Development of Novel Bead Milling Technology with Less Metal Contamination by pH Optimization of the Suspension Medium.

To develop novel contamination-less bead milling technology without impairing grinding efficiency, we investigated the effect of the formulation properties on the grinding efficiency and the metal contamination generated during the grinding process. Among the various formulations tested, the combination of polyvinylpyrrolidone and sodium dodecyl sulfate was found to be suitable for efficiently pulverizing phenytoin. However, this stabilization system included a relatively strong acid, which raised the concern of possible corrosion of the zirconia beads. An evaluation of the process clearly demonstrated that acidic pH promoted bead dissolution, suggesting that this could be suppressed by controlling the pH of the suspension. Among the various pH values tested, the metal contamination generated during the grinding process could be significantly reduced in the optimized pH range without significant differences in the particle size of the phenytoin suspension after pulverization. In addition, the contamination reduction by pH optimization in the presence of physical contact among the beads was approximately 10-times larger than that without bead contact, suggesting that pH optimization could suppress not only bead dissolution but also the wear caused by bead collisions during the grinding process. These findings show that pH optimization is a simple but effective approach to reducing metal contamination during the grinding process.

Nanocrystal Preparation of Poorly Water-Soluble Drugs with Low Metal Contamination Using Optimized Bead-Milling Technology.

Nanocrystal preparation using bead milling is an important technology to enhance the solubility of poorly water-soluble drugs. However, there are safety concerns regarding the metal contaminants generated during bead milling. We have previously reported optimized bead-milling parameters that could minimize metal contamination and demonstrated comparable performance to NanoCrystal®, a world-leading contamination-free technology. This study aimed to investigate the applicability of optimized milling parameters for preparing nanocrystals of several poorly water-soluble drugs exhibiting various physicochemical properties. Using our optimized bead-milling parameters, we found that all the tested drugs could be ground into nanosized particles within 360 min. Notably, fenofibrate, which has a low melting point, could be ground into nanosized particles owing to the low level of heat generated during bead milling. Additionally, the concentration of metal contaminants in all the drugs prepared using the optimized milling parameters were approximately ten to twentyfold lower than those prepared without the optimized parameters and were comparable to those prepared using polycarbonate beads, known to minimize metal contamination during bead milling. Our results provide insights into the development of drug nanocrystals with low metal contamination using bead milling.

Three-layered microcapsules as a long-term sustained release injection preparation.

Three-layered milli-capsules (3LMC), diameter of 1.85+/-0.07 and 0.15+/-0.09 mm thickness, were designed for the long-term subcutaneous (sc) administration of drugs. 3LMCs composed of (1) surface membrane (release rate control membrane), (2) drug-carrying layer and (3) base membrane were prepared by dispensing each solution in series. As surface membrane, poly-(epsilon-caprolactone) having MW of 70 kDa (PCL70) was used in combination with plasticizer, polysorbate 60 (Tween60). Base membrane was prepared with PCL70. Fluorescein isothiocyanate labeled dextrans (FD-4, MW=4 kDa and FD-20, MW=20 kDa) were used as model drug and in vitro release experiment was performed with PCL70 surface membrane containing Tween60 with 0.3, 1.0 and 3.0% (w/w). As the amount of Tween60 increased, release rate of FD-4 was increased. PCL70+0.3% Tween60 membrane showed a good sustained release property for 5 weeks; 50.3+/-6.0% of FD-4 was released during 5 weeks. When FD-20 was encapsulated, long-term sustained release was not obtained, 10.7+/-3.6% was released during 5 weeks. However, when lower MW drug, leuprolide acetate, was encapsulated, 3LMC composed of PCL70+0.3% Tween60 showed a good sustained release property, 63.0+/-5.9% released for 5 weeks. Leuprolide acetate encapsulated 3LMC was evaluated in rat experiment. After sc administration to rats, 0.5 and 1.0 mg, plasma leuprolide concentration showed its maximum concentration at day 1, thereafter gradually decreased and maintained the effective concentration for 14 weeks. Plasma leuprolide concentration vs. time curve showed a good dose-dependency. When surface membrane prepared by blending PCL70 and poly(lactic acid) (PLA) in the molar ratio of 5:1 was used, long-term sustained release property was not obtained. Instead, lower MW PCL, PCL40, was blended with PLA (5:1) to prepare surface membrane, sustained release of leuprolide was observed for 5 weeks. Through those studies, 3LMC has been shown to be a long-term sustained release preparation by properly selecting the surface membrane.