Eye drops of poorly soluble drugs are frequently formulated as suspensions. Bioavailability of suspended drug depends on the retention and dissolution of drug particles in the tear fluid, but these factors are still poorly understood. We investigated seven ocular indomethacin suspensions (experimental suspensions with two particle sizes and three viscosities, one commercial suspension) in physical and biological tests. The median particle size (d(50)) categories of the experimental suspensions were 0.37-1.33 and 3.12-3.50 mu m and their viscosity levels were 1.3, 7.0, and 15 mPa center dot s. Smaller particle size facilitated ocular absorption of indomethacin to the aqueous humor of albino rabbits. In aqueous humor the AUC values of indomethacin suspensions with different particle sizes, but equal viscosity, differed over a 1.5 to 2.3-fold range. Higher viscosity increased ocular absorption 3.4-4.3-fold for the suspensions with similar particle sizes. Overall, the bioavailability range for the suspensions was about 8-fold. Instillation of larger particles resulted in higher tear fluid AUC values of total indomethacin (suspended and dissolved) as compared to application of smaller particles. Despite these tear fluid AUC values of total indomethacin, instillation of the larger particles resulted in smaller AUC levels of indomethacin in the aqueous humor. This suggests that the small particles yielded higher concentrations of dissolved indomethacin in the tear fluid, thereby leading to improved ocular bioavailability. This new conclusion was supported by ocular pharmacokinetic modeling. Both particle size and viscosity have a significant impact on drug concentrations in the tear fluid and ocular drug bioavailability from topical suspensions. Viscosity and particle size are the key players in the complex interplay of drug retention and dissolution in the tear fluid, thereby defining ocular drug absorption and bioequivalence of ocular suspensions.

Nanoprecipitation is a straightforward method for the production of block copolymer nanoparticles for drug delivery applications. However, the effects of process parameters need to be understood to optimize and control the particle size distribution (PSD). To this end, we investigated the effects of material and process factors on PSD and morphology of nanoparticles prepared from an amphiphilic diblock copolymer, poly(ethylene oxide)-block-polycaprolactone. Using a Design of Experiments approach, we explored the joint effects of molecular weight, block length ratios, water volume fraction, stirring rate, polymer concentration and organic phase addition rate on hydrodynamic size and polydispersity index of the nanostructures and created statistical models explaining up to 94 % of the variance in hydrodynamic diameter. In addition, we performed morphological characterization by cryogenic transmission electron microscopy and showed that increasing the process temperature may favor the formation of vesicles from these polymers. We showed that the effects of process parameters are dependent on the polymer configuration and we found that the most useful parameters to fine-tune the PSD are the initial polymer concentration and the stirring rate. Overall, this study provides evidence on the joint effects of material and process parameters on PSD and morphology, which will be useful for rational design of formulation-specific optimization studies, scale-up and process controls.

Key message Rut depth in fine-grained boreal soils induced by an 8-wheeled forwarder is best predicted with soil moisture content, cumulative mass of machine passes, bulk density and thickness of the humus layer. Context Forest machines are today very heavy and will cause serious damage to soil and prevent future growth if forest operations are carried out at the wrong time of the year. Forest operations performed during the wettest season should therefore be directed at coarse-grained soils that are not as prone to soil damage. Aims The study aimed at investigating the significance of the most important soil characteristics on rutting and developing models that can be utilized in predicting rutting prior to forest operations. Methods A set of wheeling tests on two fine-grained mineral soil stands in Southern Finland were performed. The wheeling experiments were conducted in three different periods of autumn in order to get the largest possible variation in moisture content. The test drives were carried out with an 8-wheeled forwarder. Results Soil moisture content is the most important factor affecting rut depth. Rut depth of an 8-wheeled forwarder in fine-grained boreal soil is best predicted with soil moisture content, cumulative mass of machine passes, bulk density and thickness of the humus layer. Conclusion The results emphasize the importance of moisture content on the risk of rutting in fine-grained mineral soils, especially with high moisture content values when soil saturation reaches 80%. The results indicate that it is of high importance that soil type and soil wetness can be predicted prior to forest operations.