A bioadhesive polymer can adhere to a biological substance (usually the surface of an anatomical location) and remain there for an extended period of time, compared with a nonbioadhesive polymer or material.
Bioadhesive/mucoadhesive
polymers
A
bioadhesive polymer can adhere to a biological substance (usually the surface
of an anatomical location) and remain there for an extended period of time,
compared with a nonbioadhesive polymer or material. When the adhering surface
or the biological substance is a mucous membrane, then the bioadhesive polymer
is referred to as a mucoadhesive
polymer. All drug delivery systems come in physical contact with an anatomical
location of the body. For drugs that are systemically absorbed, the drug passes
through that anatomical location into the systemic circulation. Such an
anatomical location has been called the site
of drug absorption. The duration of time for which a drug delivery system
remains in contact with the site of absorp-tion is termed residence time. The rate of drug absorption combined with the
residence time of the drug delivery system at the site of drug absorp-tion
determines the total amount of drug absorbed. Thus, increasing the residence
time of the drug delivery system at the site of drug absorption, through the
use of bioadhesive or mucoadhesive polymers, can increase the bioavailability
of a drug.
Physiological
processes usually limit the residence time of a drug deliv-ery system. For
example, bronchiolar cilia and mucosal clearance limit the duration of contact
of a foreign material with the bronchiolar tissue due to the ciliary motion and
the mucosal clearance rate. Similarly, duration of time for which a drug stays
in the gastric compartment is a function of the gastric emptying time.
The
residence time of a drug at the site of drug absorption can be increased by the
following actions:
·
Altering the physiological processes governing the normal
residence time, for example, by slowing down normal mucosal clearance rate/
ciliary motion for bronchiolar drug delivery and increasing the gastric
emptying time for gastric drug delivery.
·
Introducing another rate-limiting process that would govern
the resi-dence time, for example, by using a gastroretentive drug delivery
sys-tem that has lower density and remains in the stomach for a prolonged
period of time or by incorporating a bioadhesive or a mucoadhesive polymer in
the drug delivery system.
The
mucus is a highly viscous aqueous fluid that serves to protect the epithelial
cell lining of various organs and organ systems such as respiratory, GI,
urogenital, visual, and auditory pathways. The muco-sal fluid, secreted by the
cells in the mucosal membranes, is typically rich in glycoproteins and may
contain other ingredients such as immu-noglobulins and inorganic salts.
Glycoproteins are natural hydrophilic polymers that consist of a protein or
polypeptide backbone with cova-lently attached oligosaccharide (i.e., glycan)
side chains. This composi-tion of the mucus indicates its high hydrophilicity
and polymeric nature. Accordingly, the polymeric materials that have strong
hydrogen-bonding groups display mucoadhesive properties. In addition, linear
long chains in high-molecular-weight polymers tend to entangle in the
glycoproteins, enhancing mucoadhesion. Common hydrogen-bonding groups in
poly-mers include hydroxyl, carboxyl, amines, and sulfates. Polymers that
exhibit such functional groups, such as several polyacrylic acid and cel-lulose
derivatives, are bioadhesive in nature. Examples of polyacrylic acid-based
polymers are carbopol, polycarbophil, polyacrylic acid, poly-acrylate,
poly(methylvinylether-co-methacrylic acid), poly(2-hydroxyethyl methacrylate),
and poly(methacrylate). Cellulose derivatives are exem-plified by CMC,
hydroxyethyl cellulose (HEC), HPC, methyl cellulose (MC), and methyl
hydroxyethyl cellulose. Some other bioadhesive poly-mers include chitosan,
gums, PVP, and PVA.
Mucoadhesive
drug delivery systems can be utilized for both local and sys-temic drug
delivery applications. In the case of local drug delivery, such as vaginal drug
delivery, the use of mucoadhesive polymer in the drug delivery system can lead
to higher residence time and prolonged duration of local action of the
medication. In the case of systemic drug delivery, such as oral administration
into the GI tract, localization of the drug delivery system to a particular
site (e.g., the site that has a high rate of drug permeability) can lead to (a)
more intimate contact between the dosage form and the site of drug absorption,
which can increase local drug concentration and the rate of drug absorption or
flux and/or (b) higher residence time at the site of drug absorption, leading
to an increase in the total amount of drug absorbed (bioavailability).
Mucoadhesive
polymers interact with a mucosal surface in two stages: (i) contact and (ii)
consolidation. The first contact of the mucoadhesive polymer with the mucosal
surface leads to surface adhesion due to mul-tiple favorable hydrogen-bond and
electrostatic interactions and polymer expansion due to water uptake and
plasticization of the drug delivery system. The polymer and the drug delivery
system expand and spread on the mucosal surface. The subsequent strong bonding
(adhesion) between the polymer and the mucus is a function of polymer chain
dif-fusion, hydration and plasticization, and interlocking bond formation.
