Water-Soluble Polymeric Derivative of Ofloxacin Ketimine: Synthesis and Antituberculosis Activity

As alveolar macrophages are attractive targets for the treatment of tuberculosis, effective methods for delivery to alveolar macrophages are under development. We investigated a pulmonary formulation for the efficient delivery of high water-soluble drugs at high concentration targeting alveolar macrophages. In this study, a surfactant-coated high water-soluble drug complex (SDC, a hydrophobic dried emulsion), which can preferably target alveolar macrophages and be expected to deliver drug at a high concentration, was prepared in the first process. OCT313, a high water-soluble sugar derivative with anti-tuberculosis activity was used. Then, a unique two-solution, mixing-type nozzle was used to prepare the SDC nanoparticles in mannitol (MAN) microparticles (SDC/MAN microparticles) because it was difficult to disperse the SDC nanoparticles in aqueous solution. The single micron size of OCT313-SDC/MAN microparticles contained OCT313-SDC nanoparticles (mean particle size of OCT313-SDC nanoparticles, 277.9 nm; drug contents, 1.31 ± 0.041 wt%). We found that the treatment of SDC/MAN microparticles exhibited significantly higher drug accumulation in macrophage cells (Raw264.7 cells, 7.5-fold, at 4 h after treatment) in vitro and in alveolar macrophages in rats (9.1-fold, at 4 h after treatment) in vivo than that of drug alone. These results suggest that the SDC/MAN microparticle formulation prepared by spray drying through a two-solution mixing-type nozzle provides efficient delivery of a water-soluble drug targeting alveolar macrophages and may be useful for tuberculosis treatment.

We have studied the interaction of a polymeric water soluble anthracenyl derivative () with salmon testes DNA. The results from UV-Vis, fluorescence, Fourier transform infrared (FT-IR) and circular dichroism spectroscopies indicate that the groove binding process regulates the interaction between and DNA. The binding constants, calculated by absorption spectroscopy at 298, 304 and 310 K, were equal to 3.2 × 10(5) M(-1), 4.7 × 10(5) M(-1), and 6.6 × 10(5) M(-1) respectively, proving a relatively high affinity of for salmon testes DNA. Results of Hoechst 33258 displacement assays strongly support the groove binding mode of to DNA. The association stoichiometry of the :DNA adduct was found to be 1 for every 5 base pairs. FT-IR spectra, recorded at different /DNA molar ratios, indicate the involvement of the phosphate groups and adenine and thymine DNA bases in the association process. Thermodynamic results suggest that hydrophobic forces regulate the binding of with DNA without excluding some extent of involvement of van der Waals forces and hydrogen bonding arising due to surface binding between the hydrophilic polymeric arms of the ligand and the functional groups positioned on the edge of the groove. The resulting composite biomaterial could constitute a valuable candidate for future biological and/or photonic applications.

New polymeric systems with controlled release action: a light scattering investigation

On the basis of hydrophilic copolymers of N-vinylamides—N-vinylpyrrolidone and N-methyl-N-vinylacetamide—that contain carboxylic or activated ester groups, new polymeric β-cyclodextrin derivatives are synthesized via polymer-analogous transformations. Their solubility in water depends on the content of β-cyclodextrin and the types of hydrophilic and reactive comonomers.

In this study, we tested the efficacy of amphotericin B (AmB)-arabinogalactan (AmB-AG) conjugates for the treatment of experimental leishmaniasis. Chemical conjugation of AmB to a water-soluble, biodegradable, and biocompatible polymer could present many advantages over presently available AmB formulations. Two conjugates were tested, a reduced (rAmB-AG) form and an unreduced (uAmB-AG) form. In vitro, the drug concentrations which lower the values of parasites (for promastigotes) or infected macrophages (for amastigotes) to 50% of the untreated values (ED(50)s) of uAmB-AG and rAmB-AG were 0.19 and 0.34 microg/ml, respectively, for Leishmania major promastigotes and 0.17 and 0.31 microg/ml, respectively, for amastigotes. The effect on Leishmania infantum-infected macrophages was more marked, with ED(50)s of 0.035 microg/ml for rAmB-AG and 0.027 microg/ml for uAmB-AG. In in vivo experiments, BALB/c mice injected with L. major were treated from day 2 onwards on alternate days for 2 weeks. Both conjugates, as well as liposomal AmB (all at 6 mg/kg of body weight) and Fungizone (1 mg/kg), significantly delayed the appearance of lesions compared to that in untreated mice. In addition, both conjugates, but not liposomal AmB, were significantly more effective than Fungizone. Subcutaneous injection of the conjugates (6 mg/kg) was significantly more effective than liposomal AmB in delaying the appearance of lesions. Higher AmB concentrations of up to 12 mg/kg could be administered by this route. When an established infection was treated, uAmB-AG was somewhat more effective than liposomal AmB. In summary, water-soluble polymeric AmB derivatives were found effective and safe for the treatment of leishmanial infections. The conjugates, which are stable and can be produced relatively cheaply (compared to lipid formulations), can be used in the future for the treatment of leishmaniasis infections.

