Chitosans as nasal absorption enhancers of peptides: comparison between free amine chitosans and soluble salts.
A total of three free amine chitosans (CS J, CS L and CS H) and two soluble chitosan salts (CS G and CS HCl) were evaluated for their efficacy and safety as nasal absorption enhancers of peptides based on in situ nasal perfusion and subacute histological evaluation in rat. At 0.5% w/v, all chitosans were effective in enhancing the nasal absorption of [D-Arg(2)]-Kyotorphin, an enzymatically stable opioid dipeptide. The enhancing effect of the free amine chitosans increased as the pH was decreased from 6.0 to 4.0 (P<0.05). However, the pH effect was not significant for the two chitosan salts (P0.05), suggesting that their adjuvant activity may be less pH-dependent than the free amine form. CS J and CS G were subsequently selected for further studies. At only 0.02% w/v, their enhancing effect was already significant and comparable to that of 5% w/v hydroxypropyl-beta-cyclodextrin (HP-beta-CD). Both chitosans at 0.1% caused minimal release of total protein and phosphorus from the rat nasal mucosa, with the values similar to that of 5% HP-beta-CD. At 0. 5% the two chitosans also stimulated smaller release of lactate dehydrogenase, an intracellular enzyme used as marker of nasal membrane damage, than 1.25% dimethyl-beta-cyclodextrin. Morphological evaluation of the rat nasal mucosa following 2-week daily administration indicated that the two chitosans (1.0%) produced only mild to moderate irritation. In conclusion, both the free amine and the acid salt forms of chitosans are effective in enhancing the nasal absorption of [D-Arg(2)]-Kyotorphin and have potential for further studies as a safe and effective nasal absorption enhancer of peptide drugs.
Tengamnuay
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Department of Pharmacy, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand. parkpoom.t@chula.ac.th
Sahamethapat
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Sailasuta
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Mitra
A K
AK
D000042:Absorption; D000281:Administration, Intranasal; D000588:Amines / Q000737:chemistry; D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002686:Chitin / Q000031:analogs & derivatives* / Q000737:chemistry; D048271:Chitosan; D004723:Endorphins / Q000008:administration & dosage / Q000493:pharmacokinetics; D005079:Excipients; D006863:Hydrogen-Ion Concentration; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009297:Nasal Mucosa / Q000033:anatomy & histology / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010477:Perfusion; D010758:Phosphorus / Q000378:metabolism; D011208:Powders; D051381:Rats; D017207:Rats, Sprague-Dawley; D012492:Salts / Q000737:chemistry
D000588:Amines; D000700:Analgesics; D004723:Endorphins; D005079:Excipients; D010455:Peptides; D011208:Powders; D012492:Salts; C019448:kyotorphin; D002686:Chitin; D010758:Phosphorus; D048271:Chitosan; D007770:L-Lactate Dehydrogenase