RESUMEN
Sustained-release (SR) formulations may appear advantageous in first-in-human (FIH) study of innovative medicines. The newly developed SR matrix tablets require prolonged maintenance of API concentration in plasma and should be reliably assessed for the risk of uncontrolled release of the drug. In the present study, we describe the development of a robust SR matrix tablet with a novel G-protein-coupled receptor 40 (GPR40) agonist for first-in-human studies and introduce a general workflow for the successful development of SR formulations for innovative APIs. The hydrophilic matrix tablets containing the labeled API dose of 5, 30, or 120 mg were evaluated with several methods: standard USP II dissolution, bio-predictive dissolution tests, and the texture and matrix formation analysis. The standard dissolution tests allowed preselection of the prototypes with the targeted dissolution rate, while the subsequent studies in physiologically relevant conditions revealed unwanted and potentially harmful effects, such as dose dumping under an increased mechanical agitation. The developed formulations were exceptionally robust toward the mechanical and physicochemical conditions of the bio-predictive tests and assured a comparable drug delivery rate regardless of the prandial state and dose labeled. In conclusion, the introduced development strategy, when implemented into the development cycle of SR formulations with innovative APIs, may allow not only to reduce the risk of formulation-related failure of phase I clinical trial but also effectively and timely provide safe and reliable medicines for patients in the trial and their further therapy.
RESUMEN
Most mucoralean fungi are common soil saprotrophs and were probably among the first land colonisers. Although Mucoromycotina representatives grow well on simple sugar media and are thought to be unable to assimilate more complex organic compounds, they are often isolated from plant substrates. The main goal of the study was to explore the effects of isolation origin and phylogenetic placement on the carbon assimilation capacities of a large group of saprotrophic Mucoromycotina representatives (i.e. Umbelopsidales and Mucorales). Fifty two strains representing different Mucoromycotina families and isolated from different substrates were tested for their capacity to grow on 99 different carbon sources using the Biolog phenotypic microarray system and agar plates containing selected biopolymers (i.e. cellulose, xylan, pectin, and starch) as a sole carbon source. Although our results did not reveal a correlation between phylogenetic distance and carbon assimilation capacities, we observed 20 significant differences in growth capacity on specific carbon sources between representatives of different families. Our results also suggest that isolation origin cannot be considered as a main predictor of the carbon assimilation capacities of a particular strain. We conclude that saprotrophic Mucoromycotina representatives are, contrary to common belief, metabolically versatile and able to use a wide variety of carbon sources.
