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162
Water-removable bases are O/W emulsions that can be easily washed off skin
with water. The USP denes these bases as creams.
Water-soluble bases are composed of only water-soluble components and no oleaginous compounds. They are also known as “greaseless ointment bases” by the
USP. These bases can also be washed off with water.
10 Topical andTransdermal Drug Delivery
10.5.2 Ointment Manufacture/Preparation
Ointments can be prepared by incorporation or fusion. In the incorporation method,
the components of the ointment are mixed together until fully incorporated and
homogeneous. In the fusion method, all or some of the components are combined by
melting together. The mixture is then cooled to room temperature while constantly
being stirred until it is congealed.
10.5.3 Gels
The intermediate solid-liquid properties of gels are derived from the formation of a
three-dimensional network formed by the solid component, which immobilizes the
liquid component. Gels are further classied as hydrogels, which have an aqueous
continuous phase, or organogels, which have an organic solvent as the continuous
phase. Examples of gelling agents can be found in Table10.2.
10.6 Transdermal Patches
Transdermal patches are used to deliver a drug transdermally (i.e., percutaneously).
Delivery of a drug intended to exert a systemic effect via a drug formulated in a
patch allows for:
(a) Avoidance of rst-pass metabolism
(b) Avoidance of enzymes within the gastrointestinal tract
(c) Long duration of drug delivery (can result in improved patient compliance)
(d) Decreased uctuations of drug levels in the blood through controlled release
A number of transdermal patch formulations are on the market, including those
containing clonidine, fentanyl, lidocaine, nicotine, nitroglycerin, estradiol, testosterone, oxybutynin, and scopolamine. The delivery of drugs transdermally is generally limited to drugs with the following properties:
(a) Potency of the drug such that daily dose is ≤20mg
(b) Molecular size of <400–500 Daltons
10.6 Transdermal Patches
Table 10.2 Examples of gelling agents
Gelling agent Example properties
Aluminum monostearate Practically insoluble in water
Bentonite Alkaline pH can make it unsuitable for certain drugs. Loses
suspending capacity at pH<7
Carbomer Rapidly wetting, but has a tendency to clump. Very small particle
size. Viscosity is reduced at pH<3 or>12 or in the presence of
strong electrolytes
Gelatin Soluble in water above 40°C, forming a colloidal solution, which
gels on cooling to 35–40°C.Forms a thixotropic and heat-reversible
system
Glyceryl monooleate Bioadhesive properties
Glyceryl palmitostearate Practically insoluble in water
Methylcellulose High concentration of electrolytes will cause polymer to precipitate
Pectin Gelling properties are dependent upon esterication with methoxy
groups. Gelation of high-methoxy pectin occurs at pH <3.5.
Low-methoxy pectin gelation is not dependent on acid
Povidone Compatible with wide range of inorganic salts, resins, and other
chemicals. Can be used to increase solubility of poorly soluble drug
Sodium
carboxymethylcellulose
Tragacanth gum Forms gel most stable at pH4–8. Must add preservative
Xanthan gum Can be used in combination with guar gum, locust bean gum, and
pH must be between 5 and 10 to maintain viscosity. Soluble in water
at all temperatures
cassia gum to create high-viscosity gel
163
(c) High lipophilicity, such that the log P is in the range 1–4
(d) Melting point of <200°C
(e) Non-irritating upon direct contact with skin
It is important for the pharmacist and pharmaceutical scientist to use appropriate
terminology when discussing transdermal patch design and function with other
healthcare professionals or patients. The following terms relating to transdermal
patches may be encountered:
(a) Adhesion refers to the transdermal patch adhering to the skin for at least
24hours.
(b) Tack , also referred to as quick stick, measures how easily and quickly an adhe-
sive can be applied to the skin.
(c) Shear strength indicates the cohesive strength and refers to the ability of the
patch to peel cleanly away from the skin without leaving any residue on the skin.
(d) Peel adhesion measures how difcult the patch is to remove from the skin after
it has been rmly attached.
(e) Edge lift means loss of adhesion at the edges of the patch, creating a ap that
leads to the patch being pulled free from the skin.
(f) Cold ow refers to spreading or ow of the adhesive layer at lower
temperatures.
