Effects of supplemental source of magnesium and inclusion of buffer on ruminal microbial fermentation in continuous culture.

Magnesium oxide (MgO) is the most common supplemental source of Mg for dairy cows and a proven ruminal alkalizer when supplemented above NRC (2001) recommendations. However, overfeeding MgO may increase feeding costs, whereas the effects of alternative sources of Mg on ruminal fermentation are not well known. Moreover, it is still unclear if Mg supplementation influences the effects of bicarbonate-based buffers on ruminal fermentation. We aimed to evaluate the effect of Mg source on ruminal fermentation with diets formulated to a final concentration of 0.25% Mg, and to determine if the effect of sodium sesquicarbonate as a buffer varies with the source of Mg. We used 8 fermentors in a duplicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments, by combining 2 factors: (1) Mg source: using either MgO or an alternative source consisting of a blend of CaMg(OH)4 and CaMg(CO3)2 (BLN) and (2) sodium sesquicarbonate buffer inclusion, at 0 or 0.6% of dry matter intake. Based on preliminary tests of reactivity, we hypothesized that BLN plus buffer would allow for greater ruminal pH, acetate molar proportion, and NDF digestibility than diets with MgO or without buffer. Four 10-d periods were completed, where the last 3 d were used for pH measurements and collection of samples for volatile fatty acids (VFA), ammonia (NH3-N), Mg solubility, N metabolism, and nutrient digestibility. Effects of Mg source (source), sodium sesquicarbonate inclusion (buffer), and their interaction (source × buffer) were tested with the MIXED procedure of SAS (SAS Institute Inc.). We did not find an effect of Mg source on ruminal fermentation variables; however, concentration of soluble Mg in ruminal fluid was greater for MgO compared with BLN. On the other hand, buffer supplementation increased average ruminal pH, acetate molar proportion, and branched-chain VFA molar proportion; tended to increase NDF digestibility; and decreased both area under the curve and time below pH 6.0. An interaction of source × buffer was found for propionate, butyrate, and NH3-N, the first one decreasing and the 2 others increasing only when buffer was supplemented to the BLN diet. Our results indicate that supplementing Mg with either MgO or BLN promotes similar ruminal fermentation in diets with total concentration of 0.25% Mg. Further evaluations are needed to assess Mg availability and animal performance in dairy cows fed BLN.

Tablet Formulation of a Polymeric Solid Dispersion Containing Amorphous Alkalinized Telmisartan.

To overcome the poor dissolution of telmisartan (TMS) at weak acidic pH, amorphous alkalinized TMS (AAT) was prepared by introducing sodium hydroxide as a selective alkalizer. AAT-containing polymeric solid dispersions were prepared by a solvent evaporation method; these solid dispersions were AAT-PEG, AAT-PVP, AAT-POL, and AAT-SOL for the polymers of PEG 6000, PVP K30, Poloxamer 407, and Soluplus, respectively. The characteristics of the different formulations were observed by differential scanning calorimetry, powder X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy. To compare the supersaturation behavior, a dissolution test was performed at 37 ± 0.5 °C either in 900 ml (plain condition) or 500 ml (limited condition) of pH 6.8-simulated intestinal fluid used as a medium. AAT-SOL exhibited enhanced dissolution, indicating the probability of extended supersaturation in the limited condition. AAT-SOL was further formulated into a tablet by introducing other excipients, Vivapur 105 and Croscarmellose, as a binder and superdisintegrant, respectively, using a direct compression method. The selected AAT-SOL tablet was superior to Micardis (the reference product) in the aspect of supersaturation maintenance during dissolution in the limited condition, suggesting that it is a promising candidate for practical development that can replace the commercial product in the future.

A novel osmotic pump-based controlled delivery system consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen: in vitro and in vivo evaluation.