Attractive interactions between the hydrophilic mucoadhesive polymer and the
hydrophilic polymeric glycoproteins in the mucus lead to mutual entanglement
and interpenetration of the polymeric chains. This facili-tates the formation
of more and deeper electrostatic and hydrogen-bond interactions, which promote
bioadhesion or mucoadhesion. Thus, muco-adhesion is facilitated by the presence
of hydrogen-bond-forming groups in the polymeric chain, flexibility of the
polymer chains, and the sur-face activity of the drug delivery system.
Mechanical forces at the site of adhesion can help in deeper penetration and
mechanical interaction of the polymers.
The
strength of mucoadhesion, Sm,
is the force, F, required to separate
two surfaces after adhesion has been established, per unit surface area (A). Thus,
Sm = F/A
The
Sm can be calculated in vitro on the isolated mucus
immobilized on an artificial surface or ex
vivo, using a biological surface, such as an isolated intestinal lumen. In vivo assessment of bioadhesion is
usually done by mea-suring the residence time of the dosage form at the site of
bioadhesion by an imaging technique.
Mucoadhesive
drug delivery systems can be used to deliver a drug to and/or through several
anatomical sites in the human physiology, including oral cavity, vagina, nasal
cavity, skin (transdermal), conjunctiva of the eye, and the GI tract.
Buccal
drug delivery systems seek to deliver drug locally into the oral cavity for
local treatment of oral lesions. When used to deliver a drug to the systemic
circulation, such as by sublingual administration, bypassing the hepatic
first-pass metabolism can contribute to higher bioavailability. Similarly, drug
delivery to the nasal mucosa and the vaginal tissue is uti-lized for local drug
action or rapid drug absorption in the systemic circula-tion, bypassing the
hepatic first-pass metabolism.
Ocular
drug delivery using mucoadhesive polymers seeks to address the problem of excessive drainage of the drug via the
lachrymal glands before adequate absorption can take place. Prolonged
retention of the drug on the cornea reduces precorneal drainage loss of the
drug and increases the duration of drug absorption, thus improving ocular
bioavailability. Mucoadhesive polymers adhere to the mucin coat covering the
conjunctiva and the corneal surface of the eye. Ocular mucoadhesion markedly
pro-longs the residence time of a drug in the conjunctival sac, since clearance
of a mucoadhesive dosage form is controlled by the much slower rate of mucus
turnover rather than the tear turnover rate.
Oral
mucoadhesive drug delivery systems have been utilized to effect adhe-sion of
particulate insoluble drugs to the GI mucosal surface. Incorporation of
mucoadhesive polymers, such as chitosan, poly(acrylic acid), alginate, poly(methacrylic
acid), and sodium carboxymethyl cellulose, into the oral solid drug delivery
systems can increase the residence time of the drug and adhesion of particulate
drug to the mucosal surface, leading to higher local concentration at the site
of drug absorption.
Mucoadhesive
dosage forms include tablets, granules, films, patches, solu-tions, gels, and
ointments. The selection of dosage form depends on the route of drug
administration as well as the desired characteristics of the drug delivery
system. For example, while tablet and granules are suitable for administration
through the oral route, solutions are more suitable for ocular and nasal drug
delivery, patches for transdermal drug delivery, films for buccal drug
delivery, and gels and ointments for vaginal drug delivery.
Transdermal
patches deliver drugs through the skin. Percutaneous absorp-tion of a drug
generally results from direct penetration of the drug through the stratum
corneum, deeper epidermal tissues, and the dermis. When the drug reaches the
vascularized dermal layer, it becomes available for absorp-tion into the
general circulation.
Among
the factors influencing percutaneous
absorption are the physico-chemical properties of the drug, including its molecular
weight, solubility, partition coefficient, nature of vehicle, and condition of
the skin. Chemical permeation enhancers, iontophoresis, or both are often used
to enhance the percutaneous
absorption of a drug.
In
general, patches are composed of three
key compartments: a pro-tective seal that forms the external surface and
protects it from dam-age, a compartment that holds the medication itself and
has an adhesive backing to hold the entire patch on the skin surface, and a
release liner that protects the adhesive layer during storage and is removed
just before application.
Most
patches belong to one of the two general types—the
reservoir system and the matrix system. The reservoir system incorporates the
drug in a compartment of the patch, which is separated from the adhe-sion
surface. Drug transport from the patch to the skin in channelized and
controlled through a rate-limiting surface layer. The matrix system, on the
other hand, incorporates the drug uniformly across the patch in a polymer
matrix. Diffusion of the drug through the polymer matrix and the bioadhesive
properties of the polymer determine the rate of drug absorption.
Marketed
transdermal patches are exemplified
by Estraderm® (estradiol), Testoderm® (testosterone),
Alora® (estradiol), Androderm® (testosterone), and
Transderm-Scop® (scopolamine). Transderm® relies on
rate-limiting polymeric membranes to control drug release. Nicoderm®
is a nicotine patch, which releases nicotine over 16 h, continuously
suppressing the smoker’s craving for a cigarette.
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