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Thursday, April 12, 2012

Therapeutic Applications of Implant

Ocular disease
Several different implantable systems have been evaluated to provide prolonged oclular delivery. These include membrane-controlled devices implantable silicone devices, and implantable infusion systems. An example of the membrane-controlled system is the ocusert containing pilocarpine base and alginic acid in a drug reservoir surrounded by a release-rate controlling ethylene-vinyl acetate membrane. The ocusert system provides an initial burst followed by a near zero order delivery of pilocarpine at 20 or 40 g/h for a period of seven days. The device is well tolerated in adults, with satisfactory control of intraocular pressure and minimal side effects. However it appears to be poorly tolerated in the geriatric population where most of the therapeutic need exists.

Implantable devices evaluated for ocular cancer treatment include silicone rubber balloon containing an antineoplastic agent. BCNU. The device consists of two sheets of silicon rubber glued at the edges with silicon adhesive to form a balloon like sac through which a silicone tube is inserted. By a diffusional process, the BCNU solution is slowly released through the silicone tube. Upon completion of delivery, the device is refilled with drug solution.

The implantable infusion pump system evaluated consists of a miniaturized and computerized pumping device with silastic tubing leading to the site for infusion so drug.

Norplant a subdermal implant for long-term delivery of the contraceptive agent levonorgestrel gas recently been approved for marketing by the FDA. The device consists of six silicone membrane capsules each containing about 36 mg of levonorgestrel. The capsules are piaced subdermally on the inside of the upper arm or the forearm in a fan-shaped pattern through a trocar from a single trocar entry point. Cumulatively the six capsules deliver about 70 g/day in vitro and 90 g/day in vivo for the first 100 days with a gradual decrease to about 30 g/day at about 800 days. This rate of delivery appears to continue for over five years. Clinically, Norplant users have a net pregnancy rate of below 1.5 in 100 women at four years. At the end of four years 42 % of the women continued with the method indicating acceptability comparable with that of other methods. Other polymer-based systems under study for contraception include vaginal rings generally composed of silicon rubber used for 3 to 76 months often with a removal period of one week monthly to allow for menstruation; the progestasert an ethylenevinyl acetate copolymer intrauterine drug-releasing device which lasts for one year: and suspensions of injectable microspheres or rods composed of biodegradable polymers.

Dental application
Polymeric implants have been evaluated for several dental applications involving local prolonged administration of fluoride antibacterials and antibiotics. For sustained-release fluoride delivery stannous fluoride was incorporated into different dental cements. Another dispersed in the hydroxyethyl methacrylate and methyl methacrylate copolymer hydrogel coated with an outer layer of the same copolymers in  different proportion so as to be rate limiting in drug release. The device, about 8 mm long and containing 42 mg of fluoride in the core was attached to the buccal surface of the maxillary first molar and designed to release 0.5 mg of fluoride per day for 30 days. Although increased fluoride concentration were found in the saliva of the subjects erythema or small ulcers were also detected on the buccal mucosal opposite to the device. A modification of this system containing only 17.5 mg of fluoride in a nylon suture system providing 0.15 mg of fluoride per day resulted in 63% fewer carious enamel lesions than in rats without any treatment.

Ethycellulose slabs containing polyethylene glycol and chlorhexidine as an antibacterial agent gave also been evaluated. The slabs have the additional advantage that they can be cut to fit the periodontal pocket and can be inserted quickly with minimal discomfort to the patient. Acrylic polymers have also been evaluated for such a system. Sustained-release implants made of hollow cellulose fibers have also been extensively evaluated. Hollow gibers containing 20% solution of chlorhexidine gluconate and placed in periodontal pockets resulted in significant clinical improvement with relief of discomfort, reduced gingival flow, and less bleeding on probe. Finally matrix systems composed of ethylene-vinyl acetate copolymer and releasing tetracycline (on site therapeutic system) are being tested clinically to treat periodontal disease. Although all these systems led to a reduction of microbial count one of their major disadvantages is the need to remove the device at the end of the 3 to 5 days release period.

The localized nature of dental diseases and the ease of implantation make sustained-release systems of resorbable and biodegradable polymers highly suitable. Research is on going in the area but for commercialization any such delivery system would need to overcome obstacles such as ease of application and patient acceptability and have to complete with conventional delivery systems such as a mouthwash.

Polymeric implants are being evaluated for enhanced immune response to antigens. The concept here is to provide pulsatile or continuous administration of the antigen over a prolonged time period. Wise et al. evaluated immunization efficacy of ethylene-vinyl acetate copolymer pellets containing bovine serum albumin as model antigen. The immune response was comparable to that achieved by two injections of bovine serum albumin in complete Freund’s adjuvant (Freund’s adjuvant is an oil-in-water suspension containing bacteria).

Silicone rod implants similar to those used for delivery of levonorgestrone have been evaluated for delivery of testosterone propionate or ethinyl estradiol in patients  with prostate cancer. Lupron depot manufactured by Takeda chemical industries is an implantation system providing one – month depot release of leuprolide acetate. a synthetic analogue of the gonadotropin-releasing hormone (GhRH).  The implat consists of biodegradable microspheres prepared from polylactic – glycolic copolymer at 50:50 composition. Containing 10% leuprolide acetate for the treatment of prostate cancer sanders et al. reported on a similar delivery system for nafarelin acetate. an agonistic analogue of lutenizing hormone releasing hormone (LHRH). Zoladex manufactured buy ICI Pharma provides one – month depot release of goserelin acetate from a biodegradable implantable rod . For the treatment of prostate cancer. Biodegradable implants Containing polyanhydrides.  P (CPP:SA) 20:80 ( copolymer of carboxyphenoxy propane and sebacic acid) and BCNU for the treatment of glioblastoma multiform. A form of brain cancer have also been evaluated. Microsphere formulations containing the same polyanhydrides have been evaluated for 24 to 36 delivery of methotrexate .

Narcotic antagonists
Naltrexone  has been extensively evaluated in implant from long- term delivery of narcotic antagonists. Natrexone  freebase. Its hydrochloride. Or the pamoate acid salt has been prepared in a variety of polymers and dosage forma for prolonged narcotic antaginist activity . Though in vitro delivery of up to 50 day has been achieved by some of the systems. in vivo duration of release has been shorter .
Nuwayser et al. reported on biodegradable polymer-coated microspheres  containing naltrexone base. The polymers  evaluated were poly lactide. poly lactic glycolide 65:35 and polycaprolactone-co-lactide 90:10. Diffusion controlled, linear naltrexone release was observed from the coated microspheres lasting for about 50 days. The microspheres produced about 60 day s of morphine antagonist response in implanted rats.

Other applications
Numerous insulin - delivery systems have been prepared and evaluated for a biofeedback approach and have been described previously.
Biodegradable implantable delivery systems have been developed to provide prolonged release of antibiotic to wou Self-regulated

These are biofeedback-controlled system, where the drug release rate is dependent on the body’s need for the drug at a given time. From a therapeutic viewpoint these systems may come closest to duplicating the release from a gland such as the pancreas. A variety of mechanisms have been employed to obtain self-regulated delivery.


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