Cembranoids from the Vietnamese soft coral Sarcophyton ehrenbergi.

Using various chromatographic separations, two new cembranoids, ehrenbergols F and G (1 and 2), along with three known analogs ehrenbergol D (3), (+)-isosarcophine (4) and sinulariol Z2 (5) were isolated from the soft coral Sarcophyton ehrenbergi. The structural elucidation was done by extensive analysis of the 1 D and 2 D NMR, HR-ESI-QTOF-MS as well as CD experiments. In addition, compounds 1 (IC50 of 38.38 ± 2.89 µM), 3 (IC50 of 37.14 ± 3.22 µM) and 4 (IC50 of 45.01 ± 2.49 µM) revealed moderate inhibitory activity on LPS-induced NO production in RAW264.7 cells, whereas 2 (IC50 of 73.32 ± 1.95 µM) and 5 (IC50 of 64.48 ± 4.93 µM) exhibited weak effect.

Upconversion NaYF4:Yb3+/Er3+@silica-TPGS Bio-Nano Complexes: Synthesis, Characterization, and In Vitro Tests for Labeling Cancer Cells.

Fluorescence imaging is an important technique used for early diagnosis and effective treatment of some incurable diseases including cancer. Herein, we report novel NaYF4:Yb3+/Er3+@silica-TPGS bio-nano complexes for labeling cancer cells. The NaYF4:Yb3+/Er3+ nanoparticles have been successfully synthesized via a hydrothermal route, further coated with a silica shell, and functionalized with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). The experimental results indicate that NaYF4:Yb3+/Er3+@silica-TPGS emits stronger upconversion luminescence than NaYF4:Yb3+/Er3+ under an excitation of 980 nm. More significantly, the NaYF4:Yb3+/Er3+@silica-TPGS bio-nano complexes could strongly label MCF-7 breast cancer cells for in vitro experiments detected by a fluorescence microscope. On the other hand, the complex could not typically probe healthy cells, which are HEK-293A human embryonic kidney cells, under the same experimental conditions. Because of their strong upconversion luminescence, good dispersibility, and biocompatibility, NaYF4:Yb3+/Er3+@silica-TPGS bio-nano complexes can be a promising candidate/probe for biomedical labeling and diagnostics.

Preventing release in the acidic environment of the stomach via occlusion in ordered mesoporous silica enhances the absorption of poorly soluble weakly acidic drugs.

This study aimed to assess the pharmaceutical performance of formulations consisting of either indomethacin or glibenclamide and the ordered mesoporous silica material SBA-15. Both compounds were loaded on SBA-15 via solvent impregnation. Adsorption in the SBA-15 mesopores was confirmed using nitrogen physisorption. Differential scanning calorimetry results suggested that both compounds were dispersed monomolecularly onto the SBA-15 surface. In in vitro experiments simulating the gastric-to-intestinal transition, the release of both compounds from SBA-15 remained under 1% in simulated gastric fluid (SGF, pH 1.2), whereas both drugs were completely released within 10 min after transfer to fasted state simulated intestinal fluid (FaSSIF, pH 6.5). As both drugs exhibited very rapid precipitation from the supersaturated state in SGF, the preferential release in FaSSIF--where conditions are more favourable by virtue of either much higher solubility (indomethacin) or more stable supersaturation (glibenclamide)--was considered crucial towards achieving optimal absorption. This hypothesis was confirmed by an in vivo study, where the extent of absorption of a glibenclamide-SBA-15 formulation was found to be more than fourfold higher than that of the commercial glibenclamide product Daonil®.

Enhanced absorption of the poorly soluble drug fenofibrate by tuning its release rate from ordered mesoporous silica.

