Effect of hexacosanol on the characteristics of novel sustained-release allopurinol solid lipospheres (SLS): factorial design application and product evaluation.

This investigation involved the evaluation of the effect of hexacosanol (HC, ceryl alcohol), a new hydrophobic wax modifier (WM) in comparison with conventional modifiers, on the development of sustained-release allopurinol (AP) solid lipospheres (SLS) intended for use in a suspension formulation and other oral dosage forms. Various beeswax (BW)/WM blends (composition ratio 1:1) were thus used to prepare SLS by a modified oil-in-water emulsion meltable disperse-phase (MDP) encapsulation method without using organic solvents and the influence of these blends on the drug encapsulation efficiency (EE), size distribution and the time for 50% of the drug to be released (t50%) was investigated. Results indicated that incorporation of HC in wall matrix of SLS provided the means to enhance the EE of AP and to modulate the rate of drug release into dissolution media (simulated gastric fluid (S.G.F.: pH 1.2) and simulated intestinal fluid (S.I.F.: pH 7.4). The effects of the process variables; HC concentration, dispersant (pluronic F-68: PF-68) concentration and drug:wax ratio were also studied on the properties of AP-loaded SLS by a 2(3) factorial design. The EE values were in the range of 80.8-92.67%. The only significant parameter affecting (P<0.01) the size and size distribution of the SLS formulations was the amount of the PF-68, whereas the factor with the biggest influence (P<0.05) on the drug EE was the initial loading of AP (in terms of the drug:wax ratio). The amount of HC blended with wax and the initial drug loading significantly (P<0.01) affected the t50% values of all of the formulations. The release of AP was more extended (t50% values (S.I.F.; pH 7.4)=9.91-25.36 h, depending on the drug:wax ratio) and surface morphology of SLS was improved with higher HC content (15%, w/w) formulations. The release patterns fitted the Baker-Lonsdale dissolution kinetics for spherical matrices. A significant decrease of plasma uric acid levels (P<0.05) and hepatic impairment in male rats was observed after oral administration of a SLS (mean size: 120 microm) suspensions of the optimum formulation, compared to suspensions of pure AP.

Novel B melatonin-loaded chitosan microcapsules: in vitro characterization and antiapoptosis efficacy for aflatoxin B1-induced apoptosis in rat liver.

The aim of this study was to prepare buoyant (B) melatonin (MT)-loaded chitosan microcapsules having favourable sustained release characteristics (in simulated gastric fluid (SGF), pH 1.2) in comparison with non-buoyant (NB) chitosan particles. The new buoyant microcapsules were prepared by the ionotropic gelation method using sodium lauryl sulfate (NaLS) for coagulation. The microcapsule characteristics were affected by the initial drug and NaLS concentrations, as well as the presence of sodium dioctyl sulfosuccinate (DOS) or pectin with NaLS in the external phase. In general, spherical microcapsules with 36.90-56.23% encapsulation efficiencies, hollow core and satisfactory release properties were produced. The best sustained release profiles (t(50%): 5h) with near zero-order kinetics were observed with the higher theoretical payload microcapsules prepared with both NaLS and DOS in a 1:2 ratio. In vivo studies were also carried out to exploit the protective effect of the MT-loaded NaLS-DOS microcapsules against aflatoxin B1 (AFB1)-induced toxicity (liver apoptosis) in male rats. The results implied that apoptotic rate was significantly reduced when MT or its microcapsules formulation was co-administered with AFB1. The levels of the oxidative stress indices (malondialdehyde (MDA), a lipid peroxidation product and nitric oxide (NO)) in liver tissues were significantly reduced, while the levels of the hepatic antioxidants (glutathione (GSH) and zinc (Zn), as well as the enzyme activities of glutathione reductase (GR), glutathione peroxidase (GSPx) and glutathione-S-transferase (GST)) which act as antiapoptosis were significantly increased as compared to AFB1 group (without MT). MT microcapsules appeared more effective in reduction of apoptotic rate than free MT as indicated by the decline of caspase-3 activities (an apoptotic marker) and confirmed by histopathology.

Aflatoxin B1 induces apoptosis in rat liver: protective effect of melatonin.

OBJECTIVES: A study of liver apoptosis after aflatoxin B1 (AFB1) administration and the effect of melatonin (MEL) was investigated in male rats. METHODS: Five groups of 15 rats each were used: controls, MEL Soln-treated rats (MEL dose,5 mg/Kg body wt), AFB1-treated rats (50 microg/Kg body wt), MEL Soln+AFB1-treated rats, and MEL micro-capsules (MEL-MC)+ AFB1-treated rats. After 8 weeks of treatment, biochemical measurements in liver homogenates and histopathological examination of liver sections of different groups using light and transmission electron microscope were done. The caspase-3 enzyme activity, apoptotic marker, was determined in liver tissues. Because hepatic antioxidants represent the major defence against toxic liver injury, and they act as anti-apoptosis. So, the levels of glutathione (GSH) and zinc (Zn) and the enzyme activities of glutathione reductase (GR), glutathione peroxidase (GSPx) and glutathione-S-transferase (GST) were determined. In addition, the levels of malondialdehyde (MDA), a lipid peroxidation product, and nitric oxide (NO) levels were measured. RESULTS: The levels of caspase-3 activities in AFB1 group were significantly higher than control group. The apoptosis was associated with degenerative and necrotic changes in the hepatocytes. Concomitantly, the levels of MDA and NO in liver tissues were significantly increased while the levels of GSH, Zn and enzyme activities of GSPx and GR in liver tissues were significantly decreased in AFB1 group compared to their levels in controls. Caspase-3 activity was positively correlated with MDA while negatively correlated with GSH, GSPx and GR in rat livers treated with AFB1. The apoptotic rate was significantly reduced when MEL co-administrated with AFB1. In rats which received MEL with AFB1, the levels of MDA and NO in liver tissues were significantly reduced while GSH and Zn levels and GSPx, GR and GST activities were significantly increased compared to AFB1 group. When MEL-MC co-administrated with AFB1 appeared more effective in reduction of apoptotic rate as detected by decline of caspase-3 activities (inhibition 66.82%) and confirmed by histopathology. CONCLUSION: AFB1 can lead to direct or indirect caspase-3 activation and consequently to apoptosis in rat liver. MEL treatment of rats could enhance hepatic antioxidant/detoxification system which consequently reduce the apoptotic rate and the necrobiotic changes in the liver. MEL-MC exhibited an efficient protective effect against AFB1. Thus, clinical application of MEL as therapy should be considered in cases of aflatoxicosis.