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Ergebnisse nach Hochschule und Institut
Publikation Incorporation of HPMCAS during loading of glibenclamide onto mesoporous silica improves dissolution and inhibits precipitation(Elsevier, 01/2020) Price, Daniel J.; Nair, Anita; Becker-Baldus, Johanna; Glaubitz, Clemens; Kuentz, Martin; Dressman, Jennifer; Saal, ChristophMesoporous silica has emerged as an enabling formulation for poorly soluble active pharmaceutical ingredients (APIs). Unlike other formulations, mesoporous silica typically does not inhibit precipitation of supersaturated API therefore, a suitable precipitation inhibitor (PI) should be added to increase absorption from the gastrointestinal (GI) tract. However, there is limited research about optimal processes for combining PIs with silica formulations. Typically, the PI is added by simply blending the API-loaded silica mechanically with the selected PI. This has the drawback of an additional blending step and may also not be optimal with regard to release of drug and PI. By contrast, loading PI simultaneously with the API onto mesoporous silica, i.e. co-incorporation, is attractive from both a performance and practical perspective. The aim of this study was to demonstrate the utility of a co-incorporation approach for combining PIs with silica formulations, and to develop a mechanistic rationale for improvement of the performance of silica formulations using the co-incorporation approach. The results indicate that co-incorporating HPMCAS with glibenclamide onto silica significantly improved the extent and duration of drug supersaturation in single-medium and transfer dissolution experiments. Extensive spectroscopic characterization of the formulation revealed that the improved performance was related to the formation of drug-polymer interactions already in the solid state; the immobilization of API-loaded silica on HPMCAS plates, which prevents premature release and precipitation of API; and drug-polymer proximity on disintegration of the formulation, allowing for rapid onset of precipitation inhibition. The data suggests that co-incorporating the PI with the API is appealing for silica formulations from both a practical and formulation performance perspective.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Opportunities for Successful Stabilization of Poor Glass-Forming Drugs: A Stability-Based Comparison of Mesoporous Silica Versus Hot Melt Extrusion Technologies(Elsevier, 04.11.2019) Ditzinger, Felix; Price, Daniel J.; Nair, Anita; Becker-Baldus, Johanna; Glaubitz, Clemens; Dressman, Jennifer; Saal, Christoph; Kuentz, MartinAmorphous formulation technologies to improve oral absorption of poorly soluble active pharmaceutical ingredients (APIs) have become increasingly prevalent. Currently, polymer-based amorphous formulations manufactured by spray drying, hot melt extrusion (HME), or co-precipitation are most common. However, these technologies have challenges in terms of the successful stabilization of poor glass former compounds in the amorphous form. An alternative approach is mesoporous silica, which stabilizes APIs in non-crystalline form via molecular adsorption inside nano-scale pores. In line with these considerations, two poor glass formers, haloperidol and carbamazepine, were formulated as polymer-based solid dispersion via HME and with mesoporous silica, and their stability was compared under accelerated conditions. Changes were monitored over three months with respect to solid-state form and dissolution. The results were supported by solid-state nuclear magnetic resonance spectroscopy (SS-NMR) and scanning electron microscopy (SEM). It was demonstrated that mesoporous silica was more successful than HME in the stabilization of the selected poor glass formers. While both drugs remained non-crystalline during the study using mesoporous silica, polymer-based HME formulations showed recrystallization after one week. Thus, mesoporous silica represents an attractive technology to extend the formulation toolbox to poorly soluble poor glass formers.