title: Effects of food on a gastrically degraded drug: azithromycin fast-dissolving gelatin capsules and HPMC capsules.
abstract: OBJECTIVE
  Commercial azithromycin gelatin capsules (Zithromax®) are known to be bioequivalent to commercial azithromycin tablets (Zithromax®) when dosed in the fasted state. These capsules exhibit a reduced bioavailability when dosed in the fed state, while tablets do not. This gelatin capsule negative food effect was previously proposed to be due to slow and/or delayed capsule disintegration in the fed stomach, resulting in extended exposure of the drug to gastric acid, leading to degradation to des-cladinose-azithromycin (DCA). Azithromycin gelatin capsules were formulated with "superdisintegrants" to provide fast-dissolving capsules, and HPMC capsule shells were substituted for gelatin capsule shells, in an effort to eliminate the food effect.
  
  
  METHODS
  Healthy volunteers were dosed with these dosage forms under fasted and fed conditions; pharmacokinetics were evaluated. DCA pharmacokinetics were also evaluated for the HPMC capsule subjects. In vitro disintegration of azithromycin HPMC capsules in media containing food was evaluated and compared with commercial tablets and commercial gelatin capsules.
  
  
  RESULTS
  When the two fast-dissolving capsule formulations were dosed to fed subjects, the azithromycin AUC was 38.9% and 52.1% lower than after fasted-state dosing. When HPMC capsules were dosed to fed subjects, the azithromycin AUC was 65.5% lower than after fasted-state dosing. For HPMC capsules, the absolute fasting-state to fed-state decrease in azithromycin AUC (on a molar basis) was similar to the increase in DCA AUC. In vitro capsule disintegration studies revealed extended disintegration times for commercial azithromycin gelatin capsules and HPMC capsules in media containing the liquid foods milk and Ensure®.
  
  
  CONCLUSIONS
  Interaction of azithromycin gelatin and HPMC capsules with food results in slowed disintegration in vitro and decreased bioavailability in vivo. Concurrent measurement of serum azithromycin and the acid-degradation product DCA demonstrates that the loss of azithromycin bioavailability in the fed state is largely (and probably entirely) due to gastric degradation to DCA. Capsules can provide a useful and elegant dosage form for almost all drugs, but may result in a negative food effect for drugs as acid-labile as azithromycin.
authors.affiliation: Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, Groton, Connecticut 06340, USA. williamcuratolo@bayberryinstitute.com
authors.forename: William
authors.initials: W
authors.lastname: Curatolo
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Johnson
authors.forename: Angela
authors.initials: A
authors.lastname: Hausberger
authors.forename: Ernest
authors.initials: E
authors.lastname: Quan
authors.forename: Thomas
authors.initials: T
authors.lastname: Vendola
authors.forename: Neha
authors.initials: N
authors.lastname: Vatsaraj
authors.forename: George
authors.initials: G
authors.lastname: Foulds
authors.forename: John
authors.initials: J
authors.lastname: Vincent
authors.forename: Richa
authors.initials: R
authors.lastname: Chandra
mesh_terms: D000284:Administration, Oral; D017963:Azithromycin / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry*; D001682:Biological Availability; D002214:Capsules / Q000737:chemistry*; D018592:Cross-Over Studies; D005502:Food; D005744:Gastric Acid / Q000737:chemistry*; D005780:Gelatin / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D065347:Hypromellose Derivatives; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D015394:Molecular Structure
chemical_list: D002214:Capsules; D065347:Hypromellose Derivatives; D017963:Azithromycin; D005780:Gelatin; D008747:Methylcellulose