Implants: mechanism and types
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.
Diffusion controlled implants
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 reservoir 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 non-biodegradable. 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 mechanism. 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 non-biodegradable implants.
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 hormone-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 testosterone 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 contains 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 dissolution 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 environment 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.
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. Nondegradable, osmotically driven system is intended to enable delivery of small drugs, peptides, proteins, and DNA for systemic or tissue-specific therapy. These implants are used for continuous therapy for up to 1 year. Viadur is a luprolide acetate-containing implant, once yearly, for the palliative treatment of advanced prostate cancer.
Classification of implants based on clinical use
Cardiac implants are devices that are surgically placed in the heart for restoring and assisting regular heart function. For example, polymeric closure 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 pacemakers and artificial heart valves is well known.
Drug loading into conventional cardiac implants can improve their clinical 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 addition, 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 treatment is frequently practiced in dental implant placement surgery to minimize 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 and penal implants
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 prolonged contact with urine. Encrustation also leads to higher risk of infection.
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 management 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 incidence 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 modification 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 intravenous (IV) therapy. Vitrasert® is a ganciclovir intravitreal implant for the treatment of patients with AIDS-related cytomegalovirus (CMV) retinitis. 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 anti-inflammatory 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.
Dermal and tissue implants
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 ethylvinylacetate 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 multiforme by implantation in or close to the tumor site. Each wafer contains 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 palliative treatment of advanced prostate cancer by suppressing testosterone levels while requiring less frequent administration than other LHRH agonists. It releases 50 mg of drug over a period of 12 months.