ABSTRACT
Amorphous solid dispersions (ASDs) enable formulations to improve the solubility of poorly soluble active pharmaceutical ingredients (APIs). The amorphous state is reached through the disruption of the crystalline lattice of an API resulting in an increased apparent solubility with faster disintegration. Nevertheless, this form is characterized by a high-energy state which is prone to re-crystallization. To ensure a stable ASD, excipients, e.g., polymers that form a matrix in which an API is dispersed, are used. The applicable polymer range is usually linked to their solubility in the respective solvent, therefore limiting the use of hydrophilic polymers. In this work, we show the applicability of the hydrophilic polymer, polyvinyl alcohol (PVA), in spray-dried solid dispersions. Using a three-fluid nozzle approach, this polymer can be used to generate ASDs with a targeted dissolution profile that is characterized by a prominent spring and desired parachute effect showing both supersaturation and crystallization inhibition. For this purpose, the polymer was tested in formulations containing the weakly basic drug, ketoconazole, and the acidic drug, indomethacin, both classified as Biopharmaceutics Classification System (BSC) class II drugs, as well as the weakly basic drug ritonavir classified as BCS IV. Furthermore, ritonavir was used to show the enhanced drug-loading capacity of PVA derived from the advantageous viscosity profile that makes the polymer an interesting candidate for spray drying applications.
ABSTRACT
Solid phase peptide synthesis (SPPS) provides the possibility to chemically synthesize peptides and proteins. Applying the method on hydrophilic structures is usually without major drawbacks but faces extreme complications when it comes to "difficult sequences." These includes the vitally important, ubiquitously present and structurally demanding membrane proteins and their functional parts, such as ion channels, G-protein receptors, and other pore-forming structures. Standard synthetic and ligation protocols are not enough for a successful synthesis of these challenging sequences. In this review we highlight, summarize and evaluate the possibilities for synthetic production of "difficult sequences" by SPPS, native chemical ligation (NCL) and follow-up protocols.
ABSTRACT
BACKGROUND: Endomicroscopy allows in vivo microscopic investigation of enteral mucosa during endoscopic examinations. The aim of this study was to determine interobserver variability in the evaluation of endomicroscopic pictures of several organs by groups of investigators composed of confocal experts, pathologists and students. METHODS: Twenty-five selected representative endomicroscopic pictures of the colon, stomach and oesophagus (total number, 75) were evaluated based on tissue, inflammatory and neoplastic changes (secondary endpoints). The endomicroscopic presence of neoplastic features was the primary endpoint and correlated with the final histological diagnosis. RESULTS: The kappa values for experts examining colon, stomach, and oesophagus pictures were 0.80, 0.91, and 0.488, respectively; for students 0.74, 0.684, and 0.527 and for pathologists 0.749, 0.633, and 0.346, respectively. Neoplasia was accurately diagnosed in 67-97% of patients with no significant differences between the 3 groups. Tissue differentiation was determined best by pathologists, whereas the degree of inflammation was better diagnosed by experts and students. In all 3 groups the diagnosis of oesophageal diseases was the most difficult. CONCLUSIONS: Endomicroscopic images can be interpreted with high concordance. In our study, the diagnostic reliability was not different between students, endomicroscopic experts, and pathologists. Thus, endomicroscopy could be an additional and reliable imaging modality for diagnosing mucosal neoplasia of the gut.
