In vitro evaluation of various buccal permeation enhancing systems for PACAP (pituitary adenylate cyclase-activating polypeptide).
OBJECTIVE
Buccal administration of pituitary adenylate cyclase-activating polypeptide (PACAP) could represent a new possibility for the treatment of type 2 diabetes. In this study the effect of various buccal permeation enhancers on PACAP and FD-4 was evaluated.


METHODS
The permeation-enhancing properties of the well-established permeation enhancers sodium deoxycholate (Na DOC) and cetrimide on the permeation of PACAP were investigated on freshly excised porcine buccal mucosa in Ussing chambers. Furthermore, the effect of chitosan and that of chitosan-4-thiobutylamidine conjugate (chitosan-TBA) optionally in combination with reduced glutathione (GSH) on the permeation of PACAP across the buccal mucosa was studied.


RESULTS
The apparent permeability coefficient (P(app)) of PACAP in buffer only was 5.7 +/- 3.1x10(-8) cm/s. In the presence of 5% (m/v) Na DOC, the enhancement of the permeation was 18.6-fold, whereas due to the addition of 5% (m/v) cetrimide an enhancement ratio of 46.5 was obtained. In the presence of the chitosan-TBA conjugate (1%), a 38.9-fold increased permeation was achieved, whereas unmodified chitosan (1%) did not show any effect. The combination of chitosan-TBA conjugate (1%) with GSH (2%) led to an increase in P(app) up to 441.7 +/- 89.9x10(-8) cm/s, which represents a 77.5-fold improvement. The P(app) of GSH per se was only 1.0 +/- 0.2x10(-9) cm/s, showing that GSH remains concentrated on the surface of the buccal mucosa. Results were confirmed by additional permeation studies performed with FD-4 used as hydrophilic macromolecular test compound.


CONCLUSIONS
Based on their permeation-enhancing properties, chitosan-TBA conjugates represent a promising tool for the buccal administration of peptide drugs, e.g., PACAP.
Langoth
Nina
N
ThioMatrix GmbH, Mitterweg 24, A-6020, Innsbruck, Austria. n.langoth@thiomatrix.com
Bernkop-Schnürch
Andreas
A
Kurka
Peter
P
D000818:Animals; D000077286:Cetrimonium; D002593:Cetrimonium Compounds / Q000494:pharmacology; D002686:Chitin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D048271:Chitosan / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003840:Deoxycholic Acid / Q000494:pharmacology; D015194:Diffusion Chambers, Culture; D005079:Excipients / Q000494:pharmacology*; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D066298:In Vitro Techniques; D008970:Molecular Weight; D009061:Mouth Mucosa / Q000187:drug effects / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000493:pharmacokinetics*; D013268:Stimulation, Chemical; D013552:Swine
D002593:Cetrimonium Compounds; D005079:Excipients; D005456:Fluorescent Dyes; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C493042:chitosan-4-thiobutylamidine; D003840:Deoxycholic Acid; D002686:Chitin; D048271:Chitosan; D016650:Fluorescein-5-isothiocyanate; D000077286:Cetrimonium