Identification of a series of substituted 2-piperazinyl-5-pyrimidylhydroxamic acids as potent histone deacetylase inhibitors.

Pursuing our efforts in designing 5-pyrimidylhydroxamic acid anti-cancer agents, we have identified a new series of potent histone deacetylase (HDAC) inhibitors. These compounds exhibit enzymatic HDAC inhibiting properties with IC(50) values in the nanomolar range and inhibit tumor cell proliferation at similar levels. Good solubility, moderate bioavailability, and promising in vivo activity in xenograft model made this series of compounds interesting starting points to design new potent HDAC inhibitors.

Effect of the unstirred water layer on permeability enhancement by hydrophilic cyclodextrins.

Saturated solutions of three test compounds, carbamazepine, griseofulvin and hydrocortisone, were prepared in aqueous buffer (pH 7.4) containing 0, 1, 5 and 10% HPbetaCD. The permeability and flux of the drugs though a PAMPA membrane at different unstirred water layer (UWL) thicknesses was determined. In absence of HPbetaCD, permeability coefficients increased two- to three-fold with decreasing UWL thickness to a certain minimum values of about 40 microm. Addition of HPbetaCD to systems exhibiting larger UWL thicknesses significantly increased compound flux. The effect of HPbetaCD was linked to its association constant (K(1:1)) with the model drugs and decreased with decreasing UWL thickness to a certain minimum value. This suggests that hydrophilic cyclodextrins enhance flux when the UWL resistance significantly contributes to the overall barrier resistance.

Self-assembling PEG-p(CL-co-TMC) copolymers for oral delivery of poorly water-soluble drugs: a case study with risperidone.

Diblock PEG-p(CL-co-TMC) [methoxypoly(ethylene glycol)-poly(caprolactone/trimethylene carbonate)] copolymers form micelles spontaneously and significantly increase the solubility of poorly water-soluble drugs. The aim of this work was to assess these diblock copolymers as oral drug delivery systems in both in vitro and in vivo experiments using risperidone as a model drug. The permeation of risperidone through Caco-2 cell monolayers showed that the apparent permeation coefficient (Papp) was slightly reduced when risperidone was formulated with the copolymer. Based on the higher apparent drug solubility, the copolymer increased drug flux or the total amount of drug which crossed the Caco-2 monolayers. The Papp of the micelle formulation was higher at 37 degrees C than at 4 degrees C. After oral administration to rats, the pharmacokinetic parameters and the pharmacological effect were evaluated. Time courses of receptor occupancy by risperidone after oral administration were similar when risperidone was encapsulated in PEG-p(CL-co-TMC) micelles or solubilized in an aqueous tartaric acid vehicle. The areas under the curve (AUC) were not significantly different although the maximal concentration (Cmax) was twofold lower with the copolymer. The polymeric micelles of PEG-p(CL-co-TMC) seem to be a good candidate for oral drug delivery of poorly soluble drugs.

Incorporation of drugs in an amorphous state into electrospun nanofibers composed of a water-insoluble, nonbiodegradable polymer.

Electrostatic spinning was applied to the preparation of drug-laden nonbiodegradable nanofiber for potential use in topical drug administration and wound healing. The specific aim of these studies was to assess whether these systems might be of interest as delivery systems for poorly water-soluble drugs. Itraconazole and ketanserin were selected as model compounds while a segmented polyurethane (PU) was selected as the nonbiodegradable polymer. For both itraconazole and ketanserin, an amorphous nanodispersion with PU was obtained when the drug/polymer solutions were electrospun from dimethylformide (DMF) and dimethylacetamide (DMAc), respectively. The collected nonwoven fabrics were shown to release the drugs at various rates and profiles based on the nanofiber morphology and drug content. Data were generated using a specially designed release apparatus based around a rotating cylinder. At low drug loading, itraconazole was released from the nanofibers as a linear function of the square root of time suggesting Fickian kinetics. No initial drug burst was observed. A biphasic release pattern was observed for ketanserin in which two sequential linear components were noted. These release phases may be temporally correlated with (1) drug diffusion through the polymer and (2) drug diffusion through formed aqueous pores.