Preparation and in vitro / ex vivo characterization of antifungal formulations for mucosal application

Within the scope of this thesis, two different formulations; mucoadhesive and mucous penetrating formulations have been prepared for the treatment of vaginal candidiasis with posaconazole (POS), a low water soluble azole group antifungal. These two formulations were further evaluated by in vitro / ex vivo characterization. In the first part of the thesis, succinyl-β-cyclodextrin (Suc-β-CD) was studied in order to develop mucoadhesive formulation to be applied to the vagina. Suc-β-CD was thiolated by pre-activation method to provide mucoadhesiveness to the oligomer, then inclusion complexes were prepared with POS to improve solubility properties of the active substance. Thiolated Suc-β-CD derivatives synthesized by two different modification rates have been chemically characterized. 521,76 ± 28,25 μmol / g 6-MNA was conjugated to the molecule. Suc-β–CD-MNA1 was found to increase the dissolution of POS in lactate buffer by 49,13 fold and Suc-β-CD-MNA2 increased by 33,61 fold. According to the results of mucoadhesion studies the inclusion complexes prepared with Suc- β-CD-MNA1 and Suc-β-CD-MNA2 exhibited 21,574 and 37,674 fold higher mucoadhesion than complexes prepared with unmodified Suc-β-CD, respectively. The cytotoxic profiles and antifungal effects of inclusion complexes prepared with Suc-β-CD-MNA derivatives and POS and derivatives were also investigated. In the second part of the thesis, the aim was to prepare a mucus permeating formulation that can reach the epithelial layer by passing the hydrophilic mucus barrier. Recently, studies showed that SNEDDS (self-nanoemulsifying drug delivery systems) have an important potential for mucosal drug administration. SNEDDS droplets are capable of penetrating the mucus layer due to their formation properties. In order to increase the mucus penetration of the formulation, an ionic complex between the mucolytic agent N-acetylcysteine (NAC) and the cationic polymer Eudragit RS 100 was prepared and added to the SNEDDS. Prepared formulations were examined in terms of particle size, polydispersity index and zeta potential, active substance release studies were performed and mucus permeation and mucolytic properties were investigated. It was also observed that the SNEDDS formulation containing the EU-NAC complex reduced mucus viscosity to about 5% of the initial value after 4 hours. Antifungal efficacy and cytotoxicity tests were also performed for SNEDDS formulations. In addition, a new release method based on Ellman Test principles has been developed to determine NAC release from SNEDDS formulations. Both mucoadhesive and mucosal penetrating systems have their own advantages when administering drugs to mucosal tissue. The trend in drug development for mucosal administration in the future is thought to be to design new drug delivery systems by combining the superior properties of both types of formulations in the same formulation.