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Ergebnisse nach Hochschule und Institut
Publikation Artificial neural networks to predict the apparent degree of supersaturation in supersaturated lipid-based formulations. A pilot study(MDPI, 05.09.2021) Bennett-Lenane, Harriett; O'Shea, Joseph; Murray, Jack; Ilie, Alexandra Roxana; Holm, Rene; Kuentz, Martin; Griffin, BrendanIn response to the increasing application of machine learning (ML) across many facets of pharmaceutical development, this pilot study investigated if ML, using artificial neural networks (ANNs), could predict the apparent degree of supersaturation (aDS) from two supersaturated LBFs (sLBFs). Accuracy was compared to partial least squares (PLS) regression models. Equilibrium solubility in Capmul MCM and Maisine CC was obtained for 21 poorly water-soluble drugs at ambient temperature and 60 °C to calculate the aDS ratio. These aDS ratios and drug descriptors were used to train the ML models. When compared, the ANNs outperformed PLS for both sLBFCapmulMC (r2 0.90 vs. 0.56) and sLBFMaisineLC (r2 0.83 vs. 0.62), displaying smaller root mean square errors (RMSEs) and residuals upon training and testing. Across all the models, the descriptors involving reactivity and electron density were most important for prediction. This pilot study showed that ML can be employed to predict the propensity for supersaturation in LBFs, but even larger datasets need to be evaluated to draw final conclusions.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Exploring precipitation inhibitors to improve in vivo absorption of cinnarizine from supersaturated lipid-based drug delivery systems(Elsevier, 01.04.2021) Kuentz, Martin; Ilie, Alexandra Roxana; Griffin, Brendan; Vertzoni, Maria; Kolakovic, Ruzica; Prudic-Paus, Anke; Malash, Ahmed; Bohets, Hugo; Herman, Jilly; Holm, ReneSupersaturated lipid-based drug delivery systems are increasingly being explored as a bio-enabling formulation approach, particularly in preclinical evaluation of poorlywater-soluble drugs. While increasing the drug load through thermally-induced supersaturation resulted in enhanced in vivo exposure for some drugs, for others, such as cinnarizine, supersaturated lipid-based systems have not been found beneficial to increase the in vivo bioavailability. We hypothesized that incorporation of precipitation inhibitors to reduce drug precipitation may address this limitation. Therefore, pharmacokinetic profiles of cinnarizine supersaturated lipid-based drug delivery systems with or without precipitation inhibitors were compared. Five precipitation inhibitors were selected for investigation based on a high throughput screening of twenty-one excipients. In vivo results showed that addition of 5% precipitation inhibitors to long chain monoglyceride (LCM) or medium chain monoglyceride (MCM) formulations showed a general trend of increases in cinnarizine bioavailability, albeit only statistically significantly increased for Poloxamer 407 + LCM system (i.e. 2.7-fold increase in AUC0-24h compared to LCM without precipitation inhibitors). It appeared that precipitation inhibitors mitigated the risk of in vivo precipitation of cinnarizine from sLBDDS and overall, bioavailability was comparable to that previously reported for cinnarizine after dosing of non-supersaturated lipid systems. In summary, for drugs which are prone to precipitation from supersaturated lipid-based drug delivery systems, such as cinnarizine, inclusion of precipitation inhibitors mitigates this risk and provides the opportunity to maximize exposure which is ideally suited in early efficacy and toxicology evaluation.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Toward simplified oral lipid-based drug delivery using mono-/di-glycerides as single component excipients(Marcel Dekker, 09.11.2020) Ilie, Alexandra Roxana; Kuentz, MartinObjective: This study aimed to systematically explore compositional effects for a series of lipid systems, on the in vitro drug solubilization and in vivo bioavailability of three poorly water-soluble drugs with different physico-chemical properties. Significance: While many lipid-based drug products have successfully reached the market, there is still a level of uncertainty on the design guidelines for such drug products with limited understanding on the influence of composition on in vitro and in vivo performance. Methods and results: Lipid-based drug delivery systems were prepared using either single excipient systems based on partially digested triglycerides (i.e. mono- and/or di-glycerides) or increasingly complex systems by incorporating surfactants and/or triglycerides. These lipid systems were evaluated for both in vitro and in vivo behavior. Results indicated that simple single component long chain lipid systems are more beneficial