Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Proguanil Hydrochloride

Plöger, Gerlinde F.; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D I R K W; Langguth, Peter; Mehta, Mehul; Parr, Alan; Polli, James E.; Shah, Vinod P.; Tajiri, Tomokazu; Dressman, Jennifer B.

doi:10.1016/j.xphs.2018.03.009

Cited by 6 publications

(13 citation statements)

References 39 publications

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“…The PKa values of the guanidine-containing therapeutic agents that have been investigated in the current in silico study have also been checked (Table S6). In comparison with the two well-known efficient anti-SARS-CoV-2 drugs (hydroxy)chloroquine (Altulea et al 2021 Mar 9 ; Liu et al xxxx), most of the investigated compounds in this study especially those possessing proved experimental/clinical activity against SARS-CoV-2 (the bolded name molecules in Table 1 including metformin and phenformin (Langmaier et al 2016 Sep 22 ), rosuvastatin, famotidine (Laurence and Lewis 2009 ), proguanil (Plöger et al 2018 Jul 1 ), pentamidine (Paul et al 1998 Jan 1 ), benznidazole (Moral Sanchez et al 2018 Oct), Berenil (Atsriku et al 2002 Nov 7 ), imatinib (Manley et al 2010 Oct 1 ), camostat and GBPA (Hempel et al 2021 ) have shown basic/extremely basic property that considering the presence the guanidine moiety, it is not surprising. Thus, according to the observed results, the guanidine-containing molecules can have a multi mechanism activity against SARS-CoV-2, and this theoretical claim needs further experimental investigations.…”

Section: Resultsmentioning

confidence: 89%

In silico investigation of the therapeutic and prophylactic potential of medicinal substances bearing guanidine moieties against COVID-19

Esam

Akhavan

Lotfi³

et al. 2022

Chem. Pap.

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The current viral pandemic, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), creates health, mental, economic, and other serious challenges that are better to say global crisis. Despite the existence of successful vaccines, the possible mutations which can lead to the born of novel and possibly more dangerous variants of the virus as well as the absence of definitive treatment for this potentially fatal multiple-organ infection in critically ill patients make us keep searching. Theoretically targeting human and viral receptors and enzymes via molecular docking and dynamics simulations can be considered a wise, rational, and efficient way to develop therapeutic agents against COVID-19. In this way, The RNA-dependent RNA polymerase (RdRP), main protease, and spike glycoprotein of SARS-CoV-2 as well as the human angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2 are the most discussed and studied targets that play essential roles in the viral life and infection cycle. In the current in silico investigation, the guanidine functionality containing drugs and medicinal substances such as metformin, famotidine, neuraminidase inhibitors, antimalarial medications, anticancer drug imatinib, CGP compounds, and human serine protease inhibitor camostat were studied against the above-mentioned therapeutic targets and most of them (especially imatinib) have revealed an incredible spectrum of free docking scores and MD results. The current in silico investigation that its novel perspective of view is corroborated by the different experimental and clinical evaluations, confirms that the guanidine moiety can be considered as a missing promising pharmacophore in drug design and development approaches against SARS-CoV-2. Considering the chemical potency of this polyamine group in chemical interaction creation, the observed outcomes in this virtual screening were not surprising. On the other hand, the guanidine functional group has unique physico-chemical properties such as basicity that can make the target cells intracellular pH undesirable for the virus entry, uncoating, and cytosolic lifecycle. According to the obtained results in the current study that are interestingly confirmed by the previously reported efficacy of some the guanidine carrying drugs in COVID-19, guanidine as a potential multi-target anti-SARS-CoV-2 functional scaffold deserves further comprehensive investigations. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11696-022-02528-y.

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Section: Resultsmentioning

confidence: 89%

In silico investigation of the therapeutic and prophylactic potential of medicinal substances bearing guanidine moieties against COVID-19

Esam

Akhavan

Lotfi³

et al. 2022

Chem. Pap.

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“…molecular structure, indication, therapeutic index, toxicity) and with respect to its physicochemical and pharmacokinetic properties (physicochemical properties could include solid and especially polymorphic forms, stereochemistry, acidic/basic properties, partition/distribution coefficient, solubility and stability, while pharmacokinetic properties comprise absorption, bioavailability, permeability, distribution, metabolism, and elimination). 30,31 Additionally, information on existing dosage forms and their performance (bioequivalence/bioinequivalence reports, dissolution results, and excipients) should be included. 30,31 Whereas at the beginning of the biowaiver project, data for solubility were extracted solely from the literature and discussed in terms of their physiological relevance, 28 a lack of solubility data at pH values of interest is now addressed by additional solubility studies.…”

