Increased bioavailability of propranolol in rats by retaining thermally gelling liquid suppositories in the rectum.
Mucoadhesive liquid suppositories were prepared by adding mucoadhesive polymers (0.6%) to a formulation of thermally gelling suppositories that contained poloxamer 407 (15%), poloxamer 188 (15%) and propranolol HCl (2%). Hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP), carbopol, polycarbophil and sodium alginate were examined as mucoadhesive polymers. The characteristics of the suppositories differed depending on the choice of mucoadhesive polymer. For example, the gelation temperature was between 30 and 36 degrees C, the mucoadhesive force was between 430 and 5800 dyne/cm2, the apparent first-order release rate constant in phosphate buffer, pH 6.8, was between 0.399 and 0.271 h-1, the migration distance of the suppository in the rectum 4 h after administration was between 1 and 5 cm, and the bioavailability of propranolol was between 60.9 and 84.7%. Rectal bioavailability increased as the mucoadhesive force increased (r=0.984, p<0.0005), and the migration distance decreased (r=-0.951, p<0.005). No relationship was found between the bioavailability and the gelation temperature, drug release or irritation of the rectal mucosal membrane by the suppository. Therefore, retaining propranolol at the dosed site in the rectum by the addition of appropriate mucoadhesives to the formulation of liquid suppositories appears to be a very important factor in avoiding first-pass hepatic elimination and thereby increasing the bioavailability of the drug. Among the mucoadhesive polymers examined, sodium alginate and polycarbophil exhibited the largest mucoadhesive force and the smallest intrarectal migration resulting in the largest bioavailability of propranolol (84.7 and 82.3%, respectively). In contrast to other polymers, sodium alginate alone caused no irritation of the rectal mucosal membrane. Thus, poloxamer liquid suppositories containing sodium alginate appears to be a preferred formulation for drugs that are sensitive to extensive first-pass metabolism.
Ryu
J M
JM
Department of Pharmaceutics, College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.
Chung
S J
SJ
Lee
M H
MH
Kim
C K
CK
ShimCK
D000268:Adhesiveness; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D005782:Gels / Q000737:chemistry; D066298:In Vitro Techniques; D007509:Irritants / Q000494:pharmacology; D008297:Male; D020442:Poloxamer / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011433:Propranolol / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000502:physiology*; D013488:Suppositories / Q000493:pharmacokinetics*; D013696:Temperature
D000319:Adrenergic beta-Antagonists; D005782:Gels; D007509:Irritants; D011108:Polymers; D013488:Suppositories; D020442:Poloxamer; D011433:Propranolol