Investigations into Drug Delivery to the Eye: Nanoparticle Comparisons

Eye disorders are on the rise as a result of an ageing population, an increasing obesity problem and a growth in the number of diabetic patients. Conventional ophthalmic formulations do not maintain therapeutic drug concentration in the target tissues for a long duration due to the physiological and anatomical eye barriers. Novel delivery systems such as nanoparticles have been explored to enhance the delivery of therapeutic agents to the eye. These delivery systems have in general been assessed using in-vivo animal models, despite ethical concerns for animal wellbeing. The aims of this thesis were to synthesise and characterise four amphiphilic polymers, subsequently prepare and characterise four nano sized polymeric self-assemblies loaded with triamcinolone acetonide (TA), develop an in-vitro porcine eye model and to evaluate the permeation of nano sized self-assemblies using the developed model. Four comb-shaped amphiphilic polymers (Pa5, Pa5-MPEG, Ch5 and Da10) were synthesised with a high yield (>81%) and good reproducibility. These polymers formed spontaneous positive self-assemblies in aqueous media (114-314 nm). The mean hydrodynamic diameters of the positive spontaneous self-assemblies entrapping TA were in the range of 200–334 nm loading high concentrations (455-1263 μg mL-1) of TA, much greater than the TA inherent aqueous solubility or concentrations achieved using conventional solubilisers. A porcine in-vitro eye model was developed to assess drug permeation through anterior and posterior ocular tissues. The model was partially validated using tritiated water and a series of hydrophilic markers with increasing molecular weights. The integrity of porcine ocular tissue was checked by monitoring the permeation of tritiated water to ensure the membrane intactness. Tritiated water permeation at 15 min was exploited as a potential method to normalise drug flux, as tritiated water percentage permeation at 15 min had an inverse relationship with tissue thickness (R2 = 0.66), to reduce the inherent variability between tissue samples thus increasing the accuracy of the in-vitro eye model. Four markers (fluorescein sodium salt, 4, 10 and 20 kDa FITC-dextran) were used for the purpose of investigating the effect of increasing molecular weight on ocular tissue permeability. The permeability of the markers displayed an inverse relationship and abrupt decline with Mw in terms of the permeability through scleral and corneal tissues of human and porcine and the molecular weight of the markers. The developed porcine in-vitro eye model showed good correlation with the human in-vitro model providing strong evidence it can be used to screen potential formulations before testing in-vivo. The TA loaded self-assemblies and a few chemical enhancers (glutamic acid, tween 80, chitosan, Pa5 and elevate temperature (45 °C)), selected to assist drug delivery via two routes (paracellular and transcellular), were tested using the developed in-vitro eye model. The results showed there was no marker permeation enhancement effect in porcine and human ocular tissues using chemical enhancers. In summary, a porcine in-vitro eye model was developed to assess hydrophobic and hydrophilic penetrant permeation across anterior and posterior ocular tissues. The porcine in-vitro eye model showed good correlation with the human in-vitro model providing strong evidence that the porcine in-vitro eye model can be used to screen potential formulations before testing in-vivo using the porcine model which ultimately might correlate well with the in-vivo human responses. Although TA self-assemblies did not significantly increase drug flux through human or porcine scleral tissues, it might be of interest for ophthalmic topically administered formulations due to their positive charge and small nano size

CCDC 676460: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures

CCDC 777010: Experimental Crystal Structure Determination

Related Article: M.P.Attfield, Y.Al-Ebini, P.Hill|2010|J.Mater.Chem.|20|8686|doi:10.1039/c0jm01429

Solriamfetol impurities: Synthesis, characterization, and analytical method (UPLC-UV) validation

Given that impurities may affect the quality and safety of drug products, impurity identification and profiling is an integral part of drug quality control and is particularly important for newly developed medications such as solriamfetol, which is used to treat excessive daytime sleepiness. Although the high-performance liquid chromatography analysis of commercial solriamfetol has revealed the presence of several impurities, their synthesis, structure elucidation, and chromatographic determination have not been reported yet. To bridge this gap, we herein identified, synthesized, and isolated eight process-related solriamfetol impurities, characterized them using spectroscopic and chromatographic techniques, and proposed plausible mechanisms of their formation. Moreover, we developed and validated a prompt impurity analysis method based on ultrahigh-performance liquid chromatography with UV detection, revealing that its selectivity, linearity, accuracy, precision, and quantitation limit meet the acceptance criteria of method validation stipulated by the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. Thus, the developed method was concluded to be suitable for the routine analysis of solriamfetol substances