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Effects of Food on a Gastrically Degraded Drug: Azithromycin Fast-Dissolving Gelatin Capsules and HPMC Capsules

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ABSTRACT

Purpose

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.

Result

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®.

Conclusion

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.

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ACKNOWLEDGMENTS

We gratefully acknowledge the excellent contributions of Mr. Scott Hessong of BAS Analytics. We also gratefully acknowledge the excellent contributions of Dr. Thomas Hunt and colleagues at Pharmaco LSR, Austin, TX, Dr. Charles Halstenson and colleagues at Hennepin County Medical Center, Minneapolis, MN, and Dr. Maria Gutierrez and colleagues at Comprehensive Phase One, Ft. Lauderdale, FL, who carried out the dosing and blood sample collections. We thank Pei-Ti Chang and Paul Bassett of the Pfizer Analytical R&D Department for dissolution data. We gratefully recognize Hylar Friedman and Olatunde Kuye of Pfizer Clinical Pharmacology, and Timothy Hagen of Pfizer Pharmaceutical R&D, for their enthusiastic support of this work.

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Authors and Affiliations

  1. Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, Groton, Connecticut, 06340, USA

    William Curatolo, Barbara A. Johnson, Angela Hausberger, Ernest Quan, Thomas Vendola & Neha Vatsaraj

  2. Clinical Pharmacology, Specialty Care, Pfizer Inc., New London, Connecticut, 06320, USA

    Ping Liu

  3. Clinical Pharmacology, Pfizer Global R&D, Groton, Connecticut, 06340, USA

    George Foulds

  4. Clinical Sciences, Primary Care, Pfizer, Inc., New York, New York, 10017, USA

    John Vincent

  5. Clinical Development, Emerging Markets, Pfizer Inc., New London, Connecticut, 06320, USA

    Richa Chandra

  6. The Bayberry Institute, 39 Oswegatchie Hills Rd., Niantic, Connecticut, 06357, USA

    William Curatolo

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  1. William Curatolo
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  2. Ping Liu
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Correspondence to William Curatolo.

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Curatolo, W., Liu, P., Johnson, B.A. et al. Effects of Food on a Gastrically Degraded Drug: Azithromycin Fast-Dissolving Gelatin Capsules and HPMC Capsules. Pharm Res 28, 1531–1539 (2011). https://doi.org/10.1007/s11095-011-0386-9

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  • DOI: https://doi.org/10.1007/s11095-011-0386-9

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