164
10 Topical andTransdermal Drug Delivery
10.6.1 Patch Design, Formulation, andManufacture
Transdermal patches can be classied into two general categories, based upon their
design (Fig.10.5):
(a) Reservoir-type patches
(b) Matrix-type patches
A reservoir-type patch typically contains four layers: an impermeable backing
layer, a solution or gel drug-reservoir layer, a semipermeable membrane that acts as
a rate-limiting barrier for drug diffusion, and an adhesive layer that contacts the skin.
A matrix-type patch typically does not contain a rate-controlling membrane and
instead consists of an impermeable backing layer, a solid drug-polymer matrix
layer, and an adhesive layer. In some cases, the adhesive can be combined with the
drug-polymer matrix.
The basic design of a transdermal patch includes a (1) backing layer, which protects the patch from the outer environment while being worn by the patient; (2) an
adhesive layer, which contains the drug and a pressure-sensitive adhesive (PSA),
controls drug release when attached to the skin; and (3) a protective layer (i.e.,
release liner), which is a removable lm that protects the adhesive layer while the
patch is in the container/closure system, and is peeled off by the patient prior to
application of the transdermal patch onto the skin. The release liner is typically a
clear polyester lm, silicone polymer, or uorocarbon/uorosilicone polymer.
When the adhesive layer contains dissolved or dispersed drug, it is often referred to
as a drug-in-adhesive (DIA) layer, but the diffusing drug should not signicantly
change properties of the adhesive layer to negatively inuence adhesion of the patch
to the skin.
Generally, there are three types of PSAs: (1) polyisobutylenes (PIBs); (2) polysiloxanes (silicones); and (3) polyacrylate copolymers (acrylics). These three PSAs
have low residual water content after drying (<0.1%) and are hydrophobic. Beyond
these, other PSAs are available but are not discussed here.
Polyisobutylenes (PIBs) are elastomeric polymers that are highly nonpolar and
soluble in typical aliphatic and aromatic hydrocarbon solvents, but not in typical
alcohols, esters, ketones, and other oxygenated solvents. PIBs are available in a
range of viscosities. The lower molecular weight PIBs are highly viscous, soft, and
Fig. 10.5 Designs of different transdermal patches. (a) A reservoir-type patch, (b) a matrix-type
patch with the drug-polymer matrix combined with the adhesive, (c) a matrix-type patch with a
separate adhesive layer
10.6 Transdermal Patches
165
tacky semi-liquids, whereas the high molecular weight PIBs are tough and elastic
rubbery solids.
Polysiloxane formulations are based on two primary components: a polysiloxane
(silicone) polymer and a silicate resin. The ratio of resin to polymer will control the
adhesive properties of the PSAs, such that increasing the polymer content yields a
softer and tackier adhesive, whereas higher resin content yields an adhesive with
less tack but more adhesion and resistance to cold ow (see Table 10.3). Watersoluble additives like ethylene glycol, glycerin, and polyethylene glycols can be
incorporated into the silicone PSA to control the water sorption into the silicone
polymer matrix and control release of drug.
Polyacrylate copolymers (i.e., poly(acrylic esters)), commonly called acrylic
polymers, have adhesive properties. They are saturated hydrocarbon polymers that
are resistant to oxidation and do not require addition of stabilizers, which can cause
skin irritation. Polyacrylates have a low Tg (−55 to -15°C) and are tacky; therefore,
they do not require tackiers and plasticizers to yield tack and softness to the patch.
Drug-loaded transdermal patches are mostly made by two techniques, a solvent
casting method and a hot-melt method. The solvent casting method is the most commonly used and typically employs an organic solvent to dissolve the drug in the
adhesive, followed by spreading the drug-containing adhesive (i.e., the adhesive
layer) onto the release liner and evaporation of the solvent typically using heat. The
hot-melt method involves heating the components of the adhesive layer (including
PSA, drug, other excipients) and then coating the molten mass onto the release liner,
followed by cooling. Saturation solubility of the drug in the adhesive layer increases
the permeation of the drug through the skin. High drug loading can cause formation
of crystals of drug that are not available for drug release from the patch. Therefore,
crystallization of the drug in the adhesive layer must be avoided because it will
cause a decrease in drug release rate.
10.6.2 Drug Release fromTransdermal Patches
Transdermal patches release the drug in proportion to their surface area covering the
skin. It is therefore critical that the patch remains in contact with the skin for the
entirety of the intended application time. In the case of a reservoir-type transdermal
patch, the release of drug from the patch is controlled by a rate-limiting membrane,
which is typically designed to impart a continuous release of drug. Prior to administration, the drug will diffuse and saturate the adhesive layer with drug, which
provides an initial bolus effect. The advantage of this type of system is that drug
release is less susceptible to changes in the skin integrity (since the rate is controlled
by a membrane within the patch).
