Sustained-release implants

S.E. Varner, N.R.F. Beeley, and E. de Juan, Sustained release implants and methods for subretinal delivery of bioactive agents to treat or prevent retinal disease, US Patent 8003124, assigned to Surmodics, Inc. (Eden Prairie, MN), August 23, 2011. 

In sustained-release implants, the general approach is to provide a barrier between the body fluid and insulin. This barrier can be microporous, where the rate of insulin release is diffusion-controlled, or it can be an erodible material that dissolves gradually and releases the entrapped insulin. By using mechanical stress or transmitted energy, externally modulated bolus release of insulin can be obtained. Even more sophisticated selfregulating (closed-loop) systems are also under development. 

Sustained-release implants for insulin delivery have been described fully in an excellent review by Wang (1991a). However, practical application of any of these systems in humans is not yet a reality. 

Wang, P. Y., 1991a, Sustained-release implants for insulin deUvety, in Biotechnology of Insulin Therapy (J. C. Pickup, ed.), Blackwell Scientific, Oxford, pp. 42-74. 

Progestin-only contraceptives (Fig. 4) contain low-doses of progestins (e.g. 350 pg norethindrone or 75 pg norgestrel) that have to be administered daily without interruption. The lowest expected failure rate during the first year of use is 0.5%, while the typical failure rate amounts to 3%. Subdermal implants of norgestrel (216 mg) for sustained release provides for long-term (for up to 5 years) contraceptive effects characterized by failure rates of only 0.05%. Reliable contraception for 3 months can be achieved by an intramuscular injection of a crystalline suspension of 150 mg medroxyprogesterone acetate (Fig. 3) (failure rate 0.3%). 

S., Catnbies, L., Depadt, G., and Vert, M., In vivo sustained release of cisplatin from bioresorbable implants in mice. Anticancer Res., 6, 1251, 1986. 

Controlled and sustained drug delivery has recently begun to make an impression in the area of treatment of dental diseases. Many researchers have demonstrated that controlled delivery of antimicrobial agents, such as chlorhexidine [128-130], ofloxacin [131-133], and metronidazole [134], can effectively treat and prevent periodontitis. The incidence of dental caries and formation of plaque can also be reduced by controlled delivery of fluoride [135,136]. Delivery systems used are film-forming solutions [129,130], polymeric inserts [132], implants, and patches. Since dental disease is usually chronic, sustained release of therapeutic agents in the oral cavity would obviously be desirable. 

One of the most obvious ways to provide sustained-release medication is to place the drug in a delivery system and inject or implant the system into the body... 

The other related subcutaneous routes are dermojet (by which, drug is projected from a microfine orifice using a high velocity jet) and pellet implantation (which provides sustained release of the drug over weeks and months e.g. testosterone). 

Polymeric membrane-based implantable drug delivery systems have been developed to deliver growth hormone, hormonal contraception, and leuprolide for the treatment of prostate cancer. Implanted sialic tubes loaded with lev-onorgestrel Norplant system) is used outside the United States to provide five years of sufficient sustained release of the... 

Nondegradable polymers are also useful as matrices for ocular implants. This application requires the polymer to be hydrophilic, to minimize local tissue irritation. Need for ocular implants stems from the challenges posed to conventional ocular medicines (i.e., eye drops) such as rapid dilution, tear washout, poor patient compliance, and limited bioavailability. Ocular implants from hydrophilic polymer matrices that provide localized sustained release may overcome the above limitations. The first polymeric sustained release product to reach the market was Ocusert , a pilocarpin sustained release ocular implant developed by Alza. Ocusert has the drug reservoir as a thin disc of pilocarpine-alginate complex sandwiched between two transparent discs of microporous membrane fabricated from ethylene-vinyl acetate copolymer. The microporous membranes permit the tear fluid to penetrate into the drug reservoir compartment to dissolve pilocarpine from the complex. Pilocarpine molecules are then released at a constant rate of 20 or 40 pg/hr for a four- to seven-day management of glaucoma. 

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