Cyclodextrin complexes of reduced bromonoscapine in guar gum microspheres enhance colonic drug delivery.

Here, we report improved solubility and enhanced colonic delivery of reduced bromonoscapine (Red-Br-Nos), a cyclic ether brominated analogue of noscapine, upon encapsulation of its cyclodextrin (CD) complexes in bioresponsive guar gum microspheres (GGM). Phase-solubility analysis suggested that Red-Br-Nos complexed with ß-CD and methyl-ß-CD in a 1:1 stoichiometry, with a stability constant (Kc) of 2.29 × 10(3) M(-1) and 4.27 × 10(3) M(-1). Fourier transforms infrared spectroscopy indicated entrance of an O-CH2 or OCH3-C6H4-OCH3 moiety of Red-Br-Nos in the ß-CD or methyl-ß-CD cavity. Furthermore, the cage complex of Red-Br-Nos with ß-CD and methyl-ß-CD was validated by several spectral techniques. Rotating frame Overhauser enhancement spectroscopy revealed that the Ha proton of the OCH3-C6H4-OCH3 moiety was closer to the H5 proton of ß-CD and the H3 proton of the methyl-ß-CD cavity. The solubility of Red-Br-Nos in phosphate buffer saline (PBS, pH ∼ 7.4) was improved by ∼10.7-fold and ∼21.2-fold when mixed with ß-CD and methyl-ß-CD, respectively. This increase in solubility led to a favorable decline in the IC50 by ∼2-fold and ∼3-fold for Red-Br-Nos-ß-CD-GGM and Red-Br-Nos-methyl-ß-CD-GGM formulations respectively, compared to free Red-Br-Nos-ß-CD and Red-Br-Nos-methyl-ß-CD in human colon HT-29 cells. GGM-bearing drug complex formulations were found to be highly cytotoxic to the HT-29 cell line and further effective with simultaneous continuous release of Red-Br-Nos from microspheres. This is the first study to showing the preparation of drug-complex loaded GGMS for colon delivery of Red-Br-Nos that warrants preclinical assessment for the effective management of colon cancer.

Molecular cycloencapsulation augments solubility and improves therapeutic index of brominated noscapine in prostate cancer cells.

We have previously shown that a novel microtubule-modulating noscapinoid, EM011 (9-Br-Nos), displays potent anticancer activity by inhibition of cellular proliferation and induction of apoptosis in prostate cancer cells and preclinical mice models. However, physicochemical and cellular barriers encumber the development of viable formulations for future clinical translation. To circumvent these limitations, we have synthesized EM011-cyclodextrin inclusion complexes to improve solubility and enhance therapeutic index of EM011. Phase solubility analysis indicated that EM011 formed a 1:1 stoichiometric complex with ß-CD and methyl-ß-CD, with a stability constant (K(c)) of 2.42 × 10(-3) M and 4.85 × 10(-3) M, respectively. Fourier transform infrared spectroscopy suggested the penetrance of either a O-CH(2) or OCH(3)-C(6)H(4)-OCH(3) moiety of EM011 in the ß-CD or methyl-ß-CD cavity. In addition, multifarious techniques, namely, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, NMR spectroscopy, and computational studies validated the cage complex of EM011 with ß-CD and methyl-ß-CD. Moreover, rotating frame overhauser enhancement spectroscopy showed that the H(a) proton of the OCH(3)-C(6)H(4)-OCH(3) moiety was in close proximity with H3 proton of the ß-CD or methyl-ß-CD cavity. Furthermore, we found that the solubility of EM011 in phosphate buffer saline (pH 7.4) was enhanced by ~11 fold and ~21 fold upon complexation with ß-CD and methyl-ß-CD, respectively. The enhanced dissolution of the drug CD-complexes in aqueous phase remarkably decreased their IC(50) to 28.5 µM (9-Br-Nos-ß-CD) and 12.5 µM (9-Br-Nos-methyl-ß-CD) in PC-3 cells compared to free EM011 (~200 µM). This is the first report to demonstrate the novel construction of cylcodextrin-based nanosupramolecular vehicles for enhanced delivery of EM011 that warrants in vivo evaluation for the superior management of prostate cancer.

