Title : In situ gels containing isoconazole nitrate/methyl-β-cyclodextrin inclusion complexes: Formulation and in vitro evaluation
Abstract:
Introduction and aims: Vaginal candidiasis is one of the most prevalent problems that women face throughout their lives. Considering the side effects and drug-drug interactions associated with the oral route, local administration of drugs is a first approach for the management of vaginal candidiasis. To obtain a desired therapeutic impact, vaginal drug delivery system must persist at infection sites for an extended period of time. In situ gel technologies improve availability by extending the time of the formulation remains in the vaginal canal. Antifungal agents within azole family like isoconazole nitrate (ISN) with lower aqueous solubility have been used as the drug of choice for vaginal fungal infections. The present work investigates the usage of methyl-Cyclodextrin (M-β-CD) as an ISN solubility improver that can be utilized to manufacture in situ gel systems for vaginal application in order to prolong the contact duration with the vaginal cavity and hence sustain medication uptake.
Methods: Solubility phase diagrams of ISN in the presence of M-β-CD were studied. According to this diagrams, molar ratios of inclusion complexes were determined and formulated by freeze drying (FD) and spray drying (SD) techniques. ISN/M-β-CD complexes were characterized by SEM, DSC, FT-IR, 1H-NMR and HPLC analyses. In situ gels were formulated with the selected inclusion complexes and thermosensitive polymers. Gels prepared by cold method were characterized for gelation temperature, gelling capacity, swelling test and rheological behaviour.
Results: AL-type dissolution phase diagrams were obtained. Complexes were prepared in a 1:1 molar ratio by SD and FD methods. With the prepared complexes, the ISN solubility was increased between 5 and 7.5 times. ISN/M-β-CD complexes formulated by FD method appeared in a typical morphology with a soft and fluffy structure while complexes formulated by SD method had a spherical shape with smooth surfaces. DSC, FT-IR and 1H-NMR analyses were confirmed the ISN inclusion into the M-β-CD cavity. Complexes prepared by SD method were selected for in situ gel formulation. After the required amount of polymer was found by testing, in situ gel systems were prepared by cold method using Pluronic® F127 and HPMC. In situ gel systems have been characterized in terms of rheological properties, etc. as stated above. The rapid gel formation of the formulations at 37°C and the long-term stability of the gel are indicative of its controlled release ability. In the evaluation of gelling capacity, it was determined that gelation occurred immediately and remained for a long time. The release values obtained as a result of the in vitro release study were evaluated in terms of kinetics and it was determined that it showed release behaviour in accordance with the Peppas-Sahlin model.
Conclusion: As a result, the solubility properties were increased by the formation of inclusion complexes and the duration of stay in the vagina and ISN release were extended by loading the complexes into in situ gels. Thus, it is thought that with less frequent and easier application (due to its sol-gel nature), patient compliance is increased and by improving the solubility properties of the active substance, vaginal drug delivery systems that can provide efficacy at low doses have been developed.
