast the mechanism of drug release of oleaginous and watersoluble suppository bases.
10. Describe the consequences of polymorph transformation of cocoa butter.
11. Describe the relationship between melting point and molecular weight of polyethylene glycol (PEG).
12. Describe the different excipients that can be incorporated in suppository
formulations.
13. Explain the proper storage conditions for suppositories.
14. Describe the different production methods for suppositories.
A. D. Brunaugh et al., Essential Pharmaceutics, AAPS Introductions in the
Pharmaceutical Sciences 12, https://doi.org/10.1007/978-3-031-52520-9_12
181© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
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Key Concepts
Students should know and be able to describe each of the following concepts as they
review this chapter:
1. Cocoa Butter, NF
2. Compression molding
3. Enemas
4. Glycerinated gelatin
5. Hydrogenated fatty bases
6. Hydroxyl value
7. Intrauterine devices
8. Matrix system (vaginal rings)
9. Melt molding
10. Reservoir system (vaginal rings)
11. Suppositories
12 Rectal andVaginal Drug Delivery
12.1 Introduction
Drug delivery to the rectal and vaginal mucosal membranes can be useful for achieving local or systemic drug effects. For local action, the drug is often formulated to
remain in the local area where it will have a therapeutic effect (e.g., relieve constipation or hemorrhoid pain). To achieve systemic action, the drug must be absorbed
through the mucous membranes of the rectum or vagina.
Suppositories are the most recognizable dosage form for the rectal and vaginal
administration routes, but foams, inserts, and semisolid dosage forms such as gels
are also used.
12.2 Rectal Route
Locally applied (also referred to as topically applied) rectal dosage forms can be
indicated to treat hemorrhoids and other diseases of the rectum. Locally acting
drugs include steroids, anesthetics, and pain-relievers.
The rectum is the most distal part of the large intestine, and the rectum epithelia
can also be well suited for systemic absorption of a drug and can permit rapid
absorption of drugs. Absorption from the lower rectum bypasses portal circulation
through the liver and thus has the important advantage of avoiding rst-pass metabolism. Administration of dosage forms via the rectal route is thus useful for drugs
for which systemic delivery is desired and in the following scenarios:
(1) The patient is unable to swallow.
(2) The drug is inactivated in the stomach acid or is unstable to proteolytic enzymes.
(3) The drug undergoes high rst-pass metabolism.
(4) The drug possesses limited absorption in the upper gastrointestinal tract.
12.2 Rectal Route
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183
(5) The drug can cause irritation to the gastric mucosa.
(6) The drug requires high doses and cannot easily be formulated as oral solid dos-
age forms.
Systemically acting drugs that are delivered rectally include a wide range of
drugs for diverse therapeutic indications and examples include indomethacin (pain
relief), ondansetron (antiemetic), prochlorperazine (sedation, antiemetic), diazepam
(seizures), and aspirin (pain, anti-inammatory).
12.2.1 Rectum Anatomy
The anatomy of the large intestines is shown in Fig.12.1. The systemic absorption
of a drug administered rectally can differ from the absorption observed when the
same drug is administered orally. Both the physiological state of the rectum and the
physicochemical properties of the drug affect rectal absorption.
The length of the rectum is ~12–20cm and the surface area available for absorption in the rectum is about 200–400cm2 in adults. The rectum contains 2–4mL of
mucus that has a neutral pH of about ~7 and practically no buffering capacity, which
means that the pH can be affected by administration of external products that can
lead to variations in drug absorption. The small amount of uid in the rectum can
result in low absorption of poorly water-soluble drugs, and adjustments in the formulation can be made.
The rectal wall is composed of a single layer of epithelium and endocrine and
goblet cells. The rectum lacks villi and digestive enzymes. Passive transport through
the epithelium cells is the primary mode of drug absorption. To passively diffuse
through the cell membrane, a certain degree of drug lipophilicity is necessary. For
absorption to occur, the drug must be in contact with the rectum surface, which can
be affected by the colonic contents.
Fig. 12.1 Anatomy of the
large intestines
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