Development of In Situ Gelling and Bio Adhesive 5-Fluorouracil Enema

Abstract

In this study, a novel 5-Fluorouracil (5-FU) enema with good bio adhesion and temperature sensitivity was developed using in situ gelling technology. The preparation was formulated as a free-flowing liquid before use, while a layer of gel film was quickly formed when administered in the rectum, with a large contact surface area. It also demonstrated good biocompatibility, appropriate gel strength and bio adhesive force with excellent adhesion to rectal mucosa and prolonged action time, allowing more effective drug absorption and diffusion to surrounding tissues. Poloxamer 407 and poloxamer 188 were applied to adjust the gelling temperature. With the addition of carbopol and polycarbophil (bio adhesive substances), the solubility of 5-FU and gel strength increased, the temperature of gelation and the surface area of drug contact on mucous epithelium decreased. Decreased adhesive force between the preparation and the mucous membrane of the rectum was demonstrated with improving carbopol and polycarbophil’s concentration. In vitro release demonstrated that 5-FU in situ gelling enema with different bases had a rapid and almost complete drug release. We used an optimized formulation of P407/P188/polycarbophil/5-FU (17/2.5/0.2/1.0) for animal experiments. The result showed that the drug evenly covered the surface of the rectum and there was no leakage in 6 hours. The in situ gelling enema showed significantly higher rectal tissue levels of 5-FU compared with suppository and intravenous administration, indicating that 5-FU could be well absorbed due to the enlarged releasing area, longer retention time and larger amount of dissolved active ingredients. Systemically, 5-FU levels in the enema group were similar to those in the suppository group and significantly lower than the intravenous group. The enema was not associated with morphological damage to rectal tissue. These results suggest that the bio adhesive and in situ gelling enema could be a more effective rectal delivery system of 5-FU.

Mucosal Applications of Poloxamer 407-Based Hydrogels: An Overview

“…The sample is gradually heated while being continuously stirred. When the magnetic bar stops moving due to gelation, the temperature displayed on the thermo-sensor is identified as the gelation temperature [ 79 , 90 , 91 ].…”

In situ delivery of thermosensitive gel-mediated 5-fluorouracil microemulsion for the treatment of colorectal cancer

“…Measurement of coverage area: The coverage area was measured using the method described in our previous report. 13 In brief, a section of tissue was taken from the rabbit rectum and secured with the mucosal side facing out on a glass plate and storing at 36.5°C. Liquid gel (1 mL) was administered to the surface of the rabbit rectum, spreading freely until a gel film formed, and the area of the gel coverage was calculated.…”

“…The tissue and plasma samples were treated as described in our previous work. 13 Briefly, the tissue sample was mashed and ground into a homogenate by adding 2 mL of distilled water. After standing for 30 minutes, the precipitate was removed by centrifugation, washed, and filtered with 0.4 mL purified water three times.…”

“…Delivering 5FU directly to the rectal site is considered a promising approach to reduce systemic side effects and provide effective tumor diffusion. 12 , 13 Numerous studies have shown that the colon suppository administration of 5FU appeared to be efficient and showed pharmacokinetics similar to that of intravenous administration, but with decreased systemic side effects and increased rectal tissue drug concentration. 14 – 19 Some animal studies demonstrated that administration of 5FU emulsion in the rectal mucous improved drug accumulation in regional lymph nodes, suggesting that 5FU emulsion therapy might be of potential in treating lymph node metastasis from rectal cancer.…”

“… 15 , 22 In addition, rectal administration of liquid forms often causes anal leakage, leading to inadequate dosing. 13 …”