Institut für Pharmazie und Lebensmittelchemie
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Für Kinder und Jugendliche stellt die Blutentnahme im Rahmen des Therapeutischen Drug Monitorings (TDM) aufgrund der Invasivität häufig eine große physische sowie psychische Belastung dar. Diese Stresssituation kann durch Speichelsammlung aufgrund des nicht invasiven Prozederes vermieden und zusätzlich der Material-, Personal- und Zeitaufwand im Vergleich zu einer Blutentnahme minimiert werden. Da die therapeutischen Referenzbereiche in der AGNP Konsensus-Leitlinie zum TDM von Psychopharmaka nur für Serum und Plasma validiert sind, sind vergleichende Untersuchungen von alternativen Matrizes mit Serum oder Plasma sowie eine klinische Validierung essenziell für die Implementierung in die klinische Praxis.
Die Zielsetzung dieser Arbeit war es daher, den Zusammenhang zwischen Speichel- und Serumkonzentrationen von Amphetamin und Guanfacin zu untersuchen, um zukünftig das Prozedere der Probenahme für TDM bei Kinder und Jugendliche unter ADHS-Pharmakotherapie durch ein nicht invasives Verfahren zu erleichtern. Zur quantitativen Bestimmung wurden zwei unterschiedliche Methoden aus der Literatur weiterentwickelt. So war es möglich, aus Speichel- und Serumproben Amphetamin mittels HPLC-FL Analytik sowie Guanfacin mittels LC-MS/MS Analytik zu quantifizieren. Die chromatographischen Methoden wurden in Anlehnung an die Richtlinien der Gesellschaft für toxikologische und forensische Chemie (GTFCh) erfolgreich validiert.
Zur Untersuchung des Zusammenhangs zwischen Speichel- und Serumkonzentrationen von Amphetamin und Guanfacin bei Kinder und Jugendlichen wurde eine klinische Studie in der Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie des Universitätsklinikum Würzburgs initiiert. Von 34 Probanden, die mit Lisdexamphetamin und/oder Guanfacin behandelt wurden, konnte jeweils eine korrespondierende Speichel- und Serumprobe gewonnen und quantifiziert werden. Für Amphetamin wurde belegt, dass der Speichel-pH-Wert einen erheblichen Einfluss auf die Wirkstoffverteilung, den Quotienten aus Speichel- und Serumkonzentration, hat (ρ = -0,712; P < 0,001). Dadurch konnte erstmalig unter Berücksichtigung des Speichel-pH-Wertes eine Berechnung der theoretischen Serumkonzentration aus der Speichelkonzentration durchgeführt werden. Es wurde zwar gezeigt, dass sich sowohl der Mittelwert der Differenzen durch die Berechnung theoretischen Serumkonzentration von -343 auf 12 ng/mL als auch die Anzahl der Messwert innerhalb des Akzeptanzintervalls von 20 % verbessern, jedoch war auch nach der Umrechnung die Differenz der Messwerte zu groß, sodass eine klinische Validierung für Amphetamin nicht möglich war. In dieser Studie wurde auch erstmals Guanfacin im Speichel nachgewiesen und quantifiziert, die Konzentrationen lagen zwischen 0,45 und 5,55 ng/mL und waren im Mittel dreifach niedriger als im Serum (2,36 ng/mL vs. 7,47 ng/mL; t (8) = 5,94; P < 0,001).
Die Speichelguanfacinkonzentration wies einen starken Zusammenhang mit der korrespondierenden Serumkonzentration auf (r = 0,758; P = 0,018). Obwohl ein nicht signifikanter Trend für den Einfluss des Speichel-pH-Wertes auf den Quotienten aus Speichel- und Serumkonzentration zu erkennen war, scheint dieser weniger stark ausgeprägt zu sein als bei Amphetamin und anderen basischen Arzneistoffen (r = -0,574; P = 0,106).
Mit der vorliegenden Arbeit konnte zum einen gezeigt werden, dass sich die Speichelbestimmung von Amphetamin nur zum qualitativen Nachweis für TDM eignet. Zum anderen konnte gezeigt werden, dass der Speichel-pH-Wert einen geringeren Einfluss auf die Speichelkonzentration von Guanfacin zu haben scheint, als es bei Amphetamin der Fall ist, und sich Guanfacin somit potenziell für TDM in Speichel eignet. Zukünftig könnten Speichelproben zur Kontrolle der Adhärenz sowohl von Amphetamin als auch von Guanfacin verwendet werden und die Probenahme für die Patienten vereinfachen.