In the case of a matrix-type transdermal system, ux (J) relies on Fick’s law for
diffusion of the drug out of the adhesive polymer matrix. This is not rate-controlled
by the patch, rather it is controlled by the skin barrier (stratum corneum). If the
matrix is formulated without an excess of drug, the transport of the drug from the
166
10 Topical andTransdermal Drug Delivery
patch to skin will decrease as the concentration of drug decreases in the patch (rst
order release). However, if the matrix is formulated with an excess of drug, the ux
of drug into the skin will remain constant (zero-order release) for the duration of the
patch use. The advantage of this type of system is that they tend to be simpler in
design compared to reservoir-type patches and carry less risk of dose-dumping due
to manipulation of the patch. However, if the permeability of the drug across the
skin is increased, as in the case of damaged or compromised skin, then the release
of drug from the polymer matrix will also be increased.
10.6.3 Patient Counseling—Transdermal Systems
It is important to provide patients with the clinical information needed to ensure
effective and safe use of transdermal delivery systems. This is especially true for
patch systems which contain an amount of drug intended to last for several days, as
alteration of the drug release mechanisms can result in a dangerous overdose.
Specic instructions relating to individual products are contained within each product’s FDA-approved label. In general, the patient should be advised to peel and
remove the release liner and apply the transdermal patch to the chosen area of the
skin, then press rmly on the patch for about 10–15seconds to ensure proper adhesion. The site of application can be rotated to prevent irritation to the skin, and the
patch should not be applied to areas of the skin having cuts, rashes, or existing
irritation.
Due to differences in the thickness of the epidermal layer, percutaneous absorption can vary with the site of application. Patients should therefore be advised on
which areas of the body that the patch can be applied. The patient should apply the
patch to clean, dry skin that is relatively free of hair. To prevent increased levels of
absorption, the skin should be unbroken. If the skin is broken, the drug will diffuse
quickly into the capillary network, bypassing the mechanism of diffusion of the
transdermal system and potentially increasing systemic exposure to a dangerous
level. Skin that is calloused can reduce the level of absorption, so these areas should
be avoided as well.
Reservoir-type patches should not be cut, as this can disrupt the rate-control
mechanism and can result in dose dumping. Matrix-type patches (e.g., drug-inadhesive patch design) generally can be cut without disruption of the rate-control
mechanism. For example, in the case of lidocaine patches, the patch is cut in order
to adjust the size to the area of treatment. However, in most cases, the prescribing
information will advise that the patch should not be cut as this makes it difcult to
accurately dose potent medications such as fentanyl.
10.7 Additional Excipients Utilized inTopical andTransdermal Dosage Forms
167
10.7 Additional Excipients Utilized inTopical
andTransdermal Dosage Forms
Table 10.4 shows the additional excipients that can be utilized in topical and transdermal dosage forms.
Table 10.4 Additional excipients utilized in topical and transdermal dosage forms
Excipient category Function Examples
Humectant Used to prevent drying of preparations,
Stiffening agent Increase viscosity of preparation Cetyl alcohol
Permeation
enhancers
particularly ointments and creams
Enhance permeation of drug through the
epidermis
Glycerin
Ammonium alginate
Butylene glycol
Cyclomethicone
Polydextrose
Propylene glycol
Sodium hyaluronate
Trehalose
Triacetin
Xylitol
Sorbitol
Cetyl esters wax
Dextrin
Microcrystalline wax
Parafn
Stearyl alcohol
White wax
Yellow wax
Alcohol
Azone
Dimethyl sulfoxide
(DMSO)
Isopropyl myristate
Isopropyl palmitate
Lauric acid
Myristic acid
Oleic acid
Palmitic acid
Propylene glycol
Pyrrolidones
Sodium lauryl sulfate
Terpenes
Thymol
Urea
(continued)
168
Table 10.4 (continued)
Excipient category Function Examples
Antimicrobial
preservative
Prevent microbial growth Ethanol
10 Topical andTransdermal Drug Delivery
Benzalkonium chloride
Benzethonium chloride
Benzoic acid
Benzyl alcohol
Boric acid
Bronopol
Butylene glycol
Calcium acetate
Calcium chloride
Calcium lactate
Cetrimide
Cetylpyridinium
chloride
Chlorhexidine
Chlorobutanol
Chlorocresol
Chloroxylenol
Cresol
Glycerin
Hexetidine
Imidurea
Monothioglycerol
Pentetic acid
Phenol
Phenoxyethanol
Phenylethyl alcohol
Phenylmercuric acetate
Phenylmercuric borate
Phenylmercuric nitrate
Potassium benzoate
Potassium metabisulte
Propionic acid
Propylene glycol
Sodium acetate
Sodium borate
Sodium lactate
Sodium metabisulte
Sodium sulte
Sulfur dioxide
Thimerosal
Further Reading
169
Further Reading
Suggested readings for the student include the following texts:
Kim YC, Park JH, Prausnitz MR.Microneedles for drug and vaccine delivery. Adv Drug Deliv
Rev. 2012;64(14):1547–68.
