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

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.

Physiological and Pharmaceutical Considerations for Rectal Drug Formulations

“…One of the main advancements in conventional rectal dosage forms is the development of liquid suppositories, which more closely resemble semi-solid dosage forms rather than solid dosage forms. This includes the development of liquid suppositories containing thermosensitive polymers (Miyazaki et al, 1998; Fakhar Ud and Khan, 2019), mucoadhesive polymers (Koffi et al, 2008; Ye et al, 2016; Xu et al, 2017; Shi et al, 2019), or a combination of thermosensitive and mucoadhesive polymers (Choi et al, 1998; Yun et al, 1999; Ryu et al, 1999; Koffi et al, 2008; Barakat, 2009; Lo et al, 2013; Liu et al, 2018; Akl et al, 2019). Poloxamers are the most commonly used thermosensitive polymers in pharmaceutical formulation.…”

“…In addition, there are an increasing number of studies investigating the potential of rectal drug delivery for the treatment of more chronic conditions, including diabetes (Matsumoto et al, 2017; Shi et al, 2019), infections (das Neves et al, 2013; Ham and Buckheit, 2017; Nunes et al, 2018), hypertension (Abou el Ela Ael et al, 2016), asthma (Shiohira et al, 2009), chronic anal fissure (Ivanova et al, 2019), and cancer (Lo et al, 2013; Seo et al, 2013; Ye et al, 2016; Din et al, 2017). Although encouraging results were reported in these studies, with many designed for sustained release activity, they generally did not evaluate the formulations over a long study period.…”

Recent Advances in the Development of In Situ Gelling Drug Delivery Systems for Non-Parenteral Administration Routes

“…Lo et al [ 88 ] developed an in situ gelling formulations based on a mixture of a thermo-sensitive poloxamer (F127) and a pH-sensitive polyacrylic acid (PAA) for colon cancer therapy. In particular, liquid and solid dosage forms were developed.…”

Achievements in Thermosensitive Gelling Systems for Rectal Administration

“…Based on these results, the thermosensitive liquid suppositories consisting of 0.25% DCT, 15% P188, 11% P407 and 10% Tween 80, were optimal and exhibited the following gel properties: mucoadhesive force 2.110 dyne/cm 2 , gel temperature 33.0 °C, and gelation time 7.5 min [ 103 ]. Thermosensitive liquid suppository has also been prepared with epirubicin (Epi), an amphiphilic anthracycline anticancer drug [ 104 , 105 ]. This formulation has been developed with temperature-sensitive P407 and pH-sensitive polyacrylic acid (PAA) at different ratios.…”