In situ gelling and mucoadhesive liquid suppository containing acetaminophen: enhanced bioavailability

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Abstract

Solutions of poloxamers and bioadhesive polymers were previously reported to undergo a phase transition to bioadhesive gels at body temperature. For the development of a convenient acetaminophen-loaded liquid suppository which gels in situ after rectal administration, we studied the release and pharmacokinetics of acetaminophen delivered by the liquid suppository systems composed of poloxamer P 188, P 407 and a bioadhesive polymer, polycarbophil. The release of acetaminophen was differently affected by the components of liquid suppository such as P 188 and polycarbophil. P 188 showed little effect on the release rates of acetaminophen from liquid suppositories. However, polycarbophil significantly delayed the release kinetics of acetaminophen from a certain concentration due to strong gel strength and bioadhesive force. The release rates of acetaminophen did not significantly differ between no polycarbophil and 0.2% polycarbophil-loaded suppositories, while they began to decrease as the concentrations of polycarbophil increased higher than 0.4%. The analysis of release mechanism showed that the release of acetaminophen was proportional to the square root of time, indicating that acetaminophen might be released from the suppositories by Fickian diffusion. Liquid suppository A [P 407/P 188/polycarbophil/acetaminophen (15:19:0.8:2.5%)], which was strongly gelled and mucoadhesive in the rectum, showed more sustained acetaminophen release profile than did other suppositories and gave the most prolonged plasma levels of acetaminophen in vivo. Liquid suppository A also showed higher bioavailibility of acetaminophen than did the conventional formulation. Moreover, liquid suppository A did not cause any morphological damage to the rectal tissues and remained stable for at least 6 month during storage. These results suggest that mucoadhesive and in situ gelling liquid suppository could be a more effective and convenient rectal delivery system of acetaminophen.

Introduction

Suppositories have been favorable dosage forms for infants, children and unconscious patients. Ideal suppository should be easy to administer without any pain during insertion and remain at the administered sites to avoid the first pass effect in the liver and the gastrointestinal tracts. However, conventional suppositories are solid dosage forms which melt or soften in the rectum. Such solid form suppositories can give a feeling of alien, discomfort and refusal to the patients, possibly lowering patient compliance. Furthermore, solid type suppository which might reach the end of the colon, may also allow the carried drugs to undergo the first-pass effect (Huang et al., 1987).

To solve the problems of conventional solid suppositories, there have been several attempts to develop suppositories which exist as liquid in vitro but gel in vivo, by modulating the gelation temperatures of poloxamer solutions (Schmolka, 1973, Holsman et al., 1984, Blackman and Ralske, 1989). Recent report showed that mucoadhesive liquid suppositories composed of poloxamers and bioadhesive polymers could not only gel at 30–36°C, but also remain in the rectum without leakage after administration (Choi et al., 1998). However, the previous studies focused on modulating the physicochemical properties of liquid suppositories and there has been lack of information on the release and absorption of drugs from the suppositories. Thus, in this study, we investigated the release and pharmacokinetic profiles of acetaminophen from the liquid suppositories. Furthermore, we evaluated the rectal tissue irritation of the liquid suppository and the stability of acetaminophen in the suppository during storage. Our results indicate that the poloxamer-based mucoadhesive liquid suppository can improve the bioavailability of acetaminophen with good safety and stability.

Section snippets

Materials

Poloxamers (P 407, P 188) were purchased from BASF (Ludwigshafen, Germany). Polycarbophil was from BF Goodrich (Brecksville, OH). Acetaminophen was of USP grade. Tetrabutylammonium dihydrogen phosphate, phosphoric acid and potassium dihydrogen phosphate were supplied from Junsei Chemical Co (Tokyo, Japan). Acetonitrile and methanol were from Aldrich Chemical Co (Milwaukee, WI). Semipermeable membrane tube (Spectra membrane tubing No. 1) was from Spectrum Medical Industries Inc. (Los Angeles,

Release of acetaminophen from liquid suppository

To test whether P 188 or polycarbophil affects the release rates of acetaminophen from the liquid suppositories, we performed the release test with the formulations composed of constant amount of P 407 (15%) and variable amounts of P 188 (15–20%) and polycarbophil (0–0.8%) as shown in Table 1. It was reported that the liquid suppositories composed of P 407/P 188 (15:15%–15:20%) had the gelation temperatures (30–36°C) suitable for acetaminophen liquid suppository (Choi et al., 1998). Also, it

Conclusion

Taken together, it is concluded that liquid suppository A, [P 407/P 188/polycarbophil/acetaminophen (15:19:0.8:2.5%)], which remained at the administered sites due to strong gel strength and mucoadhesive force, could enhance the bioavailability of acetaminophen without first-pass effect and without damaging the rectum. Furthermore, the desirable physicochemical properties such as in situ gelling property, suitable gel strength and bioadhesive force of the liquid type suppository, could

Acknowledgements

This research is partly supported by the grant from the Research Institute of Pharmaceutical Sciences in College of Pharmacy, Seoul National University.

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