betadex and tocophersolan

Multidrug resistance (MDR) remains as an obstacle for effective cancer treatment. Herein, we developed a novel and efficient nanomedicine by virtue of the carrier characters and MDR inhibition effects of β-cyclodextrin (β-CD) and d-α-tocopheryl polyethylene glycol succinate (TPGS). A series of star-shaped polymers CD-g-TPGS with different TPGS substitution degree were synthesized for doxorubicin (DOX) delivery, where β-CD was identified as a core and TPGS as branches. These star polymers can self-assemble into nanoparticles with DOX. These nanoparticles showed no significant differences in size, zeta potential and morphology except for in vitro stability. They demonstrated good biocompatibility and enhanced cellular uptake in both drug sensitive and resistant cancer cells. Notably, the nanoparticles exhibited superiority of cytotoxicity in drug resistant cancer cells against free DOX. In vivo antitumor effect also demonstrated the improved cancer inhibition effect. This work suggests that star-shaped polymers CD-g-TPGS are promising drug carriers to overcome MDR in cancer treatment.

Topics: Animals; Antibiotics, Antineoplastic; beta-Cyclodextrins; Cell Proliferation; Cell Survival; Doxorubicin; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Female; Humans; Liver Neoplasms; MCF-7 Cells; Mice; Mice, Inbred Strains; Molecular Structure; Particle Size; Polyethylene Glycols; Polymers; Succinates; Surface Properties; Tumor Cells, Cultured; Vitamin E

The pharmaceutical use of some 3-hydroxyquinolinone derivatives with high cytotoxic and cytostatic activities (under in vitro conditions) as well as potential immunosuppressive properties is seriously limited by their low solubility in water accompanied by instability in oxidative environment, like physiological fluids. In an attempt to improve the bioavailability and the stability of four of these derivatives, we propose here two different approaches: complexation with β-cyclodextrin derivatives and incorporation of these substances inside antioxidant micelles. The comparison of the two different methods is the focus of this work, as well as the investigation of some physicochemical properties of the micellar aqueous dispersions. Antioxidant micellar dispersions appear to be suitable for increasing the apparent solubility and stability for all the compounds studied, most probably because of the antioxidant activity of the specific surfactant used, combined with the low amount of water present in the center of the micelles. On this regard, (1)H NMR and UV-vis spectroscopy result as efficient tools to verify that the drug molecules are indeed placed in the core of the micelles. Moreover, freeze-drying provides a very easy and powerful technique to obtain solid formulations starting from micellar dispersions. On the contrary, cyclodextrins could potentially be used as solubilizing agents, but the drawback connected to degradation in aqueous media could not be overcome with this type of solubilizer.

Topics: Antioxidants; beta-Cyclodextrins; Biological Availability; Chemistry, Pharmaceutical; Cytostatic Agents; Drug Stability; Freeze Drying; Hydroxyquinolines; Kinetics; Magnetic Resonance Spectroscopy; Micelles; Particle Size; Photoelectron Spectroscopy; Polyethylene Glycols; Solubility; Surface-Active Agents; Vitamin E; Water

Biocompatible microparticles prepared by lyophilization were developed for intranasal protein delivery. To test for the feasibility of this formulation, stability of the incorporated protein and enhancement of in vitro permeation across the nasal epithelium were evaluated. Lyophilization was processed with hydroxypropylmethylcellulose (HPMC) or water soluble chitosan (WCS) as biocompatible polymers, hydroxypropyl-β-cyclodextrin (HP-β-CD) and d-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) as permeation enhancers, sugars as cryoprotectants and lysozyme as the model protein. As a result, microparticles ranging from 6 to 12μm were developed where the maintenance of the protein conformation was verified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), circular dichroism and fluorescence intensity detection. Moreover, in vitro bioassay showed that the lysozyme activity was preserved during the preparation process while exhibiting less cytotoxicity in primary human nasal epithelial (HNE) cells. Results of the in vitro release study revealed slower release rate in these microparticles compared to that of the lysozyme itself. On the other hand, the in vitro permeation study exhibited a 9-fold increase in absorption of lysozyme when prepared in lyophilized microparticles with HPMC, HP-β-CD and TPGS 1000 (F4-2). These microparticles could serve as efficient intranasal delivery systems for therapeutic proteins.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Absorption; Administration, Intranasal; beta-Cyclodextrins; Chitosan; Freeze Drying; Humans; Hypromellose Derivatives; Methylcellulose; Muramidase; Nasal Mucosa; Particle Size; Polyethylene Glycols; Powders; Primary Cell Culture; Protein Stability; Succinates; Vitamin E

In this work, we evaluated the chemical stability profiles of UC781 based solutions to identify excipients that stabilize the microbicidal agent UC781. When different antioxidants were added to UC781 in sulfobutylether-beta-cyclodextrin (SBE-beta-CD) solutions and subjected to a 50 degrees C stability study, it was observed that EDTA was a better stabilizing agent than sodium metabisulfite, glutathione or ascorbic acid. Some antioxidants accelerated the degradation of UC781, suggesting metal-catalyzed degradation of UC781. Furthermore, we observed substantial degradation of UC781 when stored in 1% Tween 80 and 1% DMSO solutions alone or in those with 10mM EDTA. On the other hand, improved stability of UC781 in the presence of 100 and 200mM of EDTA was observed in these solutions. The addition of both EDTA and citric acid in the stock solutions resulted in recovery of more than 60% of UC781 after 12 weeks. Generally, 10% SBE-beta-CD in the presence of EDTA and citric acid stabilized UC781 solutions: the amount of UC781 recovered approaching 95% after 12 weeks of storage at 40 degrees C. We also showed that the desulfuration reaction of the UC781 thioamide involves oxygen by running solution stability studies in deoxygenated media. Improved stability of UC781 in the present study indicates that the incorporation of EDTA, citric acid and SBE-beta-CD and the removal of oxygen in formulations of this drug will aid in increasing the stability of UC781 where solutions of the drug are required.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Anilides; Antioxidants; Antiviral Agents; Ascorbic Acid; beta-Cyclodextrins; Chemistry, Pharmaceutical; Dimethyl Sulfoxide; Drug Compounding; Drug Stability; Edetic Acid; Excipients; Fumarates; Furans; Glutathione; Hot Temperature; Models, Chemical; Oxidation-Reduction; Polyethylene Glycols; Polysorbates; Solubility; Sulfites; Technology, Pharmaceutical; Thioamides; Time Factors; Vitamin E