Pharmaceutical Sciences, PharmaTherapeutics, Pfizer Global R&D, Groton, Connecticut 06340, USA.
Pharm Res. 2011 Jul;28(7):1531-9. doi: 10.1007/s11095-011-0386-9. Epub 2011 Feb 18.
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.
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.
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®.
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.
空腹服用时，市售的阿奇霉素明胶胶囊（商品名：希舒美）与市售的阿奇霉素片剂（商品名：希舒美）具有生物等效性。而当在进食状态下服用时，胶囊的生物利用度降低，而片剂则不受影响。这种明胶胶囊的负面食物效应此前被认为是由于胶囊在进食胃中缓慢和/或延迟崩解，导致药物长时间暴露于胃酸中，从而导致去克拉定糖阿奇霉素（DCA）降解。为了消除食物效应，阿奇霉素明胶胶囊中添加了“超级崩解剂”以提供快速溶解的胶囊，并使用羟丙甲纤维素（HPMC）胶囊壳替代明胶胶囊壳。
健康志愿者在空腹和进食条件下服用这些剂型，并评估药代动力学。还评估了 HPMC 胶囊受试者的 DCA 药代动力学。评估了含有食物的介质中阿奇霉素 HPMC 胶囊的体外崩解情况，并与市售片剂和市售明胶胶囊进行了比较。
当两种快速溶解胶囊制剂给进食受试者服用时，阿奇霉素 AUC 分别比空腹状态下给药时低 38.9%和 52.1%。当 HPMC 胶囊给进食受试者服用时，阿奇霉素 AUC 比空腹状态下给药时低 65.5%。对于 HPMC 胶囊，空腹状态到进食状态下阿奇霉素 AUC 的绝对下降（以摩尔为基础）与 DCA AUC 的增加相似。体外胶囊崩解研究表明，在含有液体食物（如牛奶和 Ensure®）的介质中，商业阿奇霉素明胶胶囊和 HPMC 胶囊的崩解时间延长。
阿奇霉素明胶和 HPMC 胶囊与食物相互作用导致体外崩解缓慢，体内生物利用度降低。同时测量血清阿奇霉素和酸降解产物 DCA 表明，在进食状态下阿奇霉素生物利用度的降低主要（可能完全）是由于胃酸降解为 DCA 所致。胶囊可为几乎所有药物提供一种有用且优雅的剂型，但对于像阿奇霉素这样易酸不稳定的药物，可能会产生负面的食物效应。
