Physicochemical and Pharmacokinetic Characterization of a Spray-Dried Cefpodoxime Proxetil Nanosuspension

Abstract

Cefpodoxime proxetil (CP) is a prodrug, broad spectrum, third generation cephalosporin ester. This prodrug ester is absorbed from the intestinal tract after oral administration and is hydrolyzed in vivo into the active cefpodoxime.1) Although CP is designed to improve the permeability and thus bioavailability of cefpodoxime, it still has only 50% oral bioavailability, when administered orally.2) The reported explanations for the low bioavailability of CP include low solubility in aqueous solution, typical gelation behavior in acidic aqueous environments and pre-absorption luminal metabolism of cefpodoxime by the action of digestive enzymes. 3,4) Metabolism of CP into cefpodoxime inside the intestinal epithelial cell and preferential efflux of cefpodoxime into lumen is also another contribution to the low bioavailability of CP. 5)Recently, nanosuspensions have shown promising potential in drug delivery to offer a unique solution for the poor bioavailability of poorly water-and lipid-soluble drugs. Nanosuspensions are colloidal dispersions of nano-sized drug particles stabilized by suitable stabilizers. Nanosuspensions are unique because of their simplicity and the advantages they confer over other formulation strategies.6) Oral nanosuspensions have been specifically used to increase the rate and extent of the absorption of poorly water-soluble drug, to enhance the onset of action, to reduce the fed/fasted ratio, and to enhance the bioavailability. In other cases, the particulate nature of nanosuspensions can be useful in the targeting of the monocyte phagocytic system, bypassing the passage of drug through epithelial cells with improved pharmacokinetic consequences.7) Nanosuspensions can also be used in controlled drug delivery systems. 8)Nanosuspension is generally prepared to be a liquid form. In order to prepare the solid dosage form for the purpose of better physical and chemical stability, spray drying is one of the commonly used techniques for solidification. However, research literature that discusses the use of spray drying for nanosuspension is limited. Recently, the spray dried nanosuspension of itraconazole was prepared.9) The emphasis was to examine the impact of various formulation and processing parameters on redispersibility of the spray dried nanoparticles and in-vitro dissolution. The in-vivo study was not performed to demonstrate the bioavailability enhancement by nanosuspension.As a solid product, solid spray-dried cefpodoxime proxetil nanosuspension (SDN) will be reconstituted in aqueous solution to form the liquid state prior to administration. It's better for SDN to regain its original state. For a heterogeneous disperse system, the rheological and thixotropic properties are important for its physical stability and clinical use. However, literature for the rheological and thixotropic properties of nanosuspensions is lacking.The main objective of the present study is to characterize the physicochemical properties of the liquid nanosuspension prepared by high pressure homogenization and SDN. I...

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