Synthesis and characterization of noscapine loaded magnetic polymeric nanoparticles.

The delivery of noscapine therapies directly to the site of the tumor would ultimately allow higher concentrations of the drug to be delivered, and prolong circulation time in vivo to enhance the therapeutic outcome of this drug. Therefore, we sought to design magnetic based polymeric nanoparticles for the site directed delivery of noscapine to invasive tumors. We synthesized Fe(3)O(4) nanoparticles with an average size of 10 ± 2.5 nm. These Fe(3)O(4) NPs were used to prepare noscapine loaded magnetic polymeric nanoparticles (NMNP) with an average size of 252 ± 6.3 nm. Fourier transform infrared (FT-IR) spectroscopy showed the encapsulation of noscapine on the surface of the polymer matrix. The encapsulation of the Fe(3)O(4) NPs on the surface of the polymer was confirmed by elemental analysis. We studied the drug loading efficiency of polylactide acid (PLLA) and poly (L-lactide acid-co-gylocolide) (PLGA) polymeric systems of various molecular weights. Our findings revealed that the molecular weight of the polymer plays a crucial role in the capacity of the drug loading on the polymer surface. Using a constant amount of polymer and Fe(3)O(4) NPs, both PLLA and PLGA at lower molecule weights showed higher loading efficiencies for the drug on their surfaces.

Enhanced delivery and expression of a nanoencapsulated DNA vaccine vector for respiratory syncytial virus.

This study evaluated the efficiency of chitosan-encapsulated DNA-based respiratory syncytial virus (RSV) vaccine. Antigenic regions of RSV F, M2, and G genes were cloned into the human cytomegalovirus promoter-based constitutive expression vector, resulting in a DNA vaccine vector named DR-FM2G. This vector was used to formulate DNA-chitosan nanoparticles (DCNPs) using a complex coacervation process that yielded an encapsulation efficiency of 94.7%. The DCNP sizes ranged from 80 to 150 nm with uniform size distribution and spherical shape. DNA release was between 50% and 60% when DCNPs were incubated with similar gastrointestinal fluid (pH 2), whereas 21% to 25% of DNA was released from DCNPs in 30 minutes at pH 10. Differential scanning calorimetry showed DCNPs to be more stable than naked DNA or chitosan, offering protection from DNA degradation by nucleases. DCNPs were not toxic to cells when used at concentrations < or =400 microg/mL. Immunohistochemical and real-time polymerase chain reaction results showed a higher level of RSV protein expression in mouse tissues given when DCNPs were injected intravenously as compared with naked DNA. FROM THE CLINICAL EDITOR: This study evaluated the efficiency of chitosan-encapsulated DNA-based respiratory syncytial virus (RSV) vaccine, showing a higher level of RSV protein expression in mouse tissues given when DCNPs were injected intravenously as compared with naked DNA.

Gefitinib-cyclodextrin inclusion complexes: physico-chemical characterization and dissolution studies.

BACKGROUND: Gefitinib, an anticancer drug, has an extremely low aqueous solubility, and its oral absorption is limited by its dissolution rate. The solubility and dissolution of gefitinib can be improved by complexation with cyclodextrins (CDs). METHODS: Phase solubility studies of gefitinib with hydroxypropyl betaCD (HPbetaCD) and randomly methylated betaCD (RMbetaCD) in n various aqueous systems was conducted to characterize the complexes in the liquid state. The inclusion complexes in the solid state were prepared by freeze-drying method and characterized by X-ray diffractometry (X-RD) and differential scanning calorimetry (DSC). RESULTS: Gefitinib formed stable complexes with HPbetaCD and RMbetaCD in distilled water as indicated by the association rate constants (Ks) of 458.9 and 1096.2 M(-1) for HPbetaCD and RMbetaCD, respectively. The complexation of gefitinib with CDs in pH 4.5 acetate buffer indicated an A(N) type of phase-solubility diagrams, whereas gefitinib and HPbetaCD in distilled water in the presence of polymers such as polyvinyl pyrrolidone K-30 (PVP) or hydroxypropyl methylcellulose E3 (HPMC) resulted in A(P)-type phase-solubility diagrams. The solid-state amorphous complexes (as described by DSC and X-RD) showed substantial increases in the solubility and dissolution rate of gefitinib with both CDs. Further increases in the solubility and dissolution rate of the gefitinib-HPbetaCD freeze-dried complex were obtained by physically mixing the complex with PVP and HPMC. CONCLUSION: Gefitinib formed stable inclusion complexes with HPbetaCD and RMbetaCD, and the solubility and dissolution rate of the drug was significantly increased.