In this study, a novel controlled release osmotic pump capsule consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen (FP) was developed to improve the solubility and oral bioavailability of FP and to minimize the fluctuation of plasma concentration. The pH-modulated solid dispersion containing FP, Kollidon® 12 PF and Na2CO3 at a weight ratio of 1/4.5/0.02 was prepared using the solvent evaporation method. The osmotic pump capsule was assembled by semi-permeable capsule shell of cellulose acetate (CA) prepared by the perfusion method. Then, the solid dispersion, penetration enhancer, and suspending agents were tableted and filled into the capsule. Central composite design-response surface methodology was used to evaluate the influence of factors on the responses. A second-order polynomial model and a multiple linear model were fitted to correlation coefficient of drug release profile and ultimate cumulative release in 12 h, respectively. The actual response values were in good accordance with the predicted ones. The optimized formulation showed a complete drug delivery and zero-order release rate. Beagle dogs were used to be conducted in the pharmacokinetic study. The in vivo study indicated that the relative bioavailability of the novel osmotic pump system was 133.99% compared with the commercial preparation. The novel controlled delivery system with combination of pH-modulated solid dispersion and osmotic pump system is not only a promising strategy to improve the solubility and oral bioavailability of poorly soluble ionizable drugs but also an effective way to reduce dosing frequency and minimize the plasma fluctuation.

A 3D in-vitro biomimicking Caco-2 intestinal permeability model-based assessment of physically modified telmisartan towards an alkalizer-free formulation development.

Efficient telmisartan delivery for hypertension management requires the incorporation of meglumine and/or sodium hydroxide as an alkalizer in the formulation. Long-term use of powerful alkalis with formulation as part of chronic therapy can cause metabolic alkalosis, ulcers, diarrhea, and body pain. Here, we aimed to design a telmisartan formulation without alkalizers. Telmisartan properties were tailor-made by microfluidizer-based physical modification. After microfluidization, telmisartan nanosuspension was lyophilized to obtain telmisartan premix powder. The optimized telmisartan nanosuspension had an average particle size of 579.85 ± 32.14 nm. The lyophilized premix was characterized by FT-IR, DSC, and PXRD analysis to ensure its physicochemical characteristics. The solubility analysis of premix showed 2.2 times, 2.3 times, and 6 times solubility improvement in 0.1 N HCl, phosphate buffer pH 7.5, and pH 6.8 compared to pure telmisartan. A 3D in-vitro Caco-2 model was developed to compare apparent permeability of API and powder premix. It showed that the powder premix was more permeable than pure API. The tablet formulation prepared from the telmisartan premix showed a dissolution profile comparable to that of the marketed formulation. The technique present herein can be used as a platform technology for solubility and permeability improvement of similar classes of molecules.

Effect of High-Energy Ball Milling, Capping Agents and Alkalizer on Capacitance of Nanostructured FeOOH Anodes.

This investigation is motivated by interest in nanostructured FeOOH anodes for aqueous asymmetric supercapacitors operating in Na2SO4 electrolyte. The research goal is the fabrication of anodes with high active mass loading of 40 mg cm-2, high capacitance and low resistance. The influence of high-energy ball milling (HEBM), capping agents and alkalizer on the nanostructure and capacitive properties is investigated. HEBM promotes the crystallization of FeOOH, which results in capacitance reduction. Capping agents from the catechol family, such as tetrahydroxy-1,4-benzoquinone (THB) and gallocyanine (GC), facilitate the fabrication of FeOOH nanoparticles, eliminate the formation of micron size particles and allow the fabrication of anodes with enhanced capacitance. The analysis of testing results provided insight into the influence of the chemical structure of the capping agents on nanoparticle synthesis and dispersion. The feasibility of a conceptually new strategy for the synthesis of FeOOH nanoparticles is demonstrated, which is based on the use of polyethylenimine as an organic alkalizer-dispersant. The capacitances of materials prepared using different nanotechnology strategies are compared. The highest capacitance of 6.54 F cm-2 is obtained using GC as a capping agent. The obtained electrodes are promising for applications as anodes for asymmetric supercapacitors.

Effects of calcium-magnesium carbonate and calcium-magnesium hydroxide as supplemental sources of magnesium on ruminal microbiome.

