(70cw) Improved Dissolution Properties of a Poorly Water-Soluble Drug by the Nanosuspension Spray-Coating System

Purpose: Poorly water-soluble drugs often exhibit variable bioavailability and bio-inequivalence due to its poor water-solubility. The purpose of this study is to develop a technique to enhance the dissolution rate of poorly water-soluble drugs by the nanosuspension spray-coating system (NSCS). Methods: As model drugs, naproxen (NPX), griseofulvin (GRI), and glibenclamide (GLI) were selected. Their particle sizes as received were 32, 22, and 14 micrometers, and the water solubilities were 50, 13, and 6.0 mg/L at pH 6.8. They were formulated with soybean lecithin (SL), polyvinylpyrrolidone (PVP), and purified water at a weight ratio of drug:SL:PVP:water=3:1:0.4:20, 1:1:0.2:10, 1:3:0.4:20, and 1:9:1:50. The mixture was co-ground using a planetary ball mill. Eighty grams of zirconium oxide balls of 1 mm diameter and 2.2 g of the drug mixture were loaded into a 45-ml agate pot and then ground at 156 r.p.m.. The particle size of ball-milled drugs was analyzed by a laser scattering diffraction method. The prepared nanosuspension was spray-dried onto glass plate to characterize by the X-ray diffraction (XRD) and the differential scanning calorimetry (DSC). The formulation of the nanosuspension at a weight ratio of drug:SL:PVP:water=3:1:0.4:20 was selected in order to obtain microparticles (MPs) due to its high drug content and its low additive content. The aqueous nanosuspension was sprayed onto lactose cores (75?106 micrometers) in the Wurster coating process to prepare the MPs with a surface layer of drug-lecithin composite. Dissolution studies were preformed on JP paddle method at 100 rpm using 500 ml distilled water at 37˚C, and the second fluid was selected for a dissolution medium of GLI. The concentration of drug in the samples was determined by HPLC. Results: At a weight ratio of drug:SL:PVP:water=3:1:0.4:20, the particle size of NPX and GRI was not decreased after 60 min any more. The each particle size of drugs ball-milled for 60 min was 0.25 and 0.26 micrometers, respectively. On the other hand, GLI required 120 min until decrease in the particle size leveled off around 0.25 micrometers. In all the drugs, XRD studies showed that the lower the drug content of the prepared nanosuspension was, the lower the height of the diffraction peaks of drug was, but the positions of the diffraction peaks of drugs were not altered. The crystallinity of drug in the MPs was nearly 100%. This was as expected because the high crystallinity of drugs was desirable in order to avoid temporal change of their solubilities by the amorphous-to-crystalline transformation during the storage. MPs were obtained at a yield of more than 80%. The apparent solubility and the dissolution rate of drugs were significantly increased with both the MPs and the physical mixture (PM), compared with the original crystals: the results from the simple physical mixture seemed due to the presence of lecithin that acts as a wetting and solubilizing agent. The dissolution rate of all the drugs in the first 1 min was significantly improved in the MPs: 38, 54 and 69- fold higher when compared to that in the NPX, GRI and GLI crystals alone, respectively. The improved dissolution properties of the model drugs were mainly ascribed to a good-dispersibility of the MPs in the dissolution media due to the rapid hydration of thin-layer of drug-lecithin composites. Conclusion: The results demonstrated that the proposed NSCS technique would be an efficient method to improve the dissolution properties of poorly water-soluble drugs.