An implant may be defined as a material that is securely placed (inserted or grafted) into the body.
Implants
An
implant may be defined as a material that is securely placed (inserted or
grafted) into the body. Most of the
implants are surgically placed inside the body. A drug-containing implant is
usually a sterile, solid dosage form prepared by compression or melting for
drug delivery at a desired rate over a prolonged period of time.
Drug-containing
implants may be classified into following types:
1. Diffusion-controlled implants
2. Osmotic minipumps
These
implants differ in the mechanism of control of drug release.
The
rate of drug delivery from polymeric systems may be controlled by (a) drug
diffusion and dissolution through an insoluble matrix and/or (b) the use of a
rate-controlling membrane. Devices that use a rate-controlling membrane achieve
controlled rate of drug delivery through diffusion across the membrane. These
membrane systems contain a reservoir, which is in contact with the inner
surface of the rate-controlling membrane. The res-ervoir contains the drug in a
liquid, gel, colloid, semisolid, or solid matrix. For drug delivery systems
that utilize diffusion and dissolution through a matrix for control of drug
release rate, the matrix could be composed of hydrophilic or hydrophobic
polymers, or a combination of the two to obtain optimum drug release. Depending
on the nature of polymers used, the matrix implants could be biodegradable or
nonbiodegradable. Drug release from biodegradable implants is a function of
both the rate of drug diffusion and the rate of polymer degradation.
Kinetics
of drug release from an implant is determined by its mecha-nism. Usually, a
reservoir system gives a zero-order profile because the rate-controlling step
is the process through which the drug must diffuse from a concentrated solution
in the core. A matrix system usually provides a square root of time profile of
drug release reflecting an erosion-limited drug absorption. If the rate of
polymer degradation is slow compared to the rate of drug diffusion, drug
release kinetics obtained with a biodegradable implant can become diffusion
limited from a concentrated core and thus similar to nonbiodegradable implants.
Drug-containing
implants are exemplified by the following:
·
Zoladex® is an implant, which contains goserelin acetate
dispersed in a matrix consisting of d,l-lactic and glycolic acid copolymer.
Goserelin acetate is a potent synthetic decapeptide analogue of luteinizing
hor-mone-releasing hormone (LHRH) and is a gonadotropin-releasing hormone
(GnRH) agonist. Zoladex is implanted subcutaneously into the upper abdominal
wall. It is used for palliative treatment of advanced carcinoma of the
prostate, endometriosis, and advanced breast cancer.
·
Vantas® implant contains histrelin, which is a synthetic
analogue of GnRH agonist. It is a diffusion-controlled device that provides
drug release for up to 12 months. It is used for treating prostate cancer by
decreasing the production of certain hormones, which reduces testos-terone
levels.
In
contrast to rate-controlling membranes (that use a porous membrane), osmotic
minipumps use a membrane impermeable to the drug with well-defined openings for
drug release. The opening may be a laser-drilled orifice on a tablet coating,
for example. The core of these devices con-tains the drug alone or together
with an osmotic agent, usually a salt. The membrane is permeable to solvent
(water) but impermeable to solute (drug). Such a membrane is called semipermeable
membrane. Penetration of water inside the device through the semipermeable
membrane allows dissolu-tion of salt (osmotic agent) and creation of high
osmotic pressure inside the membrane (highly concentrated salt solution). This
osmotic pressure facilitates the release of the drug through the orifice. When
in contact with body fluids, the osmotic agent draws in water through the
semipermeable membrane because of the osmotic pressure gradient and forms a
saturated solution inside the device. The flow of saturated solution of the
drug out of the device through the delivery orifice relieves the pressure
inside. This process continues at a constant rate until the entire solid agent
has been dissolved. The drug release rate is usually unaffected by the pH of
the envi-ronment and essentially remains constant as long as the osmotic
gradient remains constant. Thus, the kinetics of drug release is governed by
the salt concentration and dosage form volume—which impact osmotic pressure,
and the orifice diameter.
Polymers,
such as cellulose acetate, ethylcellulose, polyurethane, poly-vinyl chloride,
and PVA, are used to prepare semipermeable membranes to regulate the osmotic
permeation of water. A water-insoluble polymer impregnated with a small
quantity of a water-soluble polymer allows the formation of micropores that
allow solvent diffusion across the membrane, thus making a semipermeable
membrane.
Oral
osmotic pump is one of the commonly used devices. It is com-posed of a core
tablet surrounded by a semipermeable coating. The coat-ing membrane has a 0.3–4
mm diameter hole, which is produced by a laser beam, for drug exit. This system
requires only osmotic pressure to be effective. The drug release rate is
dependent on the surface area and nature of the membrane, and the diameter of
the hole. When the dos-age form comes in contact with water, water is imbibed,
and the drug is released from the orifice at a controlled rate driven by the
resultant osmotic pressure of the core.
Drug-containing
implants are exemplified by the following:
· Alzet® miniosmotic pump (illustrated in Figure 24.2a) permits easy manipulation of drug
release rate over a range of time periods (from 1 day to 6 weeks). These
miniature infusion pumps are designed for continuous dosing of unrestrained
laboratory animals.
· Osmotic minipump for human use is exemplified by Viadur®,
which uses the DUROS® technology (illustrated in Figure
24.2b). Nondegradable, osmotically driven system is intended to enable
delivery of small drugs, peptides, proteins, and DNA for systemic
Figure 24.2 (a) An illustration of design elements of osmotic minipump devices. (b)
different components of an osmotic pump.
