Bentonite as a water-insoluble amorphous solid dispersion matrix for enhancing oral bioavailability of poorly water-soluble drugs.

Bentonite (BT), an orally administrable natural clay, is widely used for medical and pharmaceutical purposes due to its unique properties, including swelling, adsorption and ion-exchange. However, its application as a matrix of amorphous solid dispersion (ASD) formulations is rarely reported, despite the fact that drugs can adsorb to BT in an amorphous state. The objective of this study was to explore the feasibility of BT as a water-insoluble ASD matrix for enhancing the oral bioavailability of poorly water-soluble drugs, including sorafenib (SF). We prepared a novel BT-based ASD of an SF-BT composite (SFBTC) by adsorbing SF onto BT under acidic conditions using the ionic interaction between cationic SF and negatively charged BT. Scanning electron microscopy (SEM), powder X-ray diffractometry (pXRD), and differential scanning calorimetry (DSC) analyses revealed that SF adsorbed to BT in an amorphous state at SF:BT ratios from 1:3 to 1:10. In pharmacokinetic studies in rats, SFBTC (1:3) significantly improved the oral bioavailability of SF, and the AUClast of SFBTC (1:3) was 3.3-fold higher than that of NEXAVAR®, a commercial product of SF. An in vitro release study under sink conditions revealed that SFBTC (1:3) completely released SF in a pH-dependent manner, while a nonsink condition study indicated the generation of supersaturation under intestinal pH conditions. A kinetic solubility study showed that the release of SFBTC (1:3) followed the diffusion-controlled mechanism, which is a typical characteristic of water-insoluble matrix-based ASDs. The pharmacokinetic studies of drug-BT composites of various drugs belonging to BCS class II indicated that the pKa value of the adsorbed drugs is one of the most important factors determining their dissolution and oral bioavailability. These results suggest that BT could be a promising water-insoluble ASD matrix for improving the oral bioavailability of poorly water-soluble drugs, including SF.

Effect of phosphatidylcholine in bentonite-quetiapine complex on enhancing drug release and oral bioavailability.

Bentonite (BT) is a biocompatible clay mineral that has advantageous properties as a pharmaceutical excipient. However, the application of BT in controlled-release oral formulations has been challenging due to incomplete drug release from BT-drug complexes. The objective of this study was to investigate the effect of modifying BT with zwitterionic phosphatidylcholine (PC) to enhance the dissolution of drugs, thereby increasing their oral bioavailability. Quetiapine (QTP) was chosen as a model drug, and the composition of the complex (BT-PC-QTP) was optimized to have the maximum QTP content and increase the total amount of QTP released. The in vitro release study showed that the incorporation of an appropriate amount of PC into BT improved the low release rate of the BT-QTP complex at pH 7.4, while the pH-dependent release property of BT was maintained. In an in vivo pharmacokinetic study in rats, the oral administration of the BT-PC-QTP complex showed significantly higher Cmax and AUC values than the BT-QTP complex. Moreover, BT-PC-QTP showed a 2.4-fold enhancement of oral bioavailability compared to the QTP powder group. The scanning electron microscopy (SEM), powder X-ray diffraction (pXRD), and differential scanning calorimetry (DSC) studies confirmed that the intercalation of PC and QTP into BT resulted in the adsorption of QTP in an amorphous state. The characterization of the nanoparticles generated from the BT-PC-QTP complex supported that PC enhanced the dissolution of QTP by forming nanosized PC particles. Taken together, the modification of BT with PC can be applied in pharmaceutical industry as a platform strategy to control the release of the BT-drug complex and enhance the oral bioavailability of poorly water-soluble drugs.

Development of an oral bentonite-based modified-release freeze-dried powder of vactosertib: Pharmacokinetics and anti-colitis activity in rodent models of ulcerative colitis.

