Gastric floating tablet improves the bioavailability and reduces the hypokalemia effect of gossypol in vivo

Abstract

Gossypol (Gos) is a natural polyphenolic compound that has shown a number of valuable biological properties such as antifertility, antioxidation, and antitumor activities. However, the clinical application of Gos has been hindered by its notable adverse effects such as hypokalemia, hemolytic anemia, and so on. Using sustained-release dosage form provides a hopeful solution to this problem. In this study, a gastric floating tablet for sustained-release of Gos (Gos-GFT) was developed using polyvinylpyrrolidone, hydroxypropyl methyl cellulose, ethyl cellulose, lactose, sodium bicarbonate, and magnesium stearate. Gos-GFT had an average weight of around 200 mg with a drug content percentage of around 13.66%. The physicochemical properties of Gos-GFT satisfied the pharmacopoeial requirements for tablets. Gos-GFT was able to float in an acidic medium and had a sustained drug release for over 12 h. In vivo studies showed that the relative bioavailability of Gos-GFT, as compared with Gos powders, was larger than that of a non-gastric floating tablet which was a dosage form used for comparison with Gos-GFT. Furthermore, compared with the Gos powders and the non-gastric floating Gos tablets, Gos-GFT could prolong the in vivo action time of Gos, and significantly relieve hypokalemia which is a major adverse effect of Gos. These properties made Gos-GFT a promising Gos preparation that warrants further investigation for more extensive clinical applications of this natural compound.

Keywords: Adverse effect; Bioavailability; Gastric floating tablet; Gossypol; Pharmacokinetics; Sustained release.

Fig. 1

Schematic illustration for the preparation of Gos-GFT.

Fig. 2

(A) Floating lag time and (B) floating duration of Gos-GFTs with different formulations (#1–9) in the acidic medium. Data were shown as mean ± SD (n = 5). (C) The time that different Gos-GFTs (#1–9) needed to almost complete (over 95%) the release of the drug. Data were shown as mean ± SD (n = 3).

Fig. 3

Profiles of the (A) cumulative drug release, (B) swelling, and (C) erosion of Gos-GFT. Data were exhibited as mean ± SD (n = 3).

Fig. 4

The plasma drug concentration of Gos powder group, plain tablet group, and Gos-GFT group at the same dose of Gos. Data were exhibited as mean ± SD (n = 6). Compared to the other two groups, Gos-GFT could considerably prolong the residence time of Gos in vivo.

Fig. 5

Changes in the plasma potassium concentration of each group. The rabbits (with similar initial body weights of around 2.2 kg) were treated with 27.5 mg Gos powder, one plain Gos tablet (containing about 27.5 mg Gos), or one Gos-GFT (containing about 27.5 mg Gos), once every two days. Data were exhibited as mean ± SD (n = 6). ^**P < 0.01, as compared with Gos powder group.

Fig. 6

Changes in the body weight of different groups. The larger body weight increment of Gos-GFT group may reflect fewer adverse effects of Gos-GFT in vivo.