Nanocrystal formulation for poorly soluble drugs

Poorly soluble drugs are often a challenging problem in drug formulation. Reducing the particle size of the drug to a nano-scale leads to an increased surface area-to-volume ratio, increased dissolution velocity and adhesiveness, and improved in vivo performance of poorly soluble drugs. Wet media milling is one of the most popular techniques to prepare the nanocrystals. The aim of this thesis was to optimize the preparation conditions and characterization methods of nanosuspensions for poorly water-soluble drug compounds, then formulate the nanosuspensions into suitable pharmaceutical dosage forms, and finally test the efficacy in in vivo. Firstly, basic research on the preparation and characterization of nanosuspensions was done using the wet milling technique and poorly water-soluble drugs as model compounds. The various milling parameters, including the milling time, diameter of milling balls, stabilizer type and concentrations, were investigated. The particle size, size distribution and stability of nanosuspensions were considered as the important parameters to evaluate the milling conditions. The drug nanocrystals manufactured at the optimal milling environment exhibited significantly increased dissolution rates, good stability and kept a crystalline state. Secondly, the importance of particle size on dissolution was determined. The conventional dissolution method can effectively discriminate the milled and unmilled samples, but it fails to discriminate the dissolution profiles of nanosuspensions with different particle sizes. A novel condition, i.e. the sample concentration in the dissolution medium is close to the apparent saturation solubility of the drug, were found to discriminate the dissolution profiles of nanosuspensions. Thirdly, nanos-in-micros structure for suitable pharmaceutical formulations, e.g. tablet or pulmonary products was set up. The structure is that drug nanocrystals are buried inside microparticle carriers, in which the mannitol and crystalline L-leucine were as matrix and outer layer formers, respectively. Nanos-in-micros structure avoids problems in further formulation of nanopowders, such as poor flowability and aggregation/sinter, meanwhile functionality of individual nanoparticles in microparticles are remained, such as fast dissolution. Finally, the efficacy of nanocrystal formulations in vivo was tested. Brinzolamide nanosuspensions were prepared in buffers and formulated for ocular administration in order to reduce the intraocular pressure in rats. The nanocrystal formulations exhibited a low cytotoxicity and significant reduction in intraocular pressure compared to the physiologic salt solution and untreated group. In conclusion, the nanosuspensions of poorly water-soluble drug can be easily produced by the wet milling technique when the choice of stabilizers and milling parameters are appropriate. The nanosuspensions were successfully formulated and exhibited a good in vivo performance. More efficient formulations based on drug nanosuspensions should be further researched and developed.