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Novel EPDM (ethylenepropylenediene monomer) and polybutadiene polyols can be synthesized by a two-step process of controlled hydroformylation and then reduction of the formyl groups to place a desired amount of pendant alcohol groups along the polymer chain. The degree of functionalization can be controlled by measuring gas uptake from a calibrated reservoir during hydroformylation. Hydroformylation can be performed in solution or under simulated melt-phase conditions using either HRh(CO)(PPh(3))(3) of Rh(acac)(CO)(2) as catalysts. Reduction of the polyaldehyde by NaBH4 generates the polymeric alcohol without further reaction of the remaining double bonds. Polymer functionalization and further modifications were followed by H-1-NMR and FTIR. These unique hydrophobic polyols can be reacted further to produce other polymer systems. As an example, urethanes have been made with these polyols by reaction with diisocyanates. (C) 1995 John Wiley and Sons, Inc.

A new method of synthesizing tailored polymeric drug delivery systems by catalytic reactions on polymers is described. By controlled functionalization of a template polymer, key functional groups can be optimally attached to the base polymer to meet the requirements of a specific drug and its mode of action. By use of homogeneous catalysis, polybutadiene, was modified to incorporate the specialized requirements for controlled delivery of misoprostol to the stomach. An acid labile silyl ether bond to the C-11 hydroxyl of misoprostol was installed as the rate determining step for drug release, and a series of analogs, in which the steric hindrance about the silicon atom was varied, was prepared and evaluated for in vitro release rates, efficacy against indomethacin induced gastric damage and diarrheagenic activity.

Misoprostol is a synthetic 16-hydroxy analog of natural prostaglandin E, and is used for prevention of gastric ulcers caused by non-steroidal anti-inflammatory drugs. Misoprostol exerts its therapeutic effect when applied directly to the gastric mucosa. The undesired side effects of misoprostol are observed for the blood borne drug (uterotonic), or, in the case of diarrhea, combined systemic and intestinal exposure. A strategy to reduce side effects while maintaining therapeutic efficacy of the drug is controlled slow delivery of misoprostol to the stomach. A number of functionalized polymer-based systems designed to slowly release misoprostol in the stomach but not in the intestines have been developed. The key polymer-bound release mechanism is a covalent silicon ether bond to the C-ll hydroxy group of misoprostol. The silyl linker releases intact misoprostol from the polymer matrix under acidic conditions (pH 1-3) but not at the higher intestinal pH (>5).

SC-53450 is a new polybutadiene-based polymer system with an acid labile diisopropyl silyl ether linker to which the active isomer of misoprostol (SC-30249) is attached covalently at position C-11. It was studied in rats and dogs to define its profile of gastrointestinal effects relative to misoprostol-hydroxypropyl methylcellulose (HPMC) and the systemic availability of prostaglandin from the polymer. Results of rat studies indicate that SC-53450 has a spectrum of mucosal protective activity similar to misoprostol-HPMC, being protective against indomethacin-induced gastric, cysteamine/indomethacin-induced duodenal and indomethacin-induced lower small bowel damage. SC-53450, in contrast to misoprostol-HPMC, was not diarrheagenic in the rat when administered intragastrically. The observation that SC-53450 is more than 4 times more potent than misoprostol-HPMC suggests the possibility of sustained gastric availability of the prostaglandin SC-30249. SC-53450 exhibited gastric antisecretory activity in histamine-stimulated gastric fistula dogs and protected against acidified aspirin-induced gastric damage in normal fasted beagles. Rat and dog experiments indicate that little, if any, polymer-derived prostaglandin is available systemically, suggesting SC-53450 will have reduced abuse potential in abortion induction. SC-53450 is a potential candidate to replace the present misoprostol formulation in the marketplace for the prevention of nonsteroidal anti-inflammatory drug-induced gastric damage.

The application of functionalized polymers to site-directed delivery of the antiulcer prostaglandin, misoprostol, is described. By use of homogeneous catalysis, the simple polymer, polybutadiene, was modified to incorporate the specialized requirements for controlled delivery of misoprostol to the stomach. An acid labile silyl ether bond to the C-11 hydroxyl of misoprostol was installed as the primary rate determining step for drug release, and a series of analogs, in which the steric hindrance about the silicon atom was varied, was prepared and evaluated for in vitro release rates, efficacy against indomethacin induced gastric damage and diarrheagenic activity. The diisopropylsilyl analog, the slowest releasing system studied, showed efficacy equal to misoprostol against indomethacin-induced gastric damage and no diarrhea at the highest dose tested.