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches | a PEARRL review(Wiley, 04/2019) Ditzinger, Felix; Price, Daniel J.; Ilie, Alexandra Roxana; Koehl, Niklas; Jankovic, Sandra; Tsakiridou, Georgia; Aleandri, Simone; Kalantzi, Lida; Holm, Rene; Nair, Anita; Saal, Christoph; Griffin, Brendan; Kuentz, Martin01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Lipophilicity and hydrophobicity considerations in bio‐enabling oral formulations approaches – a PEARRL review(Wiley, 08/2018) Ditzinger, Felix; Price, Daniel; Ilie, Alexandra Roxana; Koehl, Niklas; Jankovic, Sandra; Tsakiridou, Georgia; Aleandri, Simone; Kalantzi, Lida; Holm, Rene; Nair, Anita; Saal, Christoph; Griffin, Brendan; Kuentz, MartinObjectives This review highlights aspects of drug hydrophobicity and lipophilicity as determinants of different oral formulation approaches with specific focus on enabling formulation technologies. An overview is provided on appropriate formulation selection by focussing on the physicochemical properties of the drug. Key findings Crystal lattice energy and the octanol–water partitioning behaviour of a poorly soluble drug are conventionally viewed as characteristics of hydrophobicity and lipophilicity, which matter particularly for any dissolution process during manufacturing and regarding drug release in the gastrointestinal tract. Different oral formulation strategies are discussed in the present review, including lipid‐based delivery, amorphous solid dispersions, mesoporous silica, nanosuspensions and cyclodextrin formulations. Summary Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Application of the solubility parameter concept to assist with oral delivery of poorly water-soluble drugs – a PEARRL review(Wiley, 07/2018) Jankovic, Sandra; Tsakiridou, Georgia; Ditzinger, Felix; Koehl, Niklas; Price, Daniel; Ilie, Alexandra Roxana; Kalantzi, Lida; Kimpe, Kristof; Holm, Rene; Nair, Anita; Griffin, Brendan; Saal, Christoph; Kuentz, MartinObjectives Solubility parameters have been used for decades in various scientific fields including pharmaceutics. It is, however, still a field of active research both on a conceptual and experimental level. This work addresses the need to review solubility parameter applications in pharmaceutics of poorly water‐soluble drugs. Key findings An overview of the different experimental and calculation methods to determine solubility parameters is provided, which covers from classical to modern approaches. In the pharmaceutical field, solubility parameters are primarily used to guide organic solvent selection, cocrystals and salt screening, lipid‐based delivery, solid dispersions and nano‐ or microparticulate drug delivery systems. Solubility parameters have been applied for a quantitative assessment of mixtures, or they are simply used to rank excipients for a given drug. Summary In particular, partial solubility parameters hold great promise for aiding the development of poorly soluble drug delivery systems. This is particularly true in early‐stage development, where compound availability and resources are limited. The experimental determination of solubility parameters has its merits despite being rather labour‐intensive because further data can be used to continuously improve in silico predictions. Such improvements will ensure that solubility parameters will also in future guide scientists in finding suitable drug formulations.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Approaches to increase mechanistic understanding and aid in the selection of precipitation inhibitors for supersaturating formulations – a PEARRL review(Wiley, 05/2018) Price, Daniel J.; Ditzinger, Felix; Koehl, Niklas; Jankovic, Sandra; Tsakiridou, Georgia; Nair, Anita; Holm, Rene; Kuentz, Martin; Dressman, Jennifer; Saal, ChristophObjectives Supersaturating formulations hold great promise for delivery of poorly soluble active pharmaceutical ingredients (APIs). To profit from supersaturating formulations, precipitation is hindered with precipitation inhibitors (PIs), maintaining drug concentrations for as long as possible. This review provides a brief overview of supersaturation and precipitation, focusing on precipitation inhibition. Trial‐and‐error PI selection will be examined alongside established PI screening techniques. Primarily, however, this review will focus on recent advances that utilise advanced analytical techniques to increase mechanistic understanding of PI action and systematic PI selection. Key findings Advances in mechanistic understanding have been made possible by the use of analytical tools such as spectroscopy, microscopy and mathematical and molecular modelling, which have been reviewed herein. Using these techniques, PI selection can be guided by molecular rationale. However, more work is required to see widespread application of such an approach for PI selection. Summary Precipitation inhibitors are becoming increasingly important in enabling formulations. Trial‐and‐error approaches have seen success thus far. However, it is essential to learn more about the mode of action of PIs if the most optimal formulations are to be realised. Robust analytical tools, and the knowledge of where and how they can be applied, will be essential in this endeavour.01A - Beitrag in wissenschaftlicher Zeitschrift