Influence of fillers in powder formulations containing N-acetyl-L-cysteine on nasal peptide absorption.
We examined the influence of filler species on the nasal absorbability of peptide drugs via a newly developed powdery formulation system containing N-acetyl-l-cysteine (NAC) as an absorption enhancer. Using salmon calcitonin (SCT) as the principal model drug, we tested the effects of various formulations with different powder materials as fillers on the nasal absorption of SCT in rats. An intranasal administration experiment revealed that the use of less wettable powders provided better nasal absorbability, and the highest absolute bioavailability (30.0% +/- 8.6%) was obtained when ethylcellulose was used as a filler. All these results were readily explicable in terms of our hypothetical enhancing mechanism. Furthermore, human parathyroid hormone and insulin were applied to this ethylcellulose formulation system, giving nasal bioavailabilities of 28.2% +/- 6.5% and 23.4% +/- 10.6%, respectively, thus suggesting that this formulation system is widely applicable to peptide drugs.
Matsuyama
Takahiro
T
Pharmaceutical Technology Department, CMC Research Laboratories, Tanabe Seiyaku Co., Ltd. Kashima 3-chome, Yodogawa-ku, Osaka, Japan. taka-m@tanabe.co.jp <taka-m@tanabe.co.jp>
Morita
Takahiro
T
Horikiri
Yuji
Y
Yamahara
Hiroshi
H
Yoshino
Hiroyuki
H
D000111:Acetylcysteine / Q000737:chemistry*; D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D002116:Calcitonin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D002482:Cellulose / Q000031:analogs & derivatives / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D005079:Excipients / Q000737:chemistry*; D005100:Expectorants / Q000737:chemistry*; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007785:Lactose / Q000737:chemistry; D008297:Male; D009297:Nasal Mucosa / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D010316:Particle Size; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D011208:Powders; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014867:Water / Q000737:chemistry; D017155:Wettability
D005079:Excipients; D005100:Expectorants; D007328:Insulin; C470125:PTH protein, human; D010281:Parathyroid Hormone; D010455:Peptides; D011208:Powders; D014867:Water; C028815:salmon calcitonin; C013517:ethyl cellulose; D002482:Cellulose; D002116:Calcitonin; D007785:Lactose; D000111:Acetylcysteine