Polymer delivery of the active isomer of misoprostol: a solution to the intestinal side effect problem.
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.
Perkins
W E
WE
Searle Discovery Research, Skokie, Illinois.
Bianchi
R G
RG
Tremont
S J
SJ
Collins
P W
PW
Casler
J J
JJ
Fenton
R L
RL
Wagner
G M
GM
McGrath
M P
MP
Stolzenbach
J C
JC
Kowalski
D L
DL
D000818:Animals; D000863:Antacids / Q000494:pharmacology; D001241:Aspirin / Q000633:toxicity; D001682:Biological Availability; D002070:Butadienes; D003864:Depression, Chemical; D003967:Diarrhea / Q000139:chemically induced; D004285:Dogs; D004337:Drug Carriers; D000431:Ethanol / Q000633:toxicity; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D065347:Hypromellose Derivatives; D007213:Indomethacin / Q000633:toxicity; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000517:prevention & control; D008297:Male; D008747:Methylcellulose / Q000031:analogs & derivatives*; D016595:Misoprostol / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D011108:Polymers; D051381:Rats; D011919:Rats, Inbred Strains; D013272:Stomach Diseases / Q000139:chemically induced* / Q000517:prevention & control
D000863:Antacids; D002070:Butadienes; D004337:Drug Carriers; D011108:Polymers; C087052:SC 53450; D016595:Misoprostol; D000431:Ethanol; D065347:Hypromellose Derivatives; D008747:Methylcellulose; D001241:Aspirin; D007213:Indomethacin