Water-soluble methanofullerene and fulleropyrrolidine derivatives were synthesized by the reactions of methanofullerenes (MFs) and fulleropyrrolidines (FPs) with poly(N-vinylpyrrolidone) (PVP) bearing one terminal amino group. The products contain MF or FP covalently bound to the polymer, corresponding polymeric complexes, and unreacted PVP. Large aggregates of the polymeric MF and FP derivatives are found in aqueous solutions. The electrooptical properties of the products differ considerably from those of the initial polymer. The phosphorus-containing MF and FP derivatives are capable of cleaving the molecule of plasmid DNA.

In this study, we compared the suitability of parent β-cyclodextrin (βCD) and its water soluble polymeric derivative (PβCD) as co-grinding additives aimed to enhance the solubility of zaleplon (ZAL), a hypnotic drug. Equimolar drug/carrier mixtures were co-ground in a high-energy micromill over different time intervals. Data obtained by differential scanning calorimetry, X-ray powder diffractometry and scanning electron microscopy showed a higher affinity of ZAL for the solid state interaction with PβCD, resulting in powders with lower relative drug crystallinity (RDC) compared to that obtained with natural βCD (RDC = 51.10 and 12.5 % for complexes with βCD and PβCD co-grounded for 90 min, respectively). On the other hand, grinding the drug alone did not result in a significant reduction of the drug crystallinity (RDC = 99.87 % for the sample ground for 90 min). Although 1H-NMR spectroscopy confirmed that both co-ground products were readily converted into inclusion complexes upon dissolution in water, they presented different dissolution properties. The dissolution velocity of co-ground complex with PβCD was 25 % faster compared to that prepared with the parent βCD and almost double compared to that of the drug alone, irrespective of the pH value of the dissolution media. This clearly demonstrated the suitability of co-ground ZAL/PβCD complex in the development of an immediate release oral formulation of ZAL.

Analysis of triclosan inclusion complexes with β-cyclodextrin and its water-soluble polymeric derivative

Synthesis and pharmacological investigation of water-soluble polymeric derivatives of glucocorticoids

Synthetic analogues of polynucleotides: VI. The synthesis of ribonucleoside dialdehyde derivatives of polyacrylic acid hydrazide and their interaction with polynucleotides

Synthesis, characterization and application of Epichlorohydrin-β-cyclodextrin polymer

Multilamellar (MLV) and large unilamellar (LUV) lipid vesicles (liposomes) trap the metallochromic dye arsenazo III [2,7-bis(arsonophenylazo)-1,8-dihydroxynaphthalene-3,6-disulfonic acid ] in their aqueous compartments. When ionophore A23187 was preincorporated into either MLV or LUV above 0.001 mol%, addition of Ca to the outside of liposomes produced spectral shifts characteristic of the Ca . AIII2 complex. The method permitted detection of two molecules of A23187 per liposome. Liposomes with A23187 were permselective: divalent cations were translocated in the order Mn greater than Ca greater than Sr greater than Mg congruent to Ba. Because prostaglandins (PGs) may act as Ca ionophores, we have incorporated into MLVs and LUVs stable prostaglandins (PGE2, PGI2, PGB1), endoperoxide analogs, and a water-soluble, polymeric derivative of PGB1:PGBx. None acted as ionophore. In contrast, when added to the outside of preformed MLV or LUV, PGBx, at concentrations above 1 micro M, provoked permselective uptake of Ca equivalent to that induced by 10 nM A23187. These studies demonstrate not only that liposomes containing arsenazo III may be employed in a sensitive asssay for agents that translocate divalent cations, but that a water-soluble derivative of a naturally occurring fatty acid, PGBx, is a potent ionophore.