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.

Cyclic RGD-Decorated Liposomal Gossypol AT-101 Targeting for Enhanced Antitumor Effect

“…The body weight loss of the mice may indicate the potential systemic toxicity and adverse effects of the drug. 2 , 39 As shown in Figure 9D , within the dose schedule adopted for each group in this study, no significant change in the body weight was observed throughout the experiment. Among the five groups, the free (-)-gossypol group showed the largest body weight loss of 4.36% at the end of the experiment, as compared with the average body weight on day 1, which may indicate slight systemic toxicity of the orally administered free drug.…”

“…Hypokalemia is a major adverse effect of gossypol (including its racemate and (-)-gossypol) that may happen after repeated/long-term treatments, which is related to the impacts of the drug on the renal tubules. 2 Therefore, monitoring the plasma K + level is a need for the safety of repeated/long-term use of gossypol. In this study, cRGD peptide with high affinity to α v β 3 integrin was incorporated into the liposome for enhanced tumor-targeted delivery of (-)-gossypol.…”

“…The dry residue was dissolved using acetonitrile and filtered through a 0.22 μm membrane, followed by the determination of the (-)-gossypol amount via high-performance liquid chromatography (HPLC). 2 The HPLC analysis was conducted at 26 °C on a 1260 Infinity II HPLC system (Agilent Technologies, Inc., USA) which was equipped with a C18 reversed-phase column (5 μm particle size, 4.6 × 250 mm) and a G7114A variable wavelength detector. Each sample (20 μL) was separated using acetonitrile-0.9% formic acid solution (77:23, v/v) as the mobile phase (0.8 mL/min), and was detected at 254 nm wavelength.…”

“…The plasma K + concentration was determined on an AU5800 biochemistry analyzer (Beckman Coulter, USA), using the matched reagent and calibration solution for the equipment. 2 , 35 …”

“…In the past few years, it was reported to show notable anticancer effects, along with antivirus, antiparasitic, and antioxidant properties. 1 , 2 More recent studies found that it is the (-)-enantiomer of gossypol ( Figure 1A ), namely (-)-gossypol (also known as AT-101), rather than (+)-gossypol or the racemic gossypol that has significant anticancer properties. 1 , 3 In this situation, it is necessary to develop single-isomer drug preparations to reduce the ineffective substance to patients and avoid potential adverse/side effects.…”