Our objective was to evaluate the inclusion of calcium-magnesium carbonate [CaMg(CO3)2] and calcium-magnesium hydroxide [CaMg(OH)4] in corn silage-based diets and their impact on ruminal microbiome. Our previous work showed a lower pH and molar proportion of butyrate from diets supplemented with [CaMg(CO3)2] compared to [CaMg(OH)4]; therefore, we hypothesized that ruminal microbiome would be affected by Mg source. Four continuous culture fermenters were arranged in a 4 × 4 Latin square with the following treatments defined by the supplemental source of Mg: 1) Control (100% MgO, plus sodium sesquicarbonate as a buffer); 2) CO 3 [100% CaMg(CO3)2]; 3) OH [100% CaMg(OH)4]; and 4) CO 3 /OH [50% Mg from CaMg(CO3)2, 50% Mg from CaMg(OH)4]. Diet nutrient concentration was held constant across treatments (16% CP, 30% NDF, 1.66 MCal NEl/kg, 0.67% Ca, and 0.25% Mg). We conducted four fermentation periods of 10 d, with the last 3 d for collection of samples of solid and liquid digesta effluents for DNA extraction. Overall, 16 solid and 16 liquid samples were analyzed by amplification of the V4 variable region of bacterial 16S rRNA. Data were analyzed with R and SAS to determine treatment effects on taxa relative abundance of liquid and solid fractions. Correlation of butyrate molar proportion with taxa relative abundance was also analyzed. Treatments did not affect alpha and beta diversities or relative abundance of phylum, class and order in either liquid or solid fractions. At the family level, relative abundance of Lachnospiraceae in solid fraction was lower for CO3 and CO3/OH compared to OH and Control (P < 0.01). For genera, abundance of Butyrivibrio (P = 0.01) and Lachnospiraceae ND3007 (P < 0.01) (both from Lachnospiraceae family) was lower and unclassified Ruminococcaceae (P = 0.03) was greater in CO3 than Control and OH in solid fraction; while abundance of Pseudobutyrivibrio (P = 0.10) and Lachnospiraceae FD2005 (P = 0.09) (both from Lachnospiraceae family) and Ruminobacter (P = 0.09) tended to decrease in CO3 compared to Control in liquid fraction. Butyrate molar proportion was negatively correlated to Ruminococcaceae (r = -0.55) in solid fraction and positively correlated to Pseudobutyrivibrio (r = 0.61) and Lachnospiraceae FD2005 (r = 0.61) in liquid. Our results indicate that source of Mg has an impact on bacterial taxa associated with ruminal butyrate synthesis, which is important for epithelial health and fatty acid synthesis.

Design and Optimization of a Novel Strategy for the Local Treatment of Helicobacter pylori Infections.

Infections with Helicobacter pylori are a global challenge. Currently, H. pylori infections are treated systemically, but the eradication rates of the different therapy regimens are declining due to the growing number of bacterial strains resistant to major antibiotics. Here, we present a strategy for the local eradication of H. pylori by the use of Penicillin G sodium (PGS). In vitro experiments revealed that PGS shows high antibiotic activity against resistant strains of Helicobacter pylori with a minimum inhibitory concentration (MIC) of 0.125 µg/ml. In order to provide luminal concentrations above the MIC for longer periods of time, an extended release tablet was developed. Alkalizers were included to prevent acidic degradation of PGS within the tablet matrix. Out of the tested alkalizers MgO, l-Lysine, NaHCO3, and Na2CO3 NaHCO3 provided the strongest rise in pH inside the hydrated matrix when tested in simulated gastric fluid. Better PGS stability can mainly reasoned from that, addition of MgO resulted in high pH values within the matrix, causing basic degradation of PGS. This work is a first step towards the use of extended release tablets containing PGS for the local treatment of H. pylori as a safe and cost-effective alternative to common systemic treatment regimens.

Enhanced gastric stability of esomeprazole by molecular interaction and modulation of microenvironmental pH with alkalizers in solid dispersion.

