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Publikation Lipophilic salts and lipid-based formulations for bridging the food effect gap of venetoclax(Elsevier, 01/2022) Koehl, Niklas; Henze, Laura; Holm, Rene; Kuentz, Martin; Keating, John; De Vijlder, Thomas; Marx, Andreas; Griffin, BrendanLipid based formulations (LBF) have shown to overcome food dependent bioavailability for some poorly water-soluble drugs. However, the utility of LBFs can be limited by low dose loading due to a low drug solubility in LBF vehicles. This study investigated the solubility and drug loading increases in LBFs using lipophilic counterions to form lipophilic salts of venetoclax. Venetoclax docusate was formed from venetoclax free base and verified by 1H NMR. Formation of stable venetoclax-fatty acid associations with either oleic acid or decanoic acid were attempted, however, the molecular associations were less consistent based on 1H NMR. Venetoclax docusate displayed a up to 6.2-fold higher solubility in self-emulsifying drug delivery systems (SEDDS) when compared to the venetoclax free base solubility resulting in a higher dose loading. A subsequent bioavailability study in landrace pigs demonstrated a 2.5-fold higher bioavailability for the lipophilic salt containing long chain SEDDS compared to the commercially available solid dispersion Venclyxto® in the fasted state. The bioavailability of all lipophilic salt SEDDS in the fasted state was similar to Venclyxto® in the fed state. This study confirmed that lipophilic drug salts increase the dose loading in LBFs and showed that lipophilic salt-SEDDS combinations may be able to overcome bioavailability limitations of drugs with low inherent dose loading in lipid vehicles. Furthermore, the present study demonstrated the utility of a LBF approach, in combination with lipophilic salts, to overcome food dependent variable oral bioavailability of drugs.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation In Silico, In Vitro, and In Vivo evaluation of precipitation inhibitors in supersaturated lipid-based formulations of venetoclax(American Chemical Society, 23.04.2021) Koehl, Niklas; Henze, Laura; Bennett-Lenane, Harriett; Faisal, Waleed; Price, Daniel J.; Holm, Rene; Kuentz, Martin; Griffin, BrendanThe concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico–in vitro–in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug–excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax(Elsevier, 18.06.2020) Koehl, Niklas; Kuentz, MartinIncreasing numbers of beyond Rule-of-Five drugs are emerging from discovery pipelines, generating a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. However, many drug candidates display insufficient lipid solubility, leading to dose-loading limitations in LBFs. The aim of this study was to explore the potential of supersaturated LBFs (sLBF) for the beyond Rule-of-Five drug venetoclax. Temperature-induced sLBFs of venetoclax were obtained in olive oil, Captex® 1000, Peceol® and Capmul MCM®, respectively. A Peceol®-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol®-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol®-based suspension and an aqueous suspension. A subsequent bioavailability study in pigs demonstrated for sLBF a 3.8-fold and 2.1-fold higher bioavailability compared to the drug powder and Peceol®-based suspension, respectively. In conclusion, sLBF is a promising bio-enabling formulation approach to enhance in vivo exposure of beyond Rule-of-Five drugs, such as venetoclax. The in vitro lipolysis results correctly predicted a higher exposure of the sLBF in vivo. The findings of this study are of particular relevance to pre-clinical drug development, where maximum exposure is required.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Exploring the Impact of Surfactant Type and Digestion: Highly Digestible Surfactants Improve Oral Bioavailability of Nilotinib(American Chemical Society, 08.09.2020) Koehl, Niklas; Kuentz, MartinThe scientific rationale for selection of the surfactant type during oral formulation development requires an in-depth understanding of the interplay between surfactant characteristics and biopharmaceutical factors. Currently, however, there is a lack of comprehensive knowledge of how surfactant properties, such as hydrophilic-lipophilic balance (HLB), digestibility, and fatty acid (FA) chain length, translate into in vivo performance. In the present study, the relationship between surfactant properties, in vitro characteristics, and in vivo bioavailability was systematically evaluated. An in vitro lipolysis model was used to study the digestibility of a variety of nonionic surfactants. Eight surfactants and one surfactant mixture were selected for further analysis using the model poorly water-soluble drug nilotinib. In vitro lipolysis of all nilotinib formulations was performed, followed by an in vivo pharmacokinetic evaluation in rats. The in vitro lipolysis studies showed that medium-chain FA-based surfactants were more readily digested compared to long-chain surfactants. The in vivo study demonstrated that a Tween 20 formulation significantly enhanced the absolute bioavailability of nilotinib up to 5.2-fold relative to an aqueous suspension. In general, surfactants that were highly digestible in vitro tended to display higher bioavailability of nilotinib in vivo. The bioavailability may additionally be related to the FA chain length of digestible surfactants with an improved exposure in the case of medium-chain FA-based surfactants. There was no apparent relationship between the HLB value of surfactants and the in vivo bioavailability of nilotinib. The impact of this study's findings suggests that when designing surfactant-based formulations to enhance oral bioavailability of the poorly water-soluble drug nilotinib, highly digestible, medium chain-based surfactants are preferred. Additionally, for low-permeability drugs such as nilotinib, which is subject to efflux by intestinal P-glycoprotein, the biopharmaceutical effects of surfactants merit further consideration.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats(Springer, 10.06.2020) Koehl, Niklas; Kuentz, MartinConclusion: Chase dosed LBF enhanced the in vivo bioavailability of nilotinib. Long chain lipids showed superior performance compared to medium chain lipids. Chase dosing appeared to prolong the absorption phase of the drug. Therefore, chase dosing of LBF is favourable compared to lipid suspensions for 'brick dust' molecules such as nilotinib. Graphical Abstract The potential of bio-enabling lipid vehicles, administered via chase dosing and lipid suspensions, has been evaluated as an approach to enhance oral bioavailability of nilotinib.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation New Insights into Using Lipid Based Suspensions for 'Brick Dust' Molecules: Case Study of Nilotinib(Springer, 22.02.2019) Koehl, Niklas; Kuentz, MartinPurposeLipid suspensions have been shown to be a suitablebio-enabling formulation approach for highly lipophilic or‘grease ball’drug molecules, but studies on‘brick dust’drugsare lacking. This study explored the utility of lipid suspensionsfor enhancing oral bioavailability of the rather hydrophobicdrug nilotinibin vivoin rats.MethodsFour lipid suspensions were developed containinglong chain triglycerides, medium chain triglyceride, longchain monoglycerides and medium chain monoglyceridesandin vivobioavailability was compared to an aqueous suspen-sion. Additionally,in vitrolipolysis and wettability tests wereconducted.ResultsNilotinib lipid suspensions did not show a bioavail-ability increase compared to an aqueous suspension. The bio-availability was lower for triglyceride suspensions, relative toboth monoglyceride and an aqueous suspension. The longchain monoglyceride displayed a significantly higher bioavail-ability relative to triglycerides.In vitrolipolysis results suggestedentrapment of nilotinib crystals within poorly dispersible tri-glycerides, leading to slower nilotinib release and absorption.This was further supported by higher wettability of nilotinibby lipids.ConclusionMonoglycerides improved oral bioavailability ofnilotinib in rats, relative to triglycerides. For‘brick dust’drugsformulated as lipid suspensions, poorly dispersible formula-tions may delay the release of drug crystals from the formula-tion leading to reduced absorption.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