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The fruit of Nitraria sibirica Pall. (N. sibirica) is a common folk medicine in the Northwest China and contains plentiful antioxidant compositions. In the study, a rapid flash extraction method (extracting for 3.3 min with 53% ethanol at the solvent-sample ratio of 34 mL/g) for the antioxidant compositions in N. sibirica fruit was optimized by response surface methodology. Twenty-seven compounds of the extract were recognized by ultra-high performance liquid chromatography combined with ion trap mass spectrometry (UPLC-IT/MS), including twelve flavonoids, twelve alkaloids and three phenolic acids. Four compounds among them were first reported in Nitraria genus. Moreover, eight main antioxidant compounds in eight batches of N. sibirica fruit collected from different regions were quantified by a rapid and reliable method of ultra-high performance liquid chromatography combined with triple quadrupole tandem mass spectrometry (UPLC-QQQ/MS). Chemometric study further revealed that the contents of two compounds, tryptophan and alcesefoliside, were highly correlated with the antioxidant activity, which provided a reference for the quality evaluation of N. sibirica fruit.

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Described here are synthesis and biological evaluations of diversified groups of over 57 ertapenem prodrugs which include alkyl, methylenedioxy, carbonate, cyclic carbonate, carbamate esters, and esters containing active transport groups (e.g., carboxyl, amino acid, fatty acids, cholesterol) and macrocyclic lactones linking the two carboxyl groups. Many of the prodrugs were rapidly hydrolyzed in rat plasma but not in human plasma and were stable in simulated gastrointestinal fluid. The diethyl ester prodrug showed the best total absorption (>30%) by intredeudenal dosing in dogs, which could potentially be improved by formulation development. However, its slow rate of the hydrolysis to ertapenem also led to the presence of large amounts of circulating monoester metabolites, which pose significant development challenges. This study also suggests that the size of susbtituents at C-2 of carbapenem (e.g., benzoic acid of ertapenem) has significant impact on the absorption and the hydrolysis of the prodrugs.

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Carbapenems are intravenous lifesaving hospital antibiotics. Once patients leave the hospital, they are sent home with antibiotics other than carbapenems since they cannot be administered orally due to lack of oral absorption primarily because of very highly polarity. A prodrug approach is a bona fide strategy to improve oral absorption of compounds. Design and synthesis, in vitro and in vivo evaluation of diversified prodrugs of ertapenem, one of the only once daily dosed carbapenems is described. Many of the prodrugs prepared for evaluation are rapidly hydrolyzed in rat plasma. Only bis-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (medoxomil) ester prodrug was rapidly hydrolyzed in most of the plasmas including rat, human, dog, and monkey. Although the rate of conversion of ertapenem diethyl ester prodrug (6) was slow in in vitro plasma hydrolysis, it showed the best in vivo pharmacokinetic profile in dog by an intraduodenal dosing giving >31% total oral absorption.

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The aim of this work was to investigate guar gum/ethylcellulose mix coated pellets for potential colon-specific drug delivery. The coated pellets, containing 5-fluorouracil as a model drug, were prepared in a fluidized bed coater by spraying the aqueous/ethanol dispersion mixture of guar gum and ethylcellulose. The lag time of drug release and release rate were adjustable by changing the ratio of guar gum to ethylcellulose and coat weight gain. In order to find the optimal coating formulation that was able to achieve drug targeting to the colon, the effect of two independent variables (the ratio of guar gum to ethylcellulose and the coat weight gain) on drug release characteristics was studied using 3 x 4 factorial design and response surface methodology. Results indicated that drug release rate decreased as the proportion of ethylcellulose in the hybrid coat and the coat weight gain increased. When the ratio of guar gum to ethylcellulose was kept in the range of 0.2 to 0.7, and the coat weight gain in the range of 250% to 500%, the coated pellets can keep intact for about 5 h in upper gastrointestine and achieve colon-specific drug delivery. The pellets prepared under optimal conditions resulted in delayed-release sigmoidal patterns with T(5%) (time for 5% drug release) of 5.1 - 7.8 h and T(90%) (time for 90% drug release) of 9.8 - 16.3 h. Further more, drug release was accelerated and T(90%) of the optimum formulation pellets decreased to 9.0 - 14.5 h in pH 6.5 phosphate buffer with hydrolase. It is concluded that mixed coating of guar gum and ethylcellulose is able to provide protection of the drug load in the upper gastrointestinal tract, while allowing enzymatic breakdown of the hybrid coat to release the drug load in the colon.

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A pH- and enzyme-dependent colon-targeted multi-unit delivery system of indomethacin was developed by coating guar gum and Eudragit FS30D sequentially onto drug-loaded pellets in a fluidized bed coater. In vitro studies showed that smaller coating weight gain of guar gum resulted in reduced release lag time t10 (10% release time), but favored degradation by enzymes (galactomannanase). A cumulative weight gain (CWG) of 44% provided sufficient enzymatic sensitivity and protection of the core. Under gradient pH conditions (pH = 1.2, 6.8, 7.4 and 6.5 for 2, 2, 1 and 15 h, respectively), indomethacin was released from Eudragit FS30D-coated pellets quickly after changing pH to 7.4. For guar gum/Eudragit FS30D double-coated pellets, only about 5% of the drug was released after another 1 h, showing retarding effect by guar gum coating. After changing pH to 6.5 and addition of galactomannanase, enzyme-dependent drug release was observed. Pharmacokinetic study in beagle dogs showed that fastest absorption with the smallest Tmax and Tlag was observed for uncoated pellets. The Tmax and Tlag of Eudragit FS30D-coated pellets were postponed to about 2.5 and 1 h, respectively. After a further guar gum coating, Tlag was further postponed to about 2.8 h, about 2 h of additional lag time on the basis of Eudragit FS30D coating. It is indicated that the guar gum/Eudragit FS30D-coated system has potential to be used to deliver drugs to the colon.

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