title: Dissolution enhancement and in vitro performance of clarithromycin nanocrystals produced by precipitation-lyophilization-homogenization method.
abstract: The gastroduodenal diseases caused by Helicobacter pylori were commonly treated with antibiotic clarithromycin as a standard regimen. According to the poorly water-soluble of clarithromycin, the nanocrystal formulation was prepared. The aim of this study was to investigate an enhancement effect of clarithromycin nanocrystals produced by precipitation-lyophilization-homogenization (PLH) method on the saturation solubility, dissolution velocity, antibiotic activity, permeability through the gastric mucus and cellular permeability. Poloxamer 407 and sodium lauryl sulfate (SLS) were chosen as combined stabilizers in the nanocrystal system. The obtained clarithromycin nanocrystals were identified as cubic particles by SEM with a bulk population of approximately 400nm existed in crystalline and/or partial amorphous form as investigated by DSC and XRPD. The saturation solubility of the clarithromycin nanocrystals was increased by 1.5- and 6-folds higher than clarithromycin powder in buffer pH 5.0 and 6.8, respectively. The dissolution profiles of clarithromycin nanocrystals at pH 5.0 and 6.8 were significantly different from clarithromycin powder and the marketed product (f1 value >15 and f2 value <50). All dissolution parameters (relative dissolution rate, percent dissolution efficiency and mean dissolution time) showed that clarithromycin nanocrystals had higher dissolution rate when compared with the clarithromycin powder, the lyophilized coarse suspension and the marketed product. The bioassay study by diffusion agar method showed a maintained antibiotic activity of clarithromycin nanocrystals solubilized in buffer solution which was greater potency than the lyophilized coarse suspension and the clarithromycin powder. Additionally, the nanocrystals possessed higher permeability through gastric mucus and cellular monolayer of Caco-2 and NCI-N87 cells as compared to the lyophilized coarse suspension and the clarithromycin powder. The results indicated that, the developed clarithromycin nanocrystals were a potential delivery system that exerts more effectiveness in H. pylori eradication.
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Thailand.
authors.forename: Boontida
authors.initials: B
authors.lastname: Morakul
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Thailand; Center of Excellence in Innovative Drug Delivery and Nanomedicine, Faculty of Pharmacy, Mahidol University, Thailand.
authors.forename: Jiraphong
authors.initials: J
authors.lastname: Suksiriworapong
authors.affiliation: Department of Microbiology, Faculty of Pharmacy, Mahidol University, Thailand.
authors.forename: Mullika Traidej
authors.initials: MT
authors.lastname: Chomnawang
authors.affiliation: Department of Biopharmaceutics and Pharmaceutical Technology, Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Langguth
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Thailand; Center of Excellence in Innovative Drug Delivery and Nanomedicine, Faculty of Pharmacy, Mahidol University, Thailand. Electronic address: varaporn.jun@mahidol.ac.th.
authors.forename: Varaporn Burapacheep
authors.initials: VB
authors.lastname: Junyaprasert
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D011232:Chemical Precipitation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D017291:Clarithromycin / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005612:Freeze Drying / Q000379:methods; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility
chemical_list: D000900:Anti-Bacterial Agents; D017291:Clarithromycin
keywords: Antibiotic activity; Clarithromycin; Dissolution; Nanocrystals; Permeability; Saturation solubility