Designing a Cervico-vaginal drug delivery system
The cervical and vaginal ecosystem is complex due to the balance between
the conflicting need for protection against infection and allowing entry
of sperm to the upper genital tract. As such, there is a pH gradient
from the acidic vaginal canal at pH 3.8 - 4.5 63–65to the alkaline cervical mucus at pH ̵̴ 7.0 66. The
accessibility of the cervix and presence of a good blood supply makes
vaginal drug delivery an ideal potential target for a locoregional
therapy. In addition, this route avoids both hepatic first pass
metabolism as the absorbed drugs enter directly into the systemic
circulation and gastrointestinal enzymatic degradation associated with
the oral route 67. Vaginal drug delivery systems in
current use comprise liquid forms including foams, douches and
irrigations, semi-solid forms such as creams, gels and ointments, and
solid forms in the form of pessaries, rings and films68. All these have limited efficacy depending on their
residence time at the genitourinary tract 69. A
vaginal drug delivery system designed for locoregional therapy should
ideally, distribute uniformly and retain the drug at the administered
the site of action for a prolonged period 69. This
depends upon the properties of the delivery system, and vaginal
physiology. Factors relating to vaginal physiology include the volume,
viscosity and pH of vaginal fluid and the thickness and porosity of the
epithelial layer which in turn varies with age and menstrual cycle70. The self-cleansing action of the vaginal tract71,72 results in a decrease in the therapeutic effects
of these delivery systems due to reduced drug bioavailability73. Furthermore, the protective mechanism of the
genitourinary tract further limits residence time, making it necessary
for multiple and frequent drug applications for effective treatment69. This would be further impacted by the additional
challenge of patient compliance if repeated applications are required
for treatment.
Pessaries in the form of tablets or suppositories provide a sustained
release of the drug as they gradually dissolve 68. The
bioavailability of the drug depends upon its residence time in the
vaginal canal 69. Creams are typically emulsions
whereas gels are three-dimensional hydrophilic polymers made up of long,
disordered chains with reversible cross-links 74. A
potential issue with using both creams and gels is that they do not
provide an exact dose and they can be messy, uncomfortable and cause
leakage 75. Patients generally tolerate gels better
than other dosage forms 76.
Over the last decade, muco-adhesive and in situ gelling
formulations have been used to increase the residence time of liquid
vaginal drug formulations at the site of action 77.
Muco-adhesive polymers such as polyacrylic acid-based Carbomers interact
with mucus proteins in the vaginal cavity by forming weak hydrogen bonds
or disulphide bonds with thiol groups, thereby prolonging the
formulation residence time at the action site 73.In-situ gelling systems are typically present in a sol-state at
room temperature, which describes a type of colloid with small
particulate solids dispersed within a liquid, before administration.
They subsequently undergo a sol–gel transition in response to
temperature, pH change or the presence of ions upon contact with
biological fluids or mucous membranes in the vaginal canal, forming a
gel. The gel releases the loaded drug in a controlled manner, resulting
in a formulation with reduced administration frequency, ease of
administration and therefore improved patient compliance and comfort77. They also include solid formulations such as
polymeric matrices and films that undergo fast hydration in biological
fluids to form a gel with controlled release properties. Nanosystems can
also be loaded onto a muco-adhesive in-situ gelling vehicle. The
intimate interface between the mucus and gel enables transfer of the
nanosystems to the site of action on the vaginal mucosa78.