Thiolated chitosans: design and in vivo evaluation of a mucoadhesive buccal peptide drug delivery system.
OBJECTIVE
Intravenous application of pituitary adenylate cyclase-activating polypeptide (PACAP) has been identified as a promising strategy for the treatment of type 2 diabetes. To generate a more applicable formulation, it was the aim of this study to develop a sustained buccal delivery system for this promising therapeutic peptide.


METHODS
2-Iminothiolane was covalently bound to chitosan to improve the mucoadhesive and permeation-enhancing properties of chitosan used as drug carrier matrix. The resulting chitosan-4-thiobutylamidine conjugate was homogenized with the enzyme inhibitor and permeation mediator glutathione (gamma-Glu-Cys-Gly), Brij 35, and PACAP (formulation A). The mixture was lyophilized and compressed into flat-faced discs (18 mm in diameter). One formulation was additionally coated on one side with palm wax (formulation B). Tablets consisting of unmodified chitosan and PACAP (formulation C) or of unmodified chitosan, Brij 35, and PACAP (formulation D) served as controls. Bioavailability studies were performed in pigs by buccal administration of these test formulations. Blood samples were analyzed via an ELISA method.


RESULTS
Formulations A and B led to an absolute bioavailability of 1%, whereas PACAP did not reach the systemic circulation when administered via formulations C and D. Moreover, in the case of formulations A and B, a continuously raised plasma level of the peptide drug being in the therapeutic range could be maintained over the whole period of application (6 h). Formulations A and B were removed by moderate force from the buccal mucosa after 6 h, whereas formulations C and D detached from the mucosa 4 h after application.


CONCLUSIONS
The study reveals this novel mucoadhesive delivery system to be a promising approach for buccal delivery of PACAP.
Langoth
Nina
N
Thiomatrix GmbH, Mitterweg 24, A-6020, Innsbruck, Austria. n.langoth@thiomatrix.com
Kahlbacher
Hermann
H
Schöffmann
Gudrun
G
Schmerold
Ivo
I
Schuh
Maximilian
M
Franz
Sonja
S
Kurka
Peter
P
Bernkop-Schnürch
Andreas
A
D000268:Adhesiveness; D000278:Administration, Buccal; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002686:Chitin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007262:Infusions, Intravenous; D009061:Mouth Mucosa / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D013552:Swine; D013607:Tablets
D007004:Hypoglycemic Agents; D010455:Peptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D013607:Tablets; C493042:chitosan-4-thiobutylamidine; D002686:Chitin