Investigation of utilization of nanosuspension formulation to enhance exposure of 1,3-dicyclohexylurea in rats: Preparation for PK/PD study via subcutaneous route of nanosuspension drug delivery

1,3-Dicyclohexylurea (DCU), a potent soluble epoxide hydrolase (sEH) inhibitor has been reported to lower systemic blood pressure in spontaneously hypertensive rats. One limitation of continual administration of DCU for in vivo studies is the compound's poor oral bioavailability. This phenomenon is mainly attributed to its poor dissolution rate and low aqueous solubility. Previously, wet-milled DCU nanosuspension has been reported to enhance the bioavailability of DCU. However, the prosperities and limitations of wet-milled nanosuspension have not been fully evaluated. Furthermore, the oral pharmacokinetics of DCU in rodent are such that the use of DCU to understand PK/PD relationships of sEH inhibitors in preclinical efficacy model is less than ideal. In this study, the limitation of orally delivered DCU nanosuspension was assessed by a surface area sensitive absorption model and pharmacokinetic modeling. It was found that dosing DCU nanosuspension did not provide the desired plasma profile needed for PK/PD investigation. Based on the model and in vivo data, a subcutaneous route of delivery of nanosuspension of DCU was evaluated and demonstrated to be appropriate for future PK/PD studies

Applications of liposomes on anti-cancer agents

Toxicity is a major limitation in clinical use of most anticancer drugs. Liposomes, especially targeted long-circulating liposomes, provide the possibility of delivering drugs specifically to targeted cancer tissues, thus increasing anticancer activity and minimizing toxicity. 2-4'-Amino-3'-methylphenylbenzothiazole (AMPB), a potent anticancer drug, is inappropriate for traditional oral or parenteral formulations because of its severe dose-limiting hepatotoxicity. Several PEG-coated liposomal formulations were developed by using different drug/lipid ratios. Particle size and encapsulation efficiency of each formulation were investigated; the most stable liposomal formulation was selected for animal testing. The formulation with AMPB/egg phosphatidyl choline/cholesterol/1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-polyethylene glycol 2000, PEG2000-DSPE in a 1/5/5/1 molar ratio is the best formulation. This formulation contains 2 mg/ml AMPB with encapsulation efficiency above 95%, average particle size 120-150 nm. Daunorubicin is a well known anti cancer agent. To minimize its cardiotoxicity, targeted folate-PEG-liposomes were developed in this study. The pH-gradient loading method was used to increase the drug loading efficiency. Above 97% loading efficiency was reached by creating a 3 to 4 unit pH difference across the liposome membrane. The final folate-PEG-liposomml formulation contained 2.5 mg/ml daunorubicin HCI, with average particle size of 110∼120 nm, pH of ∼7.4, and a drug/lipid ratio 1/20 (w/w). The solvent, chloroform, commonly used for liposome preparation, is harmful to humans. Therefore, halothane, a commonly used inhalation anesthetic, was used in this study in place of chloroform to prepare liposomes. AMPB and several other proprietary anticancer agents were formulated in liposomes by using halothane and chloroform. No obvious differences in physicochemical properties were observed between halothane and chloroform mediated liposomes

Effect of pH-sodium lauryl sulfate combination on solubilization of PG-300995 (an Anti-HIV agent): A technical note

Solubilization of PG-300995 has been achieved using SLS at low pH. However, at a pH where both the solute and surfactant are ionized, desolubilization can occur owing to the formation of an insoluble estolate salt. This salt can be solubilized by higher concentrations of SLS

Solubilization of cyclosporin A

This study investigated the solubilization of cyclosporin A (CsA), a neutral undecapeptide, by cosolvency, micellization, and complexation. Cosolvents (ethanol, propylene glycol, polyethylene glycol, tetrahydrofurfuryl alcohol polyethyleneglycol ether, and glycerin), surfactants (polyoxyethylene sorbitan monooleate [(Tween 80)], polyoxyethylene sorbitan monolaurate [(Tween 20)], and Cremophor EL), and cyclodextrins (α-cyclodextrin [(αCD)] and hydroxypropyl-β-cyclodextrin[(HP\CD)] were used as solubilizing agents in this study