Physicochemical characterization of efavirenz-cyclodextrin inclusion complexes.

Efavirenz (EFV) is an oral antihuman immunodeficiency virus type 1 drug with extremely poor aqueous solubility. Thus, its gastrointestinal absorption is limited by the dissolution rate of the drug. The objective of this study was to characterize the inclusion complexes of EFV with beta-cyclodextrin (beta-CD), hydroxypropyl beta-CD (HPbetaCD), and randomly methylated beta-CD (RMbetaCD) to improve the solubility and dissolution of EFV. The inclusion complexation of EFV with cyclodextrins in the liquid state was characterized by phase solubility studies. The solid-state characterization of various EFV and CD systems was performed by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy analyses. Dissolution studies were carried out in distilled water using US Pharmacopeia dissolution rate testing equipment. Phase solubility studies provided an A(L)-type solubility diagram for beta-CD and A(P)-type solubility diagram for HPbetaCD and RMbetaCD. The phase solubility data enabled calculating stability constants (K (s)) for EFV-betaCD, EFV-HPbetaCD, and EFV-RMbetaCD systems which were 288, 469, and 1,073 M(-1), respectively. The physical and kneaded mixtures of EFV with CDs generally provided higher dissolution of EFV as expected. The dissolution of EFV was substantially higher with HPbetaCD and RMbetaCD inclusion complexes prepared by the freeze drying method. Thus, complexation with HPbetaCD and RMbetaCD could possibly improve the dissolution rate-limited absorption of EFV.

Sonochemical effect on size reduction of CaCO3 nanoparticles derived from waste eggshells.

A novel combination of mechanochemical and sonochemical techniques was developed to produce high-surface-area, bio-based calcium carbonate (CaCO3) nanoparticles from eggshells. Size reduction of eggshell achieved via mechanochemical and followed by sonochemical method. First, eggshells were cleaned and ground, then ball milled in wet condition using polypropylene glycol for ten hours to produce fine particles. The ball milled eggshell particles were then irradiated with a high intensity ultrasonic horn (Ti-horn, 20 kHz, and 100 W/cm(2)) in the presence of N,N-dimethylformamide (DMF); decahydronaphthalene (Decalin); or tetrahydrofuran (THF). The ultrasonic irradiation times varied from 1 to 5 h. Transmission electron microscopic (TEM) studies showed that the resultant particle shapes and sizes were different from each solvent. The sonochemical effect of DMF is more pronounced and the particles were irregular platelets of ~10 nm. The BET surface area (43.687 m(2)/g) of these nanoparticles is much higher than that of other nanoparticles derived from eggshells.

Sugar Profile, Mineral Content, and Rheological and Thermal Properties of an Isomerized Sweet Potato Starch Syrup.

Currently, corn is used to produce more than 85% of the world's high fructose syrup (HFS). There is a search for alternative HFS substrates because of increased food demand and shrinking economies, especially in the developing world. The sweet potato is a feasible, alternative raw material. This study isomerized a high glucose sweet potato starch syrup (SPSS) and determined its sugar profile, mineral content, and rheological and thermal properties. Rheological and thermal properties were measured using a rheometer and DSC, respectively. Sweet potato starch was hydrolyzed to syrup with a mean fructose content of 7.6 ± 0.4%. The SPSS had significantly higher (P < 0.05) mineral content when compared to commercial ginger and pancake syrups. During 70 days of storage, the SPSS acted as a non-Newtonian, shear-thinning liquid in which the viscosity decreased as shear stress increased. Water loss temperature of the SPSS continually decreased during storage, while pancake and ginger syrups' peak water loss temperature decreased initially and then increased. Further and more detailed studies should be designed to further enhance the fructose content of the syrup and observe its stability beyond 70 days. The SPSS has the potential to be used in human food systems in space and on Earth.