Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 645

the continual presence of the agent at a receptor site [149] . Proteins have been applied
directly to tissues such as the uterine horns with the aid of biodegradable hydrogel
in an effort to stop postsurgical adhesions. This method demonstrates proteins being
targeted by direct application to the uterine horns with the aid of a polymer or device
designed to hold the protein at the site of action. Other examples of this principle
include the application of TGF- 1 to the surface of titanium hip implants coated with
hydroxyapatite and tricalcium phosphate to enhance bone growth [150] , and the appli-
cation of growth factors such as acidic fibroblast growth factor (aFGF) directly into
topical wounds with the aid of methylcellulose gels [151] .
12.3.3 Intrauterine Drug Delivery Systems
Implantable delivery systems are used for long-term controlled delivery and site-
specific activity with the use of medicated intrauterine devices (IUDs)
An IUD is a small T-shaped device, prepared from a metal or flexible polymer,
which is fitted within the uterine cavity for the purpose of preventing conception. The
most widely used IUDs are copper-bearing IUDs, although unmedicated (inert) and
medicated (levonorgestrel or progesterone) progestin-releasing IUDs are also available.
The IUD induces an intense local inflammatory response, especially by the copper-
containing devices, which in turn leads to lysosomal activation and other inflammatory
changes that are spermicidal. Whenever fertilization does occur, the same inflamma-
tory actions are directed against the developing embryo. Inert devices, such as the
Lippes loop, are more effective with increased size and extent of contact with the
endometrium. The progesterone-carrying devices induce atrophic endometrial changes
that make the endometrium a hostile site for implantation if fertilization and successful
tubal transport have occurred. Since the 1970s, WHO has conducted 10 large trials to
compare and evaluate the safety and efficacy of six different IUDs [154] . The new-
est generations of copper IUDs combine high continuation rates with very low preg-
nancy rates [155] . Because little can be done to increase the efficacy of these devices,
recent research has focused on developing devices to address side effects, particularly
bleeding and pain, which account for a significant number of removals. The levon-
orgestrel-releasing IUD, a device with high effectiveness and acceptability, reduces
menstrual blood loss compared to preinsertion levels. The levonorgestrel-releasing
IUD, Mirena TM , has been available in Europe for 10 years and has been used by 2 mil-
lion women; it was approved for sale in the USA in December 2000. Frameless IUDs,
such as the Gynefix TM [156-158] , have been specifically designed to reduce cramp-
ing and pain. This device consists of a surgical nylon thread that holds copper sleeves
and is anchored to the uterine fundus during insertion. It recently became available in
Europe, and is licensed for 5-year use. Studies suggest that the Gynefix TM is as effec-
tive as the Copper T380A, and expulsion rates are less than 1 per 100 women years.
Very recently, clinical assessments of an IUD-releasing danazol for the treatment of
endometrial hyperplasia and endometriosis-related pelvic pain have been reported.
Contraceptive-medicated IUDs (containing copper or progesterone) have been
widely used in humans. Copper-bearing IUDs consist of a copper wire wound around
the vertical leg of a T- or 7-shaped plastic device, having a surface area of 200 or