Donald W. H. Penhale

Use of poly(ortho esters) for the controlled release of 5-fluorouracyl and a LHRH analogue☆

Abstract The controlled release of 5-fluorouracyl (5FU) and a luteinizing hormone releasing hormone analogue (LHRH) from a crosslinked bioerodible poly (ortho ester) was studied. Unlike our previous results with levonorgestrel which was released by a predominant surface erosion process, the much more water-soluble 5FU and LHRH analogue are released predominantly by diffusion. However, rate of diffusion is strongly influenced by rate of polymer hydrolysis. Because the LHRH analogue has two reactive hydroxyl groups, some are chemically bound to the crosslinked matrix via ortho ester linkages. Analysis of a model polymer matrix indicates that 95% of the LHRH analogue is released in its original form and 5% is released as the propionate ester.

In vitro and in vivo release of levonorgestrel from poly(ortho esters)

Abstract The in vitro and in vivo release of levonorgestrel from linear poly(ortho ester) cylindrical devices containing 30 wt.% drug and 2 wt.% calcium lactate was studied. The in vitro release rate was a relatively constant 20 μg/day for about one year at which time the experiment was discontinued. The in vivo release rate in rabbits was about 33 μg/day. In both studies rate of polymer erosion is about the same and significantly leads rate of drug release. Therefore, factors other than polymer erosion determine rate of drug release. SEM studies of devices explanted from rabbits show the formation of a foamed drug layer surrounding the device. The formation of this layer is caused by polymer erosion around undissolved drug. Rate of drug delivery from the device is controlled by dissolution of levonorgestrel from the outside of the foamed drug layer. The higher in vivo release is attributed to the presence of lipophilic species that facilitate dissolution of levonorgestrel.

The effect of copolymerized 9,10-dihydroxystearic acid on erosion rates of poly(ortho esters) and its use in the delivery of levonorgestrel

Abstract Erosion, rates of poly(ortho esters) can be usefully accelerated by the copolymerization of 9,10-dihydroxystearic acid into the copolymer. This accelerating effect can be enhanced by using a hydrophilic diol such as triethylene glycol as one of the monomers. By using a combination of 9,10-dihydroxystearic acid and triethylene glycol precise control over erosion rate of the polymer can be achieved by small variations in the amount of 9,10-dihydroxystearic acid used. This technique has been used to develop levonorgestrel-containing devices.

Synthesis and Release of Contraceptive Steroids from Bioerodible Poly(Ortho Ester)S

Because of possible adverse effects or a desire to terminate therapy, implanted bioerodible drug delivery systems should be easily removable at any time. For this reason, solid devices that maintain their mechanical integrity throughout the major portion of their delivery regime are particularly attractive. A further desirable feature is drug release that is close to zero order.