Due to the instability of esomeprazole magnesium dihydrate (EPM), a proton pump inhibitor, in gastric fluid, enteric-coated dosage form is commonly used for therapeutic application. In this study, we prepared new gastric fluid resistant solid dispersions (SDs) containing alkalizers. Then, new mechanistic evidence regarding the effects of pharmaceutical alkalizers on the aqueous stability of EPM in simulated gastric fluid was investigated. The alkalizer-loaded SD were prepared by dissolving or dispersing EPM, hydroxypropyl methylcellulose (HPMC) 6 cps, and an alkalizer, in ethanol 50% (v/v) followed by spray drying. Nine different alkalizers were assessed for in vitro stability in two media, simulated gastric fluid (pH 1.2 buffer) and simulated intestinal fluid (pH 6.8 buffer). The microenvironmental pH (pHM) was measured to evaluate the effect of the alkalizer on the pHM of SDs. Drug crystallinity and morphology of the SDs were also examined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The interactions among EPM, the polymer, and the alkalizer were elucidated by Fourier transform infrared (FTIR) spectroscopy. The in vivo absorption studies of the optimized alkalizer-containing SD and the enteric-coated reference tablet Nexium® were then conducted in beagle dogs. Among alkalizers, MgO loaded in SDs proved to be the best alkalizer to stabilize EPM in simulated gastric fluid. pHM values of the alkalizer-containing SDs were significantly higher than that of the SD without alkalizer. The pHM values decreased in the following order: MgO, Na2CO3, Ca(OH)2, and no alkalizer. DSC and PXRD data exhibited a change in the drug crystallinity of the SDs from crystalline to amorphous form. SEM data showed a relatively spherical shape of the MgO-loaded SD compared to the less-defined shape of pure drug. FTIR indicated a strong molecular interaction among EPM, alkalizer and polymer; in particular, MgO showed the strongest interaction with EPM. It was evident that alkalizer interacts with benzimidazole ring and/or sulfonyl group of EPM for enhancing EPM stability in gastric fluid. Regarding the in vivo absorption studies in beagle dogs, the optimized SD (C16) was bioequivalent to the reference Nexium® and had a considerable greater absorption at the early stages. The current alkalizer-containing SD could provide a promising approach for aqueous stabilization of acid-labile drugs without using enteric coating method.

Development of co-processed excipients in the design and evaluation of atorvastatin calcium tablets by direct compression method.

INTRODUCTION: Co-processed excipients were prepared to improve the process ability and efficacy of commonly used excipients and to impart multi-functional qualities to the excipients and hence that the tablets with the desired attributes can be produced. In this study, acacia and calcium carbonate (CaCO3) were used to prepare a co-processing excipient suitable for the preparation of atorvastatin calcium tablets. Acacia is used as binder and CaCO3 as filler. CaCO3 also acts as alkalizer and thus suitable to improve the dissolution rate of pH dependent soluble drugs like atorvastatin. MATERIALS AND METHODS: The tablets were prepared by direct compression method and the physical properties of tablets such as hardness, friability and dissolution profiles of tablets were evaluated. Acacia was used in the form of mucilage. Various ratios of the co-processing excipients were formulated by granulation technique and the blend properties were evaluated by their Hausner's ratio and Carr's index values. Based on the Kawakita plots, it was found that the formulation with 3% acacia mucilage (0.9 mg acacia and 26.6 mg of CaCO3) showed good fluidity and the formulations with 4% (1.27 mg of acacia and 26.23 mg of CaCO3) and 5% acacia mucilage (1.62 mg of acacia and 25.88 mg of CaCO3) showed more cohesiveness. The formulations include 1-5% of the acacia mucilage as the binding agent. RESULTS: The granules of formulations with low percentage of acacia mucilage (1% and 2%) failed the test for friability. The granules of the formulations with pure acacia (F1) and pure CaCO3 (F2) showed passable flow properties. CONCLUSION: The formulation with 3% acacia mucilage (F3, 0.9 mg acacia and 26.6 mg of CaCO3) showed least dissolution time (<1 min) and is found as the best formulation among the other formulations containing 4% (F4, 1.27 mg of acacia and 26.23 mg of CaCO3) and 5% (F5, 1.62 mg of acacia and 25.88 mg of CaCO3) acacia mucilage.

Alkalizer administration improves renal function in hyperuricemia associated with obesity.

We evaluated the combination effect of the alkalizer citrate with the xanthine oxidase inhibitor allopurinol on renal function and uric acid in patients with hyperuricemia associated with obesity and/or metabolic syndrome (MetS), who were extracted from among the subjects enrolled in a prospective randomized controlled study aimed at assessing the efficacy of such a combination for improving renal function. We also conducted a post hoc analysis to examine influences on lipid profiles. Patients who consented to participate in the study were randomly allocated to receive either allopurinol alone (monotherapy) or in combination with a citrate preparation (combination therapy). The analysis population consisted of 31 obese patients with a body mass index greater than 25 kg/m(2) (monotherapy, 15 patients; combination therapy, 16 patients). The creatinine clearance rate (Ccr), serum uric acid levels, and lipid profiles were measured before and at 12 weeks after the start of treatment. In the combination therapy group, Ccr increased significantly and serum uric acid levels decreased significantly in obese patients, while Ccr tended to increase and serum uric acid levels decreased, though not significantly, in patients with MetS-related clinical parameters. Overall, blood triglyceride levels tended to improve in the combination therapy group as compared with the monotherapy group.