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      Supersaturated Lipid-Based Formulations to Enhance the Oral Bioavailability of Venetoclax

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          Abstract

          Increasing 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.

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          Drug-like properties and the causes of poor solubility and poor permeability.

          C Lipinski (2001)
          There are currently about 10000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to "drugability." In the future, "drugability" screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A "rational drug design" approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility.
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            A classification system to assess the crystallization tendency of organic molecules from undercooled melts.

            Assessing the viability of an amorphous formulation strategy is of great importance in an era of drug discovery where a large percentage of new molecules have solubility limited dissolution rates, and disruption of the crystal lattice is a potential strategy to improve this process. The objective of the current study was to evaluate the glass forming ability (GFA) of a large data set of organic molecules and also to evaluate potential links between GFA and glass stability (GS). The crystallization tendency from the undercooled melt was evaluated for a group of 51 organic molecules and separated into three separate classes [class (I), class (II), class (III)] based upon the presence/absence of observable crystallization during a heating/cooling/heating cycle, as measured using differential scanning calorimetry (DSC). Class (I) molecules were further delineated based upon the observation of a crystalline [class (I-A)] or amorphous [class (I-B)] solid after quench cooling in liquid N(2). Principal component analysis (PCA) of various physiochemical descriptors suggested that molecules with low GFA tended to be low molecular weight (MW), rigid structures while class (III) molecules tended to be higher MW, more complex structures. For select compounds, it was observed that crystallization from the glassy state was much faster for compounds with a lower GFA. It is believed that nuclei are quenched into the glass during cooling for class (I-B) and (II) molecules, leading to more facile crystallization below T(g). In addition, these quenched in nuclei are also thought to be responsible for the recrystallization observed for these classes of molecules upon heating above T(g). In conclusion, the DSC screening method and classification scheme may be a useful tool to quickly assess the GFA and potential GS of new chemical entities during early drug development.
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              The utility of the minipig as an animal model in regulatory toxicology.

              In this article we review the value and utility of the minipig as an animal model in regulatory toxicity testing. Our review is based on detailed consideration of the comparative biology of the minipig, and of the practical features of toxicity testing in the minipig. The minipig presents a favourable profile as a non-rodent toxicology model, in terms of the similarity to man and also in terms of applicability to different study types. Studies of general toxicology can be performed in the minipig by oral, cutaneous, parenteral and inhalation routes. For reproductive toxicology studies the minipig offers numerous advantages as a non-rodent model although the lack of placental transfer of macromolecules may limit the role of the minipig in reproductive testing of biotechnology products. For safety pharmacology studies the minipig is an advantageous model, particularly as regards the cardiovascular system. The immune system of the pig is better characterized than that of the dog, making the pig an interesting alternative model to the nonhuman primate for therapeutic approaches based on manipulation of the immune system. Overall, this review leads us to believe that the minipig might be a better non-rodent toxicology model than the dog. At the present time, however, insufficient comparative data is available to permit a rigorous evaluation of the predictivity of the minipig for human drug-induced toxicities and research is urgently needed to provide experimental data for evaluation of the hypothesis that minipig studies may better reflect human drug-induced toxicities than studies performed in traditional non-rodent toxicology models. It would be of particular value to gain a better vision of the potential utility of the minipig as a model for the safety testing of new biologics, where the minipig could potentially replace the use of non-human primates in the testing of some new products. Copyright © 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                18 June 2020
                June 2020
                : 12
                : 6
                : 564
                Affiliations
                [1 ]School of Pharmacy, University College Cork, College Road, T12 YN60 Cork, Ireland; Niklas.Koehl@ 123456ucc.ie (N.J.K.); Laura.Henze@ 123456ucc.ie (L.J.H.)
                [2 ]Institute of Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland, Hofackerstrasse 30, 4132 Muttenz, Switzerland; Martin.Kuentz@ 123456fhnw.ch
                [3 ]Drug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium; rholm@ 123456ITS.JNJ.com
                [4 ]Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark
                Author notes
                [* ]Correspondence: Brendan.Griffin@ 123456ucc.ie ; Tel.: +353-21-490-1657
                Author information
                https://orcid.org/0000-0002-0565-9192
                https://orcid.org/0000-0003-2963-2645
                https://orcid.org/0000-0001-5433-8398
                Article
                pharmaceutics-12-00564
                10.3390/pharmaceutics12060564
                7355533
                32570753
                35493033-3dd6-459c-b0f3-ff51b6d52f1d
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 22 May 2020
                : 16 June 2020
                Categories
                Article

                lipid-based formulation,venetoclax,super-snedds,supersaturation,amorphous solubility,landrace pigs,supersaturated lipid-based formulations,lipid suspensions,self-emulsifying drug delivery system,sedds

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