Evaluation of Epirubicin in Thermogelling and Bioadhesive Liquid and Solid Suppository Formulations for Rectal Administration

Yu-Li Lo,Yijun Lin,Hong-Ru Lin

doi:10.3390/ijms15010342

Abstract

Temperature sensitive Pluronic (Plu) and pH-sensitive polyacrylic acid (PAA) were successfully mixed in different ratios to form in situ gelling formulations for colon cancer therapy. The major formulations were prepared as the liquid and solid suppository dosage forms. Epirubicin (Epi) was chosen as a model anticancer drug. In vitro characterization and in vivo pharmacokinetics and therapeutic efficacy of Epi in six Plu/PAA formulations were evaluated. Our in vitro data indicate that Epi in Plu 14%/PAA 0.75% of both solid and liquid suppositories possess significant cytotoxicity, strong bioadhesive force, long-term appropriate suppository base, sustained release, and high accumulation of Epi in rat rectums. These solid and liquid suppositories were retained in the upper rectum of Sprague-Dawley (SD) rats for at least 12 h. An in vivo pharmacokinetic study using SD rats showed that after rectal administration of solid and liquid suppositories, Epi had greater area under the curve and higher relative bioavailability than in a rectal solution. These solid and liquid suppositories exhibited remarkable inhibition on the tumor growth of CT26 bearing Balb/c mice in vivo. Our findings suggest that in situ thermogelling and mucoadhesive suppositories demonstrate a great potential as colon anticancer delivery systems for protracted release of chemotherapeutic agents.

Highlights

Colorectal cancer is the third most lethal cause of cancer death
We developed an in situ gelling liquid suppository formulation, which is composed of Pluronic and polyacrylic acid (PAA) mixture (Table 1), for rectal administration of Epi
We used MTT assay to evaluate the cytotoxic effect of Plu/PAA formulations with various Epi concentrations in the presence of cocoa butter (0.5 g; solid suppository) or absence on growth inhibition of CT26 cells

Summary

Introduction

Colorectal cancer is the third most lethal cause of cancer death. Tumor resection, chemotherapy, and radiotherapy are major treatment types for colorectal cancer. The most common routes for chemotherapy are injection and oral administration. Oral route may have the drawbacks of substantial gastrointestinal (GI) and hepatic first-pass effect [1]. The rectal route for drug administration possesses the advantage of the decreased side effects by avoiding both oral unpleasant taste and reducing GI irritation [3]. For the target-delivery of anti-colon cancer drugs, ideal suppository should possess the mucoadhesive characteristic and remain in the lower rectum for a long period of time to reduce the first pass effect [4]. A non-mucoadhesive solid suppository has the weakness, because such a suppository quickly melts in the rectum, leading to rapid release of the carried drugs to undergo the first-pass effect [5,6]. We designed a cocoa butter-based solid suppository with an enclosed mucoadhesive, pH- and thermo-gelling system for delivering drugs

Results

Discussion

Conclusion