Synergistic absorption enhancement of salmon calcitonin and reversible mucosal injury by applying a mucolytic agent and a non-ionic surfactant.
The present study investigated the intestinal absorption enhancement of salmon calcitonin (SCT) and the intestinal mucosal damage when a mucolytic agent and a non-ionic surfactant were administered simultaneously to rats. N-acetylcysteine (NAC) and p-t-octyl phenol polyoxyethylene-9.5 (Triton X -100, TX-100) were chosen as the model mucolytic agent and the non-ionic surfactant, respectively. Dosing solutions containing these agents were administered directly into the rat jejunum, and the bioavailability of SCT up to 2 h was determined. NAC and TX-100, when they were used alone at a dose of 1 mg/head, did not show the apparent enhancement compared to the control. However, simultaneous use of NAC and TX-100 enhanced the intestinal absorption of SCT in a synergistic manner, and absolute bioavailability increased 12.5-fold compared to the control. The effect of NAC and TX-100 on SCT absorption was not dependent on their doses over the range of 0.2-2 mg/head, and the maximum effect was obtained at a dose of 1mg/head. Absorption enhancement of SCT by a combination of NAC and TX-100 was compared to those from the classical absorption enhancers. Absorption-enhancing ability of the combination of NAC and TX-100 was significantly higher than those of sodium deoxycholate, citrate, and the combination of citrate and taurocholate, and was comparable with that of the combination of citrate and taurodeoxycholate. Finally, the intestinal mucosal damage caused by the combination of NAC and TX-100 was assessed using a capsule device. Acute damage on intestinal mucosa was observed when they were exposed into rat intestine, but this morphological damage was found to be reversible. All these results suggest that simultaneous use of a mucolytic agent and a non-ionic surfactant would offer a potentiality for peroral delivery of peptide drugs like SCT.
Takatsuka
Shinya
S
Pharmaceutical Development Laboratories, Tanabe Seiyaku Co. Ltd., 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, Japan. s-taka@tanabe.co.jp
Morita
Takahiro
T
Koguchi
Atsushi
A
Horikiri
Yuji
Y
Yamahara
Hiroshi
H
Yoshino
Hiroyuki
H
D000111:Acetylcysteine / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D002116:Calcitonin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005100:Expectorants / Q000009:adverse effects / Q000494:pharmacology*; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D017830:Octoxynol / Q000009:adverse effects / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013501:Surface-Active Agents / Q000009:adverse effects / Q000494:pharmacology*
D005100:Expectorants; D013501:Surface-Active Agents; C028815:salmon calcitonin; D017830:Octoxynol; D002116:Calcitonin; D000111:Acetylcysteine