title: In vitro release--in vivo microbiological and toxicological studies on ketoconazole lipid granules.
abstract: In some multidrug therapy programs, ketoconazole (KTZ) may be administered with some antacids that could modify its dissolution rate and reduce its absorption, thus leading to therapeutic failures. The primary aim of this study was to evaluate the influence of Compritol HD5 ATO and Compritol 888 ATO on this interaction in comparison with commercial KTZ tablets. The second aim was to prepare lipid granules of KTZ that could be an alternative to the commercial formulation. Therefore, six KTZ sustained-release granules were prepared with different lipid concentrations, because they were found to be more suitable than tablets that are dissolved only in gastric medium. The results confirmed that the dissolution rate of KTZ granules was significantly reduced in the presence of antacids. The ideal formulation was selected as granules including 5% of Compritol lipids in relation to the suitability of the target profile. Therapeutic effects of orally administered, ideal KTZ granule formulations, and commercial tablets were evaluated in vivo by the experimental model of murine vulvo-vaginal candidiasis (VVC) with and without antacids. It was found that formulations were very effective on VVC, and the therapeutic effect decreased significantly in the presence of antacids. Histopathological studies were carried out for vagina, stomach, and liver tissues and hepatoxicity was also examined. The levels of reduced glutathione (GSH) were measured to assess the oxidative stress induced by KTZ and function of the liver. It was observed that orally administered formulations of KTZ were successful in treating candidiasis in mice without irritancy in stomach. However, liver tissues were damaged. The decreased GSH levels indicated toxicity in our study. This study suggested that in vitro release and in vivo microbiological-toxicological properties of KTZ were affected by antacids and drug-excipient interactions. Lipid granules of KTZ prepared with Compritol 888 ATO could be proposed as a new KTZ solid dosage form with optimum dissolution and therapeutic characteristics.
authors.affiliation: Department of Pharmaceutical Technology, Faculty of Pharmacy, Ege University, Izmir, Turkey. mine.ozyazici@ege.edu.tr
authors.forename: Mine
authors.initials: M
authors.lastname: Ozyazici
authors.forename: Evren Homan
authors.initials: EH
authors.lastname: Gokce
authors.forename: Ozgen
authors.initials: O
authors.lastname: Ozer
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Ay
authors.forename: Tamer
authors.initials: T
authors.lastname: Guneri
authors.forename: Gokhan
authors.initials: G
authors.lastname: Ertan
authors.forename: Goksel
authors.initials: G
authors.lastname: Gokce
authors.forename: Dilek Yesim
authors.initials: DY
authors.lastname: Metin
authors.forename: Suleyha
authors.initials: S
authors.lastname: Hilmioglu
authors.forename: Guliz
authors.initials: G
authors.lastname: Durmaz
authors.forename: Ayfer
authors.initials: A
authors.lastname: Yalcin
authors.forename: Cetin
authors.initials: C
authors.lastname: Pekcetin
authors.forename: Dogan
authors.initials: D
authors.lastname: Ozyurt
mesh_terms: D000536:Aluminum Hydroxide / Q000008:administration & dosage; D000818:Animals; D000863:Antacids / Q000008:administration & dosage; D000935:Antifungal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D002176:Candida albicans; D002181:Candidiasis, Vulvovaginal / Q000188:drug therapy*; D003692:Delayed-Action Preparations; D004336:Drug Antagonism; D005079:Excipients; D005227:Fatty Acids; D005260:Female; D005978:Glutathione / Q000097:blood; D005990:Glycerol / Q000031:analogs & derivatives*; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D008099:Liver / Q000473:pathology; D008276:Magnesium Hydroxide / Q000008:administration & dosage; D051379:Mice; D011092:Polyethylene Glycols; D013270:Stomach / Q000473:pathology; D013607:Tablets; D014621:Vagina / Q000473:pathology
chemical_list: D000863:Antacids; D000935:Antifungal Agents; D003692:Delayed-Action Preparations; D005079:Excipients; D005227:Fatty Acids; D013607:Tablets; C477262:compritol HD5 ATO; C086409:glyceryl behenate; D011092:Polyethylene Glycols; D000536:Aluminum Hydroxide; D005978:Glutathione; D008276:Magnesium Hydroxide; D005990:Glycerol; D007654:Ketoconazole