The aim of the present study was to evaluate the effect of release rate from ordered mesoporous silica materials on the rate and extent of absorption of the poorly soluble drug fenofibrate. Three ordered mesoporous silica materials with different pore diameter (7.3 nm, 4.4 nm and 2.7 nm) were synthesized and loaded with fenofibrate via impregnation. Release experiments were conducted under sink conditions and under supersaturating conditions in biorelevant media, simulating the fasted and the fed state. Subsequently, all silica-based formulations were evaluated in vivo (rat model). The release experiments under sink conditions indicated a clear increase in release rate with increasing pore size. However, under supersaturating conditions (FaSSIF), the, pharmaceutical performance (in terms of both the degree and duration of supersaturation), increased with decreasing pore size. The same trend was observed in vivo (fasted state): the area under the plasma concentration-time profile amounted to 102 ± 34 µMh, 86 ± 19 µMh and 20 ± 13 µMh for the materials with pore diameter of 2.7 nm, 4.4 nm and 7.3 nm, respectively. The results of this, study demonstrate that a decrease in drug release rate - and thus, a decrease of the rate at which supersaturation is created - is beneficial to the absorption of fenofibrate.

Comparison of the complexation between methylprednisolone and different cyclodextrins in solution by 1H-NMR and molecular modeling studies.

Complexation in solution between methylprednisolone and three different cyclodextrins [2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD), gamma-cyclodextrin (gamma-CD), and 2-hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD)] was studied using phase solubility analysis, one and two-dimensional (1)H-NMR and molecular modeling. Estimates of the complex formation constant (K(1:1)) show that the tendency of methylprednisolone to complex with CDs follows the order: gamma-CD > HP-gamma-CD > HP-beta-CD. The large variation of chemical shifts from protons located around the interior of the hydrophobic cavity (H-3', H-5', and H-6') coupled with minimal variation of shifts from protons located on the outer sphere of gamma-CD (H-1', H-2', and H-4') provided clear evidence of inclusion complexation. The molecular modeling study, indicated inclusion complexation between methylprednisolone and gamma-CD and HP-gamma-CD by entrance of the A and B rings of methylprednisolone into the CD cavity from its bigger rim. For the methylprednisolone: HP-beta-CD complex, the molecular modeling study could not be carried out; hence, two possibilities of complex formation are proposed: (1) methylprednisolone enters HP-beta-CD from the wider rim by its D and C ring, (2) the A and B ring of methylprednisolone enters deeper in to the CD cavity so that a part of the A ring of steroidal structure is outside of the cavity.

Combined use of ordered mesoporous silica and precipitation inhibitors for improved oral absorption of the poorly soluble weak base itraconazole.

The release of poorly soluble drugs from mesoporous silicates is often associated with the generation of supersaturation, which implies the risk of drug precipitation and reduced availability for absorption. The aim of this study was to enhance the in vivo performance of an ordered mesoporous silicate (SBA-15) by combining it with the precipitation inhibitors hydroxypropylmethylcellulose (HPMC) and hydroxypropylmethylcellulose acetate succinate (HPMCAS). The poorly soluble weak base itraconazole was used as a model compound. Formulations were prepared by physically blending itraconazole-loaded SBA-15 with the precipitation inhibitors. In vitro release experiments implementing a transfer from simulated gastric fluid to simulated intestinal fluid were used to evaluate the pharmaceutical performance. Subsequently, the formulations were evaluated in vivo in rats. When high enough amounts of HPMC were co-administered with itraconazole-loaded SBA-15 (itraconazole:SBA-15:HPMC 1:4:6), the extent of absorption was increased by more than 60% when compared to SBA-15 without precipitation inhibitors (AUC 14,937+/-1617 versus 8987+/-2726nMh). HPMCAS was found ineffective in enhancing the in vivo performance of SBA-15 due to its insolubility in the stomach. The results of this study demonstrate that the pharmaceutical performance of SBA-15 is enhanced through addition of an appropriate precipitation inhibitor.

Formulate-ability of ten compounds with different physicochemical profiles in SMEDDS.

