title: Oral nanocrystal formulations and their biopharmaceutical characterization
creator: Anhalt, Katharina
subject: ddc-570
subject: 570 Life sciences
description: The aim of this thesis was a biopharmaceutical characterization of oral nanocrystal formulations. Crystalline nanosuspensions (nanocrystals) are one of the most promising and successful formulation approaches for the bioavailability enhancement of poorly water soluble drugs. Crystalline nano- and microsuspensions of fenofibrate and the Merck Serono Compound AS were prepared by wet media milling. The suspensions covered a wide particle size range (100nm to 8µm) and exhibited narrow particle size distributions.  It was challenging to determine the solubility and dissolution of nanocrystal formulations. Very small particles with rapid dissolution kinetics complicated the separation of solid from dissolved material. Therefore, an in situ noninvasive analytical method based on the monitoring of light scattering intensities was developed. It avoided the critical separation step, both in solubility and dissolution testing. The determination of solubilities revealed that the solubility was slightly increased only by the smallest sized nanocrystals (10-20% for particle size < 200nm).  The dissolution assessment by the light scattering technique had a high temporal resolution, sensitivity, and reproducibility. A straightforward and small scale experimental setup was an additional advantage. The ideal applicability was observed for particle diameters of 100-500nm. Dissolution times as short as 90s could be determined. The method was still applicable for dissolution of particles with up to 1µm in size and a good correlation to a conventional dissolution setup (USP II apparatus with sample filtration) was demonstrated for suspensions in this size range. Biexponential modeling of the dissolution curves was successful and allowed for analysis of the dissolution kinetics. The experimental dissolution results were in good agreement to the Noyes-Whitney theory of dissolution.  The next step of biopharmaceutical characterization was the permeability assessment of drug substances formulated as crystalline suspensions with various particle sizes. The permeabilities were measured across Caco-2 cell monolayers. An assay with vertical monolayer arrangement was compared to the classical horizontal assay. The vertical setup did not improve the discriminative power and the adjustment of standardized experimental conditions was difficult. Therefore, the horizontal setup was selected for further experiments. A variation of apical transport medium by using a biorelevant medium instead of a classical buffered salt solution did not alter the permeabilities essentially.  A nanosuspension (150nm) of the Merck Serono Compound AS enabled a higher permeability with reference to larger sized suspensions (860nm and 7µm). This correlated well with an observed accelerated dissolution and an observed slight increase in solubility of the nanosuspension. On the contrary, a positive effect of size reduction on permeability was not detected for fenofibrate.  This unexpected result might be due to the enzymatic fenofibrate conversion to fenofibric acid, a better soluble and evenly permeable metabolite. A correlation of permeability with apical fenofibric acid concentration dominated the correlation of permeability with particle size. The metabolization interfered with the effects of particle size reduction. However, this phenomenon was not explicitly investigated in this study.  The biopharmaceutical investigation was completed by pharmacokinetic studies on the oral administration of suspensions to rats. Nanosuspensions of both drug substances improved the bioavailability with reference to microsuspensions.  The presented work covers a thorough particle size distribution analysis, solubility, dissolution, permeation and in vivo pharmacokinetic investigation of micro- and nanosuspensions of two drug substances. These data are very useful to investigate the in vitro-in vivo relation of oral nanocrystal formulations. In this work a good linear correlation of the logarithmic dissolution times to the bioavailability was demonstrated. Furthermore plasma concentration-time profiles were successfully simulated using the Advanced Compartmental Absorption and Transit (ACAT) model. For nanocrystal formulations the fit of simulated to observed profiles was improved by applying the nanofactor effect implemented in the ACAT model.
date: 2012
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/13978/1/Doktorarbeit.pdf
identifier: DOI:10.11588/heidok.00013978
identifier: urn:nbn:de:bsz:16-heidok-139782
identifier:   Anhalt, Katharina  (2012) Oral nanocrystal formulations and their biopharmaceutical characterization.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/13978/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng