Enhancement of nasal absorption of large molecular weight compounds by combination of mucolytic agent and nonionic surfactant.
For improving the nasal absorption of poorly absorbable hydrophilic compounds, the suitability of a combination of a mucolytic agent, N-acetyl-L-cysteine (NAC), and a nonionic surfactant, polyoxyethylene (C25) lauryl ether (laureth-25), was examined. Rat studies with fluorescent isothiocyanate-labeled dextran (molecular weight ca. 4.4 kDa, FD-4) as a model hydrophilic compound revealed dramatic enhancement of nasal absorption when NAC and laureth-25 were simultaneously applied. The nasal bioavailability of FD-4 in saline solution was 8.2+/-0.6% but increased to 40.0+/-5.5% when 5% NAC and 5% laureth-25 were added. This synergistic enhancement could result from the mucolytic activity of NAC in reducing mucous viscosity by which the accessibilities of FD-4 and laureth-25 to the epithelial membrane were increased. Further rat studies proved that this formulation increased nasal absorption of salmon calcitonin. Absolute bioavailability from saline solution containing 5% NAC and 1% laureth-25 was 26.8+/-2.2%, 3.5 times that of the commercial calcitonin nasal spray Miacalcin (7.7+/-2.1%). The potential of the new formulation to cause tissue damage in terms of hemolytic activity and liberation of phospholipid from the nasal membranes was nil or slight. The combination of NAC and laureth-25 appears suitable for use in development of nasal products for poorly absorbable drugs, especially peptide and protein drugs.
Matsuyama
Takahiro
T
Pharmaceutical Development Laboratories, Tanabe Seiyaku Co. Ltd. 16-89 Kashima 3-chome, Yodogawa-ku, Osaka 532-8505, Japan. Electronic address: taka-m@tanabe.co.jp.
Morita
Takahiro
T
Pharmaceutical Development Laboratories, Tanabe Seiyaku Co. Ltd. 16-89 Kashima 3-chome, Yodogawa-ku, Osaka 532-8505, Japan.
Horikiri
Yuji
Y
Pharmaceutical Development Laboratories, Tanabe Seiyaku Co. Ltd. 16-89 Kashima 3-chome, Yodogawa-ku, Osaka 532-8505, Japan.
Yamahara
Hiroshi
H
Pharmaceutical Development Laboratories, Tanabe Seiyaku Co. Ltd. 16-89 Kashima 3-chome, Yodogawa-ku, Osaka 532-8505, Japan.
Yoshino
Hiroyuki
H
Pharmaceutical Development Laboratories, Tanabe Seiyaku Co. Ltd. 16-89 Kashima 3-chome, Yodogawa-ku, Osaka 532-8505, Japan.
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D002116:Calcitonin / Q000008:administration & dosage / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D003911:Dextrans / Q000493:pharmacokinetics; D005100:Expectorants / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D016166:Free Radical Scavengers / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D008297:Male; D008970:Molecular Weight; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism; D000077423:Polidocanol; D011092:Polyethylene Glycols; D051381:Rats; D017208:Rats, Wistar; D013501:Surface-Active Agents / Q000494:pharmacology*
D003911:Dextrans; D005100:Expectorants; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D004364:Pharmaceutical Preparations; D010743:Phospholipids; D013501:Surface-Active Agents; C015219:fluorescein isothiocyanate dextran; D000077423:Polidocanol; D011092:Polyethylene Glycols; D002116:Calcitonin; D016650:Fluorescein-5-isothiocyanate; D000111:Acetylcysteine