Martins PP, Estrada AD, Smyth HD.A human skin high-throughput formulation screening method
using a model hydrophilic drug. Int J Pharm. 2019;565:557–68.
Prausnitz MR, Langer R.Transdermal Drug Delivery. Nat Biotechnol. 2008;26:1261–8.
Tarbox TN, Watts AB, Cui Z, Williams RO III.An update on coating/manufacturing techniques of
microneedles. Drug Deliv Transl Res. 2018;8(6):1828–43.
Chapter 11
Oral Transmucosal Delivery
Abstract This chapter is new to this edition and provides an overview of dosage
forms for drug delivery via the transmucosal route, with an emphasis on buccal and
sublingual drug delivery. Barriers to drug absorption are discussed and frequently
used excipients are covered. The manufacturing and special formulation considerations for oral transmucosal drug products are reviewed.
Keywords Buccal administration · Sublingual administration · Oral mucosa ·
Bioadhesion
Learning Objectives
1. Explain the advantages of the oral cavity as a site for drug delivery.
2. Describe the barriers related to oral mucosal administration.
3. Compare the oral mucosal route to other routes of administration such as
transdermal.
4. Compare and contrast the different regions of the oral cavity that can be used for
drug delivery.
5. Understand the difference between transcellular and paracellular permeation of
drugs through oral mucosa.
6. Understand the pH-partition theory and how it relates to buccal drug delivery.
7. Explain the differences between the different dosage forms intended for oral
transmucosal delivery.
Key Concepts
Students should know and be able to describe each of the following concepts as they
review this chapter:
1. Bioadhesion
2. Bioerodible buccal lm
3. Buccal administration
4. Film
5. Oral mucosa
A. D. Brunaugh et al., Essential Pharmaceutics, AAPS Introductions in the
Pharmaceutical Sciences 12, https://doi.org/10.1007/978-3-031-52520-9_11
171© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
172
11 Oral Transmucosal Delivery
6. Paracellular permeation
7. Sublingual administration
8. Transcellular permeation
11.1 Introduction
The oral mucosa, dened as the mucous membrane lining the inside of the mouth,
is well known as a site for the absorption of certain active ingredients (i.e., the drug).
The highly vascular nature (i.e., the presence of many blood vessels) close to the
surface of the oral mucosa allows drugs with appropriate physicochemical properties to have rapid and direct access to the systemic circulation. The anatomy of the
oral cavity, as discussed below, generally allows for two modes of administration
for the absorption of drugs systemically from the oral cavity (see Fig.11.1). In sub-
lingual administration, the drug product is placed under the tongue. In buccal
administration, the drug product is placed between the tongue and cheek. In either
case, the drug is released from the dosage form upon contact with the mucosa and
absorption occurs through the mucosal membranes. For both of these modes of
delivery to be effective, the dosage form must be retained in the oral cavity for an
appropriate amount of time and contact between the dosage form and oral mucosa
maximized while the drug is being released.
The advantages of oral mucosal delivery include the following:
1. Easy accessibility of the oral cavity
2. Low enzymatic and mild pH environment for labile drugs
3. Rapid absorption, which can be desirable for fast onset of the drug and, there-
fore, faster therapeutic benet to the patient
4. Avoidance of drug loss through rst-pass hepatic metabolism
5. Easy removal of the dosage form in the case of adverse side effects
6. Successful administration of drugs that have slow or poor absorption through the
gastrointestinal tract sublingually or buccally
Fig. 11.1 Different anatomical regions of the oral cavity