In order to gain a better understanding of the reasons of successful self-microemulsifying drug delivery systems (SMEDDS) formulation, ten poorly water-soluble drugs, exhibiting different physicochemical properties, were selected. The solubility of the compounds was determined in various oils (long and medium chain) and surfactants (HLB>12 and HLB<10). The best performing excipients were selected for SMEDDS formulation. The droplet size and zeta potential of SMEDDS were measured in the absence and the presence of drug. Media, time and the presence of drug showed little or no influence on droplet size of most systems. Some systems displayed a different zeta potential in the presence of drugs. In vitro pharmaceutical performance of the SMEDDS formulations was investigated using the dialysis bag method in reverse mode next to conventional in vitro release methodology. The results suggested that the measured concentration of the compounds inside the dialysis bag corresponded to solubility of the compound in the release medium, which suggested that the formation of micelles inside the dialysis bag was delayed or disturbed. Conventional in vitro release methodology with pH change from acidic to neutral appeared as a simple method which gives valuable information about the dispersion and the solubilization ability of the SMEDDS formulation at different pHs. In general, formulate-ability in SMEDDS was found to depend on the solubility of the drugs in the excipients and log P of the compounds (the optimal log P was found between 2 and 4).

Ordered mesoporous silica material SBA-15: a broad-spectrum formulation platform for poorly soluble drugs.

Encapsulating poorly soluble drugs in mesoporous silicates is an emerging strategy to improve drug dissolution. This study evaluates the applicability of the ordered mesoporous silicate SBA-15 as an excipient to enhance dissolution, for a test series of 10 poorly soluble compounds with a high degree of physicochemical diversity (carbamazepine, cinnarizine, danazol, diazepam, fenofibrate, griseofulvin, indomethacin, ketoconazole, nifedipine, and phenylbutazone). A generic solvent impregnation method was used to load all model compounds. The target drug content was 20%. The physical nature of the formulations was investigated using differential scanning calorimetry (DSC) and the pharmaceutical performance evaluated by means of in vitro dissolution. Aliquots of each formulation were stored at 25 degrees C/52% RH for 6 months, and again subjected to DSC and in vitro dissolution. The target drug content of 20% was attained in all cases. DSC data evidenced the noncrystalline state of the confined drugs. All SBA-15 formulations exhibited an enhanced dissolution as compared to their corresponding crystalline materials, and the high pharmaceutical performance of all formulations was retained during the 6 months storage period. The results of this study suggest that encapsulation in SBA-15 can be applied as a dissolution-enhancing formulation approach for a very wide variety of poorly soluble drugs.

High-throughput study of phenytoin solid dispersions: formulation using an automated solvent casting method, dissolution testing, and scaling-up.

A high-throughput experimentation method for studying the dissolution of phenytoin, a poorly water soluble drug, was developed and validated. Solid dispersions with 12 excipients (7 polymers and 5 surfactants) were prepared and tested. Each excipient was screened with three drug loadings: 10, 20, and 40% (w/w). Each solid dispersion was prepared in triplicate, for a total of 108 samples. The drug dissolution was studied in simulated gastric fluid without pepsin plus 1% sodium laurylsulfate. This study led to the identification of three improved formulations, exhibiting an extent of dissolution higher than 90% after both 30 and 60 min. The HTE results could be reproduced at a larger scale using a conventional solvent evaporating method, proving the reliability of the HTE protocol.

Precision study on capillary electrophoresis methods for metacycline.

A CE method for metacycline (MTC) determination was investigated in an inter-laboratory experiment. Many problems were encountered in this study, most of which were related to the transfer of the method to different CE equipment. The reported problems could be classified into different categories: problems related to the precision, to the parameters in the protocol, and to the MTC peak shape. As the peak shape problem was partially responsible for the poor precision, a new CE method was developed in order to obtain a good MTC peak shape on all equipment. The precision of this new method for MTC determination was examined in an intermediate precision study, where the influence of the factors "time" and "equipment" was investigated. Although the new method could be transferred to different instruments, the precision remained poor mainly due to the contributions of the between-replicate and the between-injection variances.