Vactosertib is a novel inhibitor of transforming growth factor-ß signaling. Clinical applications of vactosertib have been challenging since conventional oral formulations such as immediate-release tablets demonstrate a rapid rise and fast decline in plasma concentrations. In this study, a novel bentonite-based, modified-release, freeze-dried powder of vactosertib was developed and evaluated to determine its potential in the treatment of ulcerative colitis. The formulation released vactosertib slowly and steadily in an in vitro drug release test. The extent of vactosertib released from the formulation was markedly low (18.0%) at pH 1.2 but considerably high (95.6%) at pH 7.4. Compared with vactosertib oral solution, the formulation demonstrated a 52.5% lower mean maximum concentration of vactosertib and three times longer median time to maximum concentration without a significant change in the extent of vactosertib absorption in a rodent colitis model. Furthermore, colitis mice administered with this formulation showed a significant reduction in the total histopathological score by 30% compared with those administered with the positive control, whereas the administration of vactosertib oral solution resulted in only a 10% reduction. Collectively, this novel formulation resolved the pharmacokinetic drawbacks of vactosertib and is expected to enhance its therapeutic effect by delivering vactosertib to the colitis lesions in the lower gastrointestinal tract.

Can Aminoglycosides Be Used as a New Treatment for Helicobacter pylori? In vitro Activity of Recently Isolated Helicobacter pylori.

BACKGROUND: Smectite can serve as a drug delivery system and gentamicin-intercalated smectite hybrids are expected to supersede the standard therapy for Helicobacter pylori eradication. The aim of this study was to confirm whether the minimum inhibitory concentration (MIC) of aminoglycosides applied as smectite hybrids remained low against recently isolated H. pylori strains. MATERIALS AND METHODS: A total of 140 strains were collected for a minimum period of 3 years. Antimicrobial susceptibility tests were performed, and the MICs of eight antibiotics (amoxicillin, clarithromycin, metronidazole, tetracycline, levofloxacin, gentamicin, netilmicin, and tobramycin) were determined by using the Epsilometer test and following the European Committee on Antimicrobial Susceptibility Testing recommendations. RESULTS: The resistance rate of clarithromycin was high, up to 30.7%, although it is a major antimicrobial agent used in standard therapy. The MIC50 and MIC90 of gentamicin (0.25 mg/L and 0.75 mg/L) and netilmicin (0.19 mg/L and 0.75 mg/L) were lower than other alternative therapies for H. pylori eradication. In clarithromycin-resistant strains, the MIC50 was 0.25 mg/L and the MIC90 was 1 mg/L for gentamicin; for netilmicin, the values were 0.25 mg/L and 0.75 mg/L, respectively. CONCLUSION: Through the use of gentamicin and netilmicin, which have low MICs for H. pylori, aminoglycoside-intercalated smectite hybrids are expected to emerge as a new standard therapy for H. pylori eradication.

Peptide Nucleic Acid Probe-Based Analysis as a New Detection Method for Clarithromycin Resistance in Helicobacter pylori.

Background/Aims: Helicobacter pylori eradication rates are decreasing because of increases in clarithromycin resistance. Thus, finding an easy and accurate method of detecting clarithromycin resistance is important. Methods: We evaluated 70 H. pylori isolates from Korean patients. Dual-labeled peptide nucleic acid (PNA) probes were designed to detect resistance associated with point mutations in 23S ribosomal ribonucleic acid gene domain V (A2142G, A2143G, and T2182C). Data were analyzed by probe-based fluorescence melting curve analysis based on probe-target dissociation temperatures and compared with Sanger sequencing. Results: Among 70 H. pylori isolates, 0, 16, and 58 isolates contained A2142G, A2143G, and T2182C mutations, respectively. PNA probe-based analysis exhibited 100.0% positive predictive values for A2142G and A2143G and a 98.3% positive predictive value for T2182C. PNA probe-based analysis results correlated with 98.6% of Sanger sequencing results (κ-value=0.990; standard error, 0.010). Conclusions: H. pylori clarithromycin resistance can be easily and accurately assessed by dual-labeled PNA probe-based melting curve analysis if probes are used based on the appropriate resistance-related mutations. This method is fast, simple, accurate, and adaptable for clinical samples. It may help clinicians choose a precise eradication regimen.

Gentamicin-intercalated smectite as a new therapeutic option for Helicobacter pylori eradication.

