Leveraging bile solubilization of poorly water-soluble drugs by rational polymer selection

Schlauersbach, Jonas; Hanio, Simon; Lenz, Bettina; Vemulapalli, Sahithya Phani Babu; Griesinger, Christian; Pöppler, Ann‐Christin; Harlacher, Cornelius; Galli, Bruno; Meinel, Lorenz

doi:10.1016/j.jconrel.2020.12.016

Cited by 15 publications

(38 citation statements)

References 76 publications

(83 reference statements)

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“…In silico molecular modeling may substantially leverage formulation development by providing a priori working hypotheses. , Thereby, a trial and error approach may be replaced by rational development schemes following predicted avenues to success. , One way of building such models is by generalizing molecular interactions seen for many drug substances with relevant biopharmaceutical input parameters, including bile. − The complexity of bile is approximated by surrogate media, including fasted and fed state simulating intestinal fluids (FaSSIF/FeSSIF) containing taurocholate (TC), lecithin (L), and lipids. − Some poorly water-soluble drugs and vitamins rely on solubilization with bile, such as apparent solubility improvement or transport across mucus. , Impairing bile solubilization by pharmaceutical excipients including frequently chosen polymers may reduce bioavailability. , …”

Section: Introductionmentioning

confidence: 99%

“…All drugs were systematically classified as bile or lipid interacting or noninteracting using the 1 H NMR shifts of Metoprolol for reference. Metoprolol was previously characterized as not interacting with TC/L or lipids. , The classification led to molecular descriptors and models for predicting TC/L and lipid interaction. The bile interaction model was further tested for predicting bile-related food effects.…”

Section: Introductionmentioning

confidence: 99%

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Predicting Bile and Lipid Interaction for Drug Substances

et al. 2022

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Predicting biopharmaceutical characteristics and food effects for drug substances may substantially leverage rational formulation outcomes. We established a bile and lipid interaction prediction model for new drug substances and further explored the model for the prediction of bile-related food effects. One hundred and forty-one drugs were categorized as bile and/or lipid interacting and noninteracting drugs using 1H nuclear magnetic resonance (NMR) spectroscopy. Quantitative structure–property relationship modeling with molecular descriptors was applied to predict a drug’s interaction with bile and/or lipids. Bile interaction, for example, was indicated by two descriptors characterizing polarity and lipophilicity with a high balanced accuracy of 0.8. Furthermore, the predicted bile interaction correlated with a positive food effect. Reliable prediction of drug substance interaction with lipids required four molecular descriptors with a balanced accuracy of 0.7. These described a drug’s shape, lipophilicity, aromaticity, and hydrogen bond acceptor capability. In conclusion, reliable models might be found through drug libraries characterized for bile interaction by NMR. Furthermore, there is potential for predicting bile-related positive food effects.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Predicting Bile and Lipid Interaction for Drug Substances

et al. 2022

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“…This details our previous report, in that screening of individual, plain polymers in FeSSIF may not be sufficient to account for the multifaceted behaviour of polymerdrug formulations in simulating intestinal fluids as indicated here for two polymers with the model drug efavirenz. [41] This could also have implications for patients with co-morbidities taking multiple pharmaceutical products. They could form a complex multicomponent mixture in the intestinal tract not just with respect to potential drug-drug interferences but also with respect to polymeric excipients.…”

Section: Detailed Study Of Pox/pozi As Well As Pox/pozi /Efv In Fessifmentioning

confidence: 99%

“…[37] Moreover, an increasing number of reports also shows the interaction of bile colloids with different polymer excipients, e.g. Pluronics®, [38,39] Triton® X-100, [40] Eudragit® E or Soluplus® [41] and thus their influence on the mutual aggregation behaviour. Consequently, the inclusion of polymeric excipients, solubility enhancers and transport vehicles into formulations adds a layer of complexity as the additional and largely unexplored polymer-drug and polymer-bile interactions affect the existing drug-bile interactions.…”

Section: Introductionmentioning

confidence: 99%

Concentration and Composition Dependent Aggregation of Pluronic- and Poly-(2-Oxazolin)-Efavirenz Formulations in Biorelevant Media

Endres¹,

Karaev²,

Hanio³

et al. 2021

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Interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood. Here, diffusion ordered spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY), complemented by cryo-TEM were employed to address this. Efavirenz as model drug, the triblock copolymers Pluronic F-127 (PF127) and poly(2-oxazolin) based pMeOx-b-pPrOzi-b-pMeOx (pOx/pOzi) and their respective formulations were studied in simulated fed-state intestinal fluid (FeSSIF). For the individual polymers, the bile interfering nature of PF127 was confirmed and pure pOx/pOzi was newly classified as non-interfering. A different and more complex behaviour was observed if EFV was involved. The formulations showed multi-facetted concentration and composition dependent aggregation. This demonstrates that separate evaluation of polymers or drugs in biorelevant media is not sufficient and their mixtures need to be carefully studied.<br>

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“…In addition, knowledge of drug-induced changes in colloidal structures may further refine predictions of pharmacokinetic profiles, , in particular for PWSDs with bile affected bioavailability . We hypothesize that taking advantage of the dynamics of our endogenous solubilization system will be beneficial to tackle the challenging oral uptake of PWSDs. ,− …”

Section: Introductionmentioning

confidence: 99%

Drug-Induced Dynamics of Bile Colloids

et al. 2021

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Bile colloids containing taurocholate and lecithin are essential for the solubilization of hydrophobic molecules including poorly water-soluble drugs such as Perphenazine. We detail the impact of Perphenazine concentrations on taurocholate/lecithin colloids using analytical ultracentrifugation, dynamic light scattering, small-angle neutron scattering, nuclear magnetic resonance spectroscopy, coarse-grained molecular dynamics simulations, and isothermal titration calorimetry. Perphenazine impacted colloidal molecular arrangement, structure, and binding thermodynamics in a concentration-dependent manner. At low concentration, Perphenazine was integrated into stable and large taurocholate/lecithin colloids and close to lecithin. Integration of Perphenazine into these colloids was exothermic. At higher Perphenazine concentration, the taurocholate/lecithin colloids had an approximately 5-fold reduction in apparent hydrodynamic size, heat release was less exothermic upon drug integration into the colloids, and Perphenazine interacted with both lecithin and taurocholate. In addition, Perphenazine induced a morphological transition from vesicles to wormlike micelles as indicated by neutron scattering. Despite these surprising colloidal dynamics, these natural colloids successfully ensured stable relative amounts of free Perphenazine throughout the entire drug concentration range tested here. Future studies are required to further detail these findings both on a molecular structural basis and in terms of in vivo relevance.

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Leveraging bile solubilization of poorly water-soluble drugs by rational polymer selection

Cited by 15 publications

References 76 publications

Predicting Bile and Lipid Interaction for Drug Substances

Predicting Bile and Lipid Interaction for Drug Substances

Concentration and Composition Dependent Aggregation of Pluronic- and Poly-(2-Oxazolin)-Efavirenz Formulations in Biorelevant Media

Drug-Induced Dynamics of Bile Colloids

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