Jm. Ryu et al., Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories in the rectum, J CONTR REL, 59(2), 1999, pp. 163-172
Mucoadhesive liquid suppositories were prepared by adding mucoadhesive poly
mers (0.6%) to a formulation of thermally gelling suppositories that contai
ned poloxamer 407 (15%), poloxamer 188 (15%) and propranolol HCl (2%). Hydr
oxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carbopol, polycarboph
il and sodium alginate were examined as mucoadhesive polymers. The characte
ristics of the suppositories differed depending on the choice of mucoadhesi
ve polymer. For example, the gelation temperature was between 30 and 36 deg
rees C, the mucoadhesive force was between 430 and 5800 dyne/cm(2), the app
arent first-order release rate constant in phosphate buffer, pH 6.8, was be
tween 0.399 and 0.271 h(-1), the migration distance of the suppository in t
he rectum 4 h after administration was between 1 and 5 cm, and the bioavail
ability of propranolol was between 60.9 and 84.7%. Rectal bioavailability i
ncreased as the mucoadhesive force increased (r=0.984, p<0.0005), and the m
igration distance decreased (r=-0.951, p<0.005). No relationship was found
between the bioavailability and the gelation temperature, drug release or i
rritation of the rectal mucosal membrane by the suppository. Therefore, ret
aining propranolol at the dosed site in the rectum by the addition of appro
priate mucoadhesives to the formulation of Liquid suppositories appears to
be a very important factor in avoiding first-pass hepatic elimination and t
hereby increasing the bioavailability of the drug. Among the mucoadhesive p
olymers examined, sodium alginate and polycarbophil exhibited the largest m
ucoadhesive force and the smallest intrarectal migration resulting in the l
argest bioavailability of propranolol (84.7 and 82.3%, respectively). In co
ntrast to other polymers, sodium alginate alone caused no irritation of the
rectal mucosal membrane. Thus, poloxamer Liquid suppositories containing s
odium alginate appears to be a preferred formulation for drugs that are sen
sitive to extensive first-pass metabolism. (C) 1999 Elsevier Science B.V. A
ll rights reserved.