@phdthesis{Tietz2019,
  author    = {Katharina Tietz},
  title     = {Entwicklung diskriminierender und biopr{\"a}diktiver Methoden zur Bestimmung der Wirkstofffreisetzung aus langwirksamen kontrazeptiven Darreichungsformen},
  journal    = {Development of discriminative and bio-predictive drug release methods for long-acting contraceptive dosage forms},
  url       = {https://nbn-resolving.org/urn:nbn:de:gbv:9-opus-34857},
  pages     = {169},
  year      = {2019},
  abstract  = {In the last decades, the development of methods for drug release testing of different dosage forms has gained in importance. These methods are used for quality control and they can also be useful in early stage development of novel dosage forms. Today, biorelevant aspects are also included in methods for determining drug release of dosage forms. The implementation of biorelevant aspects can be a useful tool for predicting in vivo profiles based on results of in vitro drug release studies. Due to the increasing number of long-acting dosage forms on the market, there will be an increasing demand for accelerated drug release methods. One objective of this thesis was the development of discriminative and accelerated in vitro test methods for the determination of drug release from LNGB-containing injectable suspensions of different particle sizes. Based on the method to be developed, it should be possible to distinguish between the different particle sizes, which were in the range of 8-41 µm, despite acceleration of the method. In a first step, the saturation solubility of LNGB was determined in different dissolution media. Due to the poor solubility of LNGB in the investigated dissolution media, a varying amount of SDS (sodium dodecyl sulfate) was added to increase LNGB solubility in the respective media. For investigating drug release of the LNGB injectable suspensions, methods for USP apparatus II and for USP apparatus IV were developed. In a first set of experiments performed in the USP apparatus II, the influence of the added amount of SDS was investigated. To reach a minimum of 3-fold sink conditions, all of the following tests were performed with an addition of 0,75 \% SDS. In a systematic screening, the influence of the agitational speed, the dissolution medium and the temperature on LNGB drug release in USP apparatus II was investigated. In all performed experiments significant differences could be observed between the group of smaller particles (suspensions with very small and small LNGB particles) and the group of larger LNGB particles (suspensions with medium and large LNGB particles). The greatest influence on LNGB drug release from the investigated injectable suspensions was obtained by increasing the temperature from 37,0 °C to 50,0 °C. Drug release from LNGB injectable suspensions was also investigated using the USP apparatus IV (flow-through cell, FTC). The FTC was used either in open-loop or closed-loop mode. In the open-loop mode as well as in the closed-loop mode the influence of the flow rate, i.e. 10 mL/min or 20 mL/min, on LNGB release was investigated. Determining the LNGB release with the open-loop configuration showed several disadvantages. During the first minutes of the test LNGB particles were rinsed out despite appropriate filter packing in the FTC head. In addition, the relatively high flow rate required a large amount of dissolution medium. For this reason, the influence of the increased test temperatures on the drug release from the LNGB injectable suspensions using the FTC was only investigated in the closed-loop configuration. Similar to the LNGB release results obtained with the USP 2 apparatus, a significant difference between the results of the LNGB release from the suspensions at 37.0 °C and 50.0 °C could be observed. A distinction between the group of smaller LNGB particles and the larger LNGB particles was possible at the different flow rates as well as under test conditions with elevated temperatures. Another aim of this thesis was the development of a novel bio-predictive dissolution method for vaginal rings. This novel method should be able to detect the so-called burst release in vitro that can be observed for reservoir-type vaginal rings. A burst release is characterized by an initial high drug release rate compared to daily release rates and can lead to unwanted side effects. The investigated formulations, the NuvaRing and the Cyclelle ring, are representatives of the reservoir-type vaginal rings. Reservoir-type vaginal rings consist of a core polymer in which both APIs, i.e. ethinyl estradiol (EE) and etonogestrel (ENG) are homogenously dispersed. The core polymer is surrounded by a drug-free membrane, which controls the release of both APIs. During the storage of such reservoir-type vaginal rings, EE and ENG diffuse into the membrane until both hormones are present in a saturated state. Due to the saturation of the membrane, the burst release occurs after insertion of a vaginal ring. In previous experiments for determining drug release from vaginal rings with the so-called shake-flask method the burst release was not detected since samples are only taken every 24 h followed by a complete exchange of the dissolution medium. The novel dissolution method should be more biorelevant than the existing shake-flask methods. Therefore, two further compartments were integrated in the novel dissolution cell, which should simulate the absorption of EE and ENG similar to the in vivo situation. Since the data obtained with the novel dissolution method were later to be correlated with in vivo plasma levels from clinical studies with the NuvaRing and the Cyclelle vaginal ring, the sampling time points for the in vitro drug release experiments were adapted from the clinical in vivo studies. Due to the poor solubility of EE and ENG and the low volumes used in the novel dissolution cell, 0.5 \% SDS was added to the dissolution media to provide tenfold sink conditions throughout the experiment. Drug release from the NuvaRing® and the Cyclelle® vaginal ring was determined using both the modified shake-flask method and the novel dissolution method for vaginal rings. The burst release could be more accurately detected by the novel dissolution method than the commonly used shake-flask method. The declared daily release rates of 120 μg ENG and 15 μg EE from the investigated vaginal ring formulations were also achieved with the novel dissolution method. Following the burst release both investigated vaginal ring formulations released EE and ENG following zero-order kinetics. The in vitro release data, which followed a zero-order kinetic, were correlated with the deconvoluted in vivo plasma levels. For both in vitro methods a linear correlation could be found for EE. The novel dissolution method represents a promising approach for determining drug release from vaginal ring formulations. With the help of the novel dissolution method, the burst release from reservoir-type vaginal rings could be determined better than with the commonly used shake-flask methods. Despite the low volumes used in the novel dissolution cell, the addition of 0.5 \% SDS allowed tenfold sink conditions in both compartments throughout experiments. Correlations of the absorbed EE fractions deconvoluted from in vivo plasma levels and the cumulatively in vitro released EE amounts showed a linear relationship between the in vivo absorbed fraction and the in vitro cumulatively released drug amount.},
  language  = {de}
}