Controlled release of a protein kinase inhibitor UCN-01 from liposomes influenced by the particle size.

A protein kinase inhibitor UCN-01 binds with high affinity to human alpha 1-acid glycoprotein (hAGP) which may compromise the drugs therapeutic effectiveness. Liposomal formulations of UCN-01 have been evaluated as a means of reducing the impact of binding to hAGP. However, in an initial study, UCN-01 was released rapidly from liposomes added to rat plasma containing hAGP. The purpose of this study was to develop a liposomal formulation of UCN-01 that only slowly released drug. Liposomes composed of lipids with a high phase transition temperature and having an average particle size of 120 nm and above reduced leaking of UCN-01 when the formulations were evaluated by adding to rat plasma containing hAGP. Furthermore, formulations composed of larger liposomes were also more effective in vivo; in tests in which liposomal preparations were injected together with hAGP into rats, more UCN-01 was retained in liposomes for 24h after administration of 155 nm liposomes as compared to 112 nm liposomes.

Development of wrapped liposomes: novel liposomes comprised of polyanion drug and cationic lipid complexes wrapped with neutral lipids.

Novel wrapped liposomes comprised of polyanion drug and cationic lipid complexes wrapped with neutral lipids were prepared using an efficient, innovative procedure. In this study, dextran fluorescein anionic (DFA) was used as an example of a polyanionic compound. During the process, neutral lipids accumulated around the complexes and eventually covered the complexes. The resulting liposomes were 120-140 nm in diameter and the encapsulation efficiency was up to 90%. In fetal bovine serum, DFA/cationic lipid complexes degraded rapidly but the wrapped liposomes were considerably more stable. Following intravenous administration to rats, DFA/cationic lipid complexes were rapidly eliminated whereas the wrapped liposomes exhibited a much longer blood half-life. These data suggest that DFA is located on the surface of the complexes, but DFA is present inside the wrapped liposomes. The drug-delivery properties of the wrapped liposomes established in the present study suggests that formulations based on this technology could offer important advantages for the administration of many types of drug including antisense oligonucleotides, plasmids and siRNAs which may therefore lead to improved therapeutic effectiveness of this range of drugs. The method of preparation of the wrapped liposomes is so simple that it should be straightforward to adapt to a manufacturing scale.

Improved formulations of antisense oligodeoxynucleotides using wrapped liposomes.

Previously, we demonstrated that wrapping dextran fluorescein anionic/cationic lipid complexes with neutral lipids produced a stable formulation that markedly increased the duration of the compound in plasma after intravenous administration to rats. The improved drug-delivery properties of the wrapped liposomes (WL) relative to other formulations suggested that this technology could offer important advantages for the administration of other polyanionic drugs, including antisense oligodeoxynucleotides (ODN). In the present study, we investigated the value of WL for formulating fluorescence-labeled phosphorothioated ODN (F-ODN). WL encapsulating F-ODN/cationic lipid complexes were prepared efficiently using similar methodology to that used in our earlier study. Studies confirmed that these WL were stable in vitro. Following intravenous administration to mice, free F-ODN and naked F-ODN/cationic lipid complexes were rapidly eliminated whereas administration of the WL resulted in high blood concentrations of drug that were maintained for several hours. Additional studies were conducted in mice that were inoculated with tumor cells (Caki-1 xenograft model, human kidney); in these experiments, intravenous administration of WL delivered 13 times more F-ODN to the tumor site than achieved after injection of free F-ODN.

Characterization of latex particles for aqueous polymeric coating by electroacoustic method.

Concentrated dispersions are used as coating dispersions for aqueous polymeric coatings, and characterization of the actual concentrated dispersions is an important in the pharmaceutical industry. The commonly used aqueous coating polymers are acrylic polymers and cellulose derivatives. We conducted a characterization study of polymethacrylate-based aqueous polymeric latex for aqueous coating, Eudragit L30D-55 (A-latex) and Eudragit RL30D (C-latex), by electroacoustic method. Colloidal Vibration Current (CVI) is one of the most important parameters relating to dynamic electrophoretic mobility and zeta potential, so we evaluated this parameter first. Volume fractions var of the latex in concentrated dispersions affect the CVIs according to the theory of Dukhin et al. The A-latex and C-latex CVI(*)s which were corrected with regard to the effect of volume fraction by the theoretical equation were nearly constant independent of phi in the ranges >0.04 and >0.03, respectively. The zeta potentials and colloidal stabilities of the concentrated dispersions were evaluated using an electroacoustic method by altering the pH and salt concentration. A-latex strongly aggregated at and below pH 2.5 and at and beyond 0.06 mol/L of electrolyte concentration. Regarding C-latex, instable dispersion was observed at 0.3 and 1 mol/L of NaCl concentration. The total potential energy of interaction between pairs of latex particles was changed by altering the salt concentration in this dispersion based on DLVO theory. The experimental results of stability in the concentrated latex dispersions can be explained by the total interaction energies.

Colloidal stability of aqueous polymeric dispersions: effect of water insoluble excipients.

An important issue in the aqueous coating process is dispersion stability. An unstable dispersion results in aggregation of the colloidal particles, thereby affecting the film coating process. In the coating suspension containing pigment, a latex for aqueous film coating might interact with pigment, resulting in unstable dispersion. We therefore conducted a stability investigation in a mixed dispersion including latexes, EudragitL30D-55 (A-latex), EudragitRL30D (C-latex) and EudragitNE30D (N-latex) and pigments, titanium dioxide and iron oxide yellow. An aggregation of the dispersion containing A-latex was observed at pH 2. Regarding the dispersions with C-latex and N-latex, no aggregation was observed in the range pH 2-11. We calculated total interaction energy between latex-latex particles, pigment-pigment particles and latex-pigment particles based on DLVO theory. The calculated results explained two mechanisms of the stable mixed dispersion. The first was that the individual latex particle and the pigment particle dispersed without aggregation in the mixed dispersion because of the electrostatic interaction. The next was that the latexes adsorbed onto the surface of the pigments, making electrostatically stable heterocoaggregates. We also calculated the binding constant of iron oxide yellow for C-latex at pH 10. The value of the constant was determined to be 1.1 x 10(-2).

Release of drugs from liposomes varies with particle size.

The efficacy of many drugs is improved by liposomal formulations. The greatest improvements in therapeutic benefits are achieved if the drug is retained in the liposomes for several hours after administration. Many basic drugs can be concentrated efficiently into liposomes in response to a transmembrane pH gradient. However, the rate of release from liposomal formulations is drug-dependent; for example, doxorubicin is released slowly from liposomes whereas vincristine leaks out rapidly. The aim of this study was to identify the causes of the rapid release of drugs from liposomes and then to apply this knowledge to the development of more stable formulations. Our initial focus was to explore the influence of liposomal size on the rate of release of drugs. The retention of doxorubicin within liposomes was independent of the particle size as far as this experimental condition was concerned. However, the rate of release of vincristine varied in relation to the particle size of the liposomes; vincristine was retained more effectively in larger liposomes. Experimental data generated using (31)P-NMR analysis and trap volume measurements, indicated that the number of lipid bilayers in liposomes increased as the particle size was increased. Additional lipid bilayers are likely to present a more effective barrier thereby slowing the release of drugs.