@phdthesis{Werthmueller2024,
  author    = {Werthm{\"u}ller, Dominic Pascal},
  title     = {Relevance of bioaccessibility for the oral bioavailability of poorly water-soluble drugs},
  doi       = {10.25972/OPUS-29920},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299200},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2024},
  abstract  = {Poor or variable oral bioavailability is of major concern regarding safety and efficacy for the treatment of patients with poorly water-soluble drugs (PWSDs). The problem statement of this work involves a pharmaceutical development perspective, the physicochemical basis of the absorption process and physiological / biopharmaceutical aspects. A methodology was developed aiming at closing the gap between drug liberation and dissolution on the one hand and the appearance of drug in the blood on the other. Considering what is out of control from a formulation development perspective, a clear differentiation between bioavailability and bioaccessibility was necessary. Focusing on the absorption process, bioaccessibility of a model compound, a poorly soluble but well permeable weak base, was characterized by means of flux across artificial biomimetic membranes. Such setups can be considered to reasonably mimic relevant oral absorption resistances in vitro in terms of diffusion through an unstirred water layer (UWL) and a lipidic barrier. Mechanistic understanding of the driving force for permeation was gained by differentiating drug species and subsequently linking them to the observed transfer rates using a bioaccessibility concept. The three key species that need to be differentiated are molecularly dissolved drug, drug associated in solution with other components (liquid reservoir) and undissolved drug (solid reservoir). An innovative approach to differentiate molecularly dissolved drug from the liquid reservoir using ultracentrifugation in combination with dynamic light scattering as control is presented. A guidance for rational formulation development of PWSDs is elaborated based on the employed model compound. It is structured into five guiding questions to help drug formulation scientists in selecting drug form, excipients and eventually the formulation principle. Overall, the relevance but also limitations of characterizing bioaccessibility were outlined with respect to practical application e.g. in early drug formulation development.},
  subject      = {Bioverf{\"u}gbarkeit},
  language  = {en}
}