Objectives: Novel antibacterial strategies against Helicobacter pylori are needed because H. pylori strains are acquiring resistance to antibiotics. We evaluated the efficacy of gentamicin-intercalated smectite hybrid (S-GEN)-based treatment regimens in a murine model of H. pylori infection. Methods: Two groups of 10 rats were administered either smectite or S-GEN to measure coverage of the gastric mucosa. To evaluate anti-H. pylori efficacy, mice were divided into eight groups of 10 mice each given different treatments, and H. pylori eradication was assessed by a Campylobacter-like organism (CLO) test and H. pylori PCR of the gastric mucosa, and H. pylori antigen and H. pylori PCR analysis of mouse faeces. The levels of proinflammatory cytokines were examined. Results: S-GEN was retained in the gastric mucosal layer with a >60% distribution ratio for up to 1 h, and the S-GEN-based triple regimen decreased bacterial burden in vivo compared with that of untreated mice or mice treated with other regimens. The cure rates in the CLO test and H. pylori PCR from gastric mucosa were 70%, 60%, 80%, 50%, 60% and 60% in Groups III-VIII, respectively. Those for H. pylori PCR in the faeces of mice were 90% and 100% in Group III with standard therapy and Group V with triple therapy including S-GEN, respectively. S-GEN triple therapy also reduced the levels of proinflammatory cytokines. Conclusions: These results suggest that S-GEN is a promising and effective therapeutic agent for the treatment of H. pylori infection.

Effects of Nonalcoholic Fatty Liver Disease on Hepatic CYP2B1 and in Vivo Bupropion Disposition in Rats Fed a High-Fat or Methionine/Choline-Deficient Diet.

Nonalcoholic fatty liver disease (NAFLD) refers to hepatic pathologies, including simple fatty liver (SFL), nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, that may progress to hepatocellular carcinoma. These liver disease states may affect the activity and expression levels of drug-metabolizing enzymes, potentially resulting in an alteration in the pharmacokinetics, therapeutic efficacy, and safety of drugs. This study investigated the hepatic cytochrome P450 (CYP) 2B1-modulating effect of a specific NAFLD state in dietary rat models. Sprague-Dawley rats were given a methionine/choline-deficient (MCD) or high-fat (HF) diet to induce NASH and SFL, respectively. The induction of these disease states was confirmed by plasma chemistry and liver histological analysis. Both the protein and mRNA levels of hepatic CYP2B1 were considerably reduced in MCD diet-fed rats; however, they were similar between the HF diet-fed and control rats. Consistently, the enzyme-kinetic and pharmacokinetic parameters for CYP2B1-mediated bupropion metabolism were considerably reduced in MCD diet-fed rats; however, they were also similar between the HF diet-fed and control rats. These results may promote a better understanding of the influence of NAFLD on CYP2B1-mediated metabolism, which could have important implications for the safety and pharmacokinetics of drug substrates for the CYP2B subfamily in patients with NAFLD.

Effects of properties of metal-contaminated soils on bacterial bioluminescence activity, seed germination, and root and shoot growth.

This study examined the effects of several factors (metal contents and soil properties) on bacterial bioluminescence activity, seed germination and root/shoot growth of Lactuca in metal-contaminated soils. Each bioassay showed different sensitivities to extractants of soil samples. Average sensitivities of the bioassay were in the following order: root growth > bioluminescence ≥ shoot growth ≥ seed germination. Both total and weak acid-extracted metal contents showed no observable correlations with the activity of any bioassays (r(2) < 0.279). However, reasonable correlations were observed between the bioluminescence activity and organics (r(2) = 0.7198) as well as between root growth and CEC (r(2) = 0.6676). Effects of soils were difficult to generalize since they were dependent on many factors, such as soil properties, metal contents, and the organism used in each test. Nonetheless, these results indicated that a battery of bioassays is an effective strategy for assessment of contaminated soils. Furthermore, specific soil factors were shown to more influence on soil toxicity, depending on the type of bioassay.

Mineral carbonation of gaseous carbon dioxide using a clay-hosted cation exchange reaction.

The mineral carbonation method is still a challenge in practical application owing to: (1) slow reaction kinetics, (2) high reaction temperature, and (3) continuous mineral consumption. These constraints stem from the mode of supplying alkaline earth metals through mineral acidification and dissolution. Here, we attempt to mineralize gaseous carbon dioxide into calcium carbonate, using a cation exchange reaction of vermiculite (a species of expandable clay minerals). The mineralization is operated by draining NaCI solution through vermiculite powders and continuously dropping into the pool of NaOH solution with CO2 gas injected. The mineralization temperature is regulated here at 293 and 333 K for 15 min. As a result of characterization, using an X-ray powder diffractometer and a scanning electron microscopy, two types of pure CaCO3 polymorphs (vaterite and calcite) are identified as main reaction products. Their abundance and morphology are heavily dependent on the mineralization temperature. Noticeably, spindle-shaped vaterite, which is quite different from a typical vaterite morphology (polycrystalline spherulite), forms predominantly at 333 K (approximately 98 wt%).