for the absorption of the weak acid celecoxib and the weak base cinnarizine compared to equivalent single component medium chain lipid systems. Similarly, a two-component system produced by incorporating small amount of hydrophilic surfactant yields similar overall pharmacokinetic effects. The lipid drug delivery systems based on medium chain lipid excipients improved the in vivo exposure of the neutral drug JNJ-2A. The higher in vivo bioavailability of long chain lipid systems compared to medium chain lipid systems was in agreement with in vitro dilution and dispersion studies for celecoxib and cinnarizine. Conclusions: The present study demonstrated the benefits of using mono-/di-glycerides as single component excipients in LBDDS to streamline formulation screening and improve oral bioavailability for the three tested poorly water-soluble drugs.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Exploring impact of supersaturated lipid-based drug delivery systems of celecoxib on in vitro permeation across Permeapad Ⓡ membrane and in vivo absorption(Elsevier, 03.07.2020) Ilie, Alexandra Roxana; Kuentz, MartinSupersaturated lipid-based drug delivery systems have recently been investigated for oral administration for a variety of lipophilic drugs and have shown either equivalent or superior oral bioavailability compared to conventional non-supersaturated lipid-based drug delivery systems. The aim of the present work was to explore supersaturated versus non-supersaturated lipid-based systems at equivalent lipid doses, on in vivo bioavailability in rats and on in vitro permeation across a biomimetic PermeapadⓇ membrane to establish a potential in vivo - in vitro correlation. A secondary objective was to investigate the influence of lipid composition on in vitro and in vivo performance of lipid systems. Results obtained indicated that increasing the celecoxib load in the lipid-based formulations by thermally-induced supersaturation resulted in increased bioavailability for medium and long chain mono-/di-glycerides systems relative to their non-supersaturated (i.e. 85%) reference formulations, albeit only significant for the medium chain systems. Long chain systems displayed higher celecoxib bioavailability than equivalent medium chain systems, both at supersaturated and non-supersaturated drug loads. In vitro passive permeation of celecoxib was studied using both steady-state and dynamic conditions and correlated well with in vivo pharmacokinetic results with respect to compositional effects. In contrast, permeation studies indicated that flux and percentage permeated of supersaturated systems, either at steady-state or under dynamic conditions, decreased or were unchanged relative to non-supersaturated systems. This study has shown that by using two cell-free PermeapadⓇ permeation models coupled with rat-adapted gastro-intestinal conditions, bio-predictive in vitro tools can be developed to be reflective of in vivo scenarios. With further optimization, such models could be successfully used in pharmaceutical industry settings to rapidly screen various prototype formulations prior to animal studies.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Supersaturated lipid-based drug delivery systems - exploring impact of lipid composition type and drug properties on supersaturability and physical stability(Marcel Dekker, 24.01.2020) Ilie, Alexandra Roxana; Kuentz, MartinObjective: The objective of this study was to systematically investigate the impact of lipid composition on the ability to design supersaturated lipid-based drug delivery systems (sLBDDS) using three model drugs with different physico-chemical properties.Significance: This study expands the list of investigated sLBDDS by using alternative vehicle compositions relative to current literature.Methods and results: Drug supersaturation was thermally-induced based on previously reported methods and was successfully achieved for celecoxib and cinnarizine. For the novel drug, JNJ-2A, a lower supersaturation potential was observed for the tested LBDDS. For celecoxib and cinnarizine, crystalline precipitate was observed for some sLBDDS upon storage at 25 °C/65%RH, particularly for medium chain sLBDDS (celecoxib) and long chain sLBDDS (cinnarizine). The greater risk of precipitation observed for celecoxib and cinnarizine, particularly at higher apparent degree of supersaturation (aDS) may be related to their higher crystallization tendency as determined by differential scanning calorimetry.Conclusions: The potential for supersaturation in LBDDS, and the risk of precipitation, was found to be highly drug dependent. The apparent degree of supersaturation was considered a major factor impacting the ability to maintain drug supersaturation upon storage.01A - Beitrag in wissenschaftlicher Zeitschrift