Implants may also be classified based on the organ in which the device is implanted. These implants can be drug-containing or nondrug-containing devices. Drugs may also be incorporated into or on the surface of devices used in routine clinical medicine, such as cardiac stents.
Cardiac
implants are devices that are surgically placed in the heart for restoring and
assisting regular heart function. For example, polymeric clo-sure devices, such
as Amplatzer® and CardioSEAL®, are used to close a hole or an opening between
the right and the left side of the heart to correct birth defects located in
the interatrial septum. The use of cardiac pacemak-ers and artificial heart
valves is well known.
Drug
loading into conventional cardiac implants can improve their clini-cal outcome.
For example, drug eluting stents are
used for the prevention of in-stent restenosis (fibrosis and thrombus-induced
blockade of the stented artery). These stents contain drugs, such as sirolimus
(Cypher®), paclitaxel (Taxus®), zotarolimus (Endeavour®), and everolimus
(Xience V®). In addi-tion, iontophoretic cardiac drug delivery system allows
cardiac electrical pulse-induced drug release for the treatment of arrhythmias.
Dental
implants, such as artificial tooth, fillings, and dentures, are fairly common
in the practice of dentistry. Antibiotics and analgesic drugs are commonly used
in medicated dental implants. Prophylactic antibiotic treat-ment is frequently
practiced in dental implant placement surgery to mini-mize chances of infection
at the implant site. Local release of the antibiotic from a polymeric matrix
close to the implant has greater efficacy while minimizing systemic side
effects.
Atridox®
is a FDA-approved product designed for controlled delivery of the antibiotic
doxycycline for the treatment of periodontal disease. When injected into the
periodontal cavity, the formulation sets, forming a drug delivery depot that
delivers the antibiotic to the cavity.
Urological
implants, such as urethral and ureteral stents and catheters, can be used for
local drug therapy. Penile implants are surgically placed inside the penis for
male infections and impotence.
Surface
deposition of ionic and organic components (encrustation) can affect drug
release from these devices. Encrustation is promoted by high urinary pH, which
is common with urinary infection, and due to their pro-longed contact with
urine. Encrustation also leads to higher risk of infec-tion. Glycosaminoglycans
can act as crystal growth inhibitors. Therefore, surface coating of the
glycosaminoglycan heparin on the stent has been proposed to minimize
encrustation.
Infection
of the implants is a relatively common problem that requires expensive and
invasive replacement of the prosthesis. This problem can be overcome by the use
of antibiotic-releasing implants. An antibiotic eluting implant, Inhibizone®,
was introduced to minimize the risk of infection by providing a controlled
release of antibiotics minocycline and rifampin in the microenvironment
surrounding the implant.
Cosmetic
breast enhancement implants are fairly common. Pain man-agement with the
implant involves the use of oral medication, including narcotic analgesics.
Intraoperative administration of analgesics into the implant pocket facilitates
early postoperative recovery and reduces the inci-dence of pain in patients
undergoing surgery.
Capsular
fibrosis is one of the most serious complications associated with silicone
breast implants. Fibrosis is mediated by the transforming growth factor-β, which is inhibited by the drug
halofuginone lactate. Surface modi-fication of silicone breast implants with
halofuginone lactate reduces the risk of fibrosis.
Local
drug delivery by the use of ophthalmic implants provides higher local drug
concentration and improves patient response compared to intrave-nous (IV)
therapy. Vitrasert® is a ganciclovir intravitreal implant for the treatment of
patients with AIDS-related cytomegalovirus (CMV) retini-tis. Vitrasert contains
ganciclovir embedded in a polymer matrix, which releases the drug over a period
of 5–8 months.
Retisert®
is a controlled-release intravitreal implant of the corticosteroid
antiinflammatory agent fluocinolone acetonide used for the treatment of chronic
noninfectious uveitis—a leading cause of blindness. This insert contains 0.59
mg drug, which is released over a period of about 30 months.
Intravitreal-controlled
drug delivery can be achieved with the use of implantable devices. For example,
I-vation® intravitreal implant is made of a nonferrous metal alloy, which is
placed inside the vitreous humor of the eye using a 25 gauge needle. Drugs are
delivered by coating onto its surface. The helical shape of this implant
maximizes drug loading and release. The use of this device helps reduce
frequent intraocular injections. Duration of drug release from this device
could range from 6 months to 2 years.
Drug
implants in the SC region or within certain tissues are used for
controlled/prolonged drug release for local or systemic action. These implants
are exemplified by the following:
·
SC contraceptive implants provide slow drug release over a
prolonged period of time. Most of these implants contain a progestogen, such as
levonorgestrel, etonorgestrel, nestorone, elcometrine, or nomegestrol acetate.
The polymers used in these inserts are exemplified by ethylvin-ylacetate and
polydimethyl/polymethyl-vinyl-siloxanes. These implants have a steroid load of
50–216 mg, are placed under the skin, and release the hormone at 30–100 μg/day over a period of 6 months to 7
years.
·
Gliadel® wafer, which contains the antitumor agent
carmustine in a biodegradable polyanhydride copolymer, is used for the
treatment of malignant glioma (brain tumor) and recurrent glioblastoma
multi-forme by implantation in or close to the tumor site. Each wafer con-tains
7.7 mg carmustine and is 1 mm thick and 1.45 cm in diameter. It is used as an
adjunct to surgery and radiation.
·
Vantas® SC implant contains histrelin acetate and is
indicated for pal-liative treatment of advanced prostate cancer by suppressing
testos-terone levels while requiring less frequent administration than other
LHRH agonists. It releases 50 mg of drug over a period of 12 months.
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