Effective utilization of incinerated municipal solid waste incineration ash: zeolitic material synthesis and silica extraction.

In this study the effective utilization of two types of municipal solid waste incinerator (MSWI) ashes, namely air-cooled ash (ACS) and water-cooled ash (WCS) samples obtained from a municipal solid waste incineration plant, was examined by applying zeolitic material synthesis and silica extraction. The influence of the experimental conditions including the ratio of sample : NaOH solution, the reaction temperature and time, and the concentration of NaOH solution were investigated. The results for the 25 experimental trials can be summarized as: (1) the formation of tobermorite and/or pectolite-1A as a major component in most conditions; (2) the synthesis of hydroxycancrinite as a major phase at 200 degrees C; (3) a dramatic increase in the extracted SiO(2) yield at 1 : 30 value of sample : NaOH ratio and 200 degrees C, even at short reaction times; and (4) relatively high SiO(2) yields for WCS ashes rather than ACS ashes. An increase in the reaction time improved the quantity of synthesized zeolitic materials. The reaction temperature determined the type of zeolite. An increase in the NaOH concentration can be an essential factor to improve zeolitic material synthesis, but it significantly reduced the yield of SiO(2) extraction. In conclusion, suitable conditions for obtaining both SiO(2) extraction and synthesized zeolites from the ashes of the incinerated solid waste materials should be: 200 degrees C reaction temperature; a 1 : 30 (g : mL) value for the sample : NaOH ratio; 2 mol L(-1) NaOH concentration; and a reaction time of more than 24 h.

Single-walled hollow nanospheres assembled from the aluminogermanate precursors.

Ordered single-walled hollow aluminogermanate (ALGE) nanospheres (NSs) with average monodisperse diameters of 5 nm have been synthesized for the first time using simple pH control. This involved basification of the ALGE precursors (having an Al/Ge ratio of 1.33) to a pH value of 13, followed by immediate acidification to a pH value of 9.

Development and validation of a high performance liquid chromatography-tandem mass spectrometry for the determination of etodolac in human plasma.

A simple and specific method using a one-step liquid-liquid extraction (LLE) with butyl acetate followed by high performance liquid chromatography (HPLC) coupled with positive ion electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection was developed for the determination of etodolac in human plasma, using indomethacin as an internal standard (IS). Chromatographic separation was performed isocratically using a Capcellpak MGII C(18) column with 65% acetonitrile and 35% water containing 10mM ammonium formate (adjusted to pH 3.5 with formic acid). Acquisition was performed in multiple reaction monitoring (MRM) mode by monitoring the transitions: m/z 287.99>172.23 for etodolac and m/z 357.92>139.01 for IS. The method was validated to determine its selectivity, linearity, sensitivity, precision, accuracy, recovery and stability. The limit of quantitation (LLOQ) was 0.1microg/mL with a relative standard deviation of less than 15%. The devised method provides an accurate, precise and sensitive tool for determining etodolac levels in plasma.

An optimized analytical method of fluconazole in human plasma by high-performance liquid chromatography with ultraviolet detection and its application to a bioequivalence study.

A sensitive and accurate HPLC-UV method for the quantification of fluconazole (FLA) level in human plasma has been developed. The sample was prepared by one-step liquid-liquid extraction (LLE) of FLA from plasma using dichloromethane. Phenacetin was used as the internal standard. The chromatographic retention times of FLA and phenacetin were 4.6 and 8.3 min, respectively. The lower limit of quantitation (LLOQ) was 0.05 microg/mL, and no interferences were detected in the chromatograms. The devised HPLC-UV method was validated by evaluating its intra- and inter-day precisions and accuracies in a linear concentration range between 0.05 and 10.00 microg/mL. The devised method was successfully applied to a bioequivalence studies involving the oral administration of a single 150 mg FLA tablet and 3 x 50 mg FLA capsules in healthy Korean male volunteers.