Most medicines are taken orally. To enter the systemic circulation, they dissolve in the intestinal fluid, cross the epithelial barrier, and pass through the liver. Intestinal absorption is driven by the unique features of the gastrointestinal tract, including the bile colloids formed in the lumen and the mucus layer covering the intestinal epithelium. Neglecting this multifaceted environment can lead to poor drug development decisions, especially for poorly water-soluble drugs that interact with bile and mucus. However, there is a lack of a rationale nexus of molecular interactions between oral medicines and gastrointestinal components with drug bioavailability. Against this background, this thesis aims to develop biopharmaceutical strategies to optimize the presentation of oral therapeutics to the intestinal epithelial barrier.
In Chapter 1, the dynamics of bile colloids upon solubilization of the poorly-water soluble drug Perphenazine was studied. Perphenazine impacted molecular arrangement, structure, binding thermodynamics, and induced a morphological transition from vesicles to worm-like micelles. Despite these dynamics, the bile colloids ensured stable relative amounts of free drug substance. The chapter was published in Langmuir.
Chapter 2 examined the impact of pharmaceutical polymeric excipients on bile-mediated drug solubilization. Perphenazine and Imatinib were introduced as model compounds interacting with bile, whereas Metoprolol did not. Some polymers altered the arrangement and geometry of bile colloids, thereby affecting the molecularly soluble amount of those drugs interacting with bile. These insights into the bile-drug-excipient interplay provide a blueprint to optimizing formulations leveraging bile solubilization. The chapter was published in Journal of Controlled Release.
Chapter 3 deals with the impact of bile on porcine intestinal mucus. Mucus exposed to bile solution changed transiently, it stiffened, and the overall diffusion rate increased. The bile-induced changes eased the transport of the bile-interacting drug substance Fluphenazine, whereas Metoprolol was unaffected. This dichotomous pattern was linked to bioavailability in rats and generalized based on two previously published data sets. The outcomes point to a bile-mucus interaction relevant to drug delivery. The chapter is submitted.
The Appendix provides a guide for biopharmaceutical characterization of drug substances by nuclear magnetic resonance spectroscopy aiming at establishing a predictive algorithm.
In summary, this thesis deciphers bile-driven mechanisms shaping intestinal drug absorption. Based on these molecular insights, pharmaceuticals can be developed along a biopharmaceutical optimization, ultimately leading to better oral drugs of tomorrow.
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.
Even though the international combat against Neglected Tropical Diseases such as schistosomiasis or soil-transmitted helminthiases depends on reliable therapeutics, anthelminthic pharmacovigilance has been neglected on many national African drug markets. Therefore, quality and composition of 88 different batches of Albendazole, Mebendazole and Praziquantel locally collected from randomly selected facilities in Western Burkina Faso, Southeast Côte d’Ivoire, Southwest Ghana and Northwest Tanzania were analysed.
Visual examination of both packaging and samples was performed according to the WHO ‘Be Aware’ tool. Products were then screened with the GPHF Minilab, consisting of tests of mass uniformity, disintegration times and thin-layer chromatography (TLC). Confirmatory tests were performed according to international pharmacopoeiae, applying assays for dissolution profiles and high-performance liquid chromatography (HPLC).
Despite minor irregularities, appearance of the products did not hint at falsified medicines. However, 19.6 % of the brands collected in Ghana and Tanzania were not officially licensed for sale. Mass uniformity was confirmed in 53 out of 58 brands of tablets. 41 out of 56 products passed disintegration times; 10 out of the 15 failing products did not disintegrate at all.
TLC results did not reveal any falsifications or pronounced dosing errors. HPLC findings confirmed the TLC results despite shifted specification limits: ten of the 83 tested batches contained less than 90 %, none more than 110 % label claim. However, no more than 46.3 % (31 / 67) of the tablet batches assayed passed the respective criteria for dissolution.
In the four study countries, no falsified anthelminthic medicine was encountered. The active pharmaceutical ingredient was not found to either exceed or distinctively fall below specification limits. Galenic characteristics as most critical criteria however, especially dissolution profiles, revealed substantial deficits.
In this thesis, a new approach of a qNMR method has been investigated to demonstrate the reliability and importance of this method as an alternative solution for analyzing oil quality parameters, especially in RFO, which has particular characteristics (red color). This study also includes the chemometric evaluation of spectral data for authentication, visual grouping, and prediction of RFO quality based on the degree of unsaturation, FFA value, and unsaturated fatty acid content.
The analytical measurement procedure of NMR spectroscopy begins with optimization of the analytical acquisition parameters, including effect of solvent, effect of sample concentration, selection of appropriate internal standards, determination of T1, and method validation. Furthermore, the results of the method development were interpreted to RFO samples evaluation, which began with determining the assignment of signal spectra for the determination of AV, SV, EV, and IV simultaneously with: the hydrolysis approach and standard addition of palmitic acid.