Section: Biowaiver Monograph Seriesmentioning

confidence: 99%

“…30,31 Additionally, information on existing dosage forms and their performance (bioequivalence/bioinequivalence reports, dissolution results, and excipients) should be included. 30,31 Whereas at the beginning of the biowaiver project, data for solubility were extracted solely from the literature and discussed in terms of their physiological relevance, 28 a lack of solubility data at pH values of interest is now addressed by additional solubility studies. 29 Dissolution data of the API and -if possible -reference and generic products can also be generated and reported in the monograph.…”

Section: Biowaiver Monograph Seriesmentioning

confidence: 99%

“…29 The risk considerations should contain a careful evaluation of the risk for products not to be bioequivalent due to excipients and/or the manufacturing process, as well as an assessment of the risks of a false-positive biowaiver approval for patients and for public health. [29][30][31] The final assessment of the monograph should also identify gaps in the existing data. If a positive decision is reached about suitability of the biowaiver procedure, the monograph recommends testing conditions and requirements for a biowaiver application (e.g.…”

Section: Biowaiver Monograph Seriesmentioning

confidence: 99%

“…miniaturized approach to obtain reliable solubility data. 52 For the solubility studies for proguanil and cephalexin as well as for the solubility classification of newly added compounds of the EML, the miniaturized approach was implemented by use of a Uniprep TM filter system (depicted in figure 3), 30,31,55 following the Glomme approach. 52 The experiments were performed over a period of 24 hours.…”

Section: Requirements For Solubility Determinations For a Bcs Biowaiv...mentioning

confidence: 99%

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Optimization of solubility studies performed in the context of BCS biowaiver monographs

Plöger¹

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Die vorliegende Dissertation stellt eine Methode zur Löslichkeitsbestimmung vor, die für die Anwendung im Rahmen von BCS-Biowaiver Monografien entwickelt wurde. Der Methode und dem dafür konzipierten Studienprotokoll liegt das Prinzip der „Minimallöslichkeit“ zugrunde. Damit lässt sich einfach, kosteneffizient und wissenschaftlich verlässlich feststellen, ob ein Arzneistoff „hochlöslich“ gemäß den BCS-Biowaiver Richtlinien der Gesundheitsbehörden FDA, EMA und WHO ist und sich dementsprechend generische Produkte des Arzneistoffs grundsätzlich für das BCS-Biowaiver Zulassungsverfahren eignen. Dieses Verfahren für die Zulassung von Generika erlaubt die Beurteilung der Bioäquivalenz eines festen generischen Arzneimittels zur peroralen Anwendung auf Basis von in vitro-Freisetzungsuntersuchungen anstatt von in vivo-Studien wie z.B. pharmakokinetischen Studien am Menschen und erleichtert dadurch eine Marktzulassung sowohl durch Zeit- als auch Kosteneinsparung. Die Anwendung des Verfahrens ist von Vorteil, um die Verfügbarkeit von qualitativ hochwertigen, generischen (und damit kostengünstigen) Arzneimitteln zu erhöhen. Dies ist besonders wünschenswert für die Verfügbarkeit von gemäß der Weltgesundheitsorganisation essenziellen Arzneistoffen und unter denen gerade von solchen, die zur Bekämpfung von Krankheiten mit nur wenigen und/oder teuren therapeutischen Alternativen benötigt werden. Entstanden ist die Löslichkeitsbestimmungsmethode im Rahmen von zwei Projekten, die beide zu diesem Ziel einer guten globalen Gesundheitsversorgung beitragen: die Erstellung der Biowaiver Monografien von Proguanilhydrochlorid (ein Malaria-Prophylaktikum) und Cefalexinmonohydrat (ein Antibiotikum aus der Gruppe der Cephalosporine) setzt die Publikationsreihe „Biowaiver Monograph Series“ der FIP Focus Group „Bioclassification/Biowaiver“ fort. Jede Monografie gibt eine umfassende wissenschaftliche Empfehlung zur Eignung eines Wirkstoffs der WHO „Model List of Essential Medicines“ und seiner generischen Produkte für das BCS-Biowaiver Verfahren hinsichtlich aller regulatorisch geforderten Aspekte ab. Proguanilhydrochlorid (BCS Klasse III – „hochlöslich“ und nicht „hoch permeabel“) und Cefalexinmonohydrat (BCS Klasse I – „hochlöslich“ und „hoch permeabel“) sind beide für dieses Zulassungsverfahren geeignet. Im Zuge des anderen Projektes wurde die Löslichkeit und anschließend die BCS Klasse von Wirkstoffen bestimmt, die der 16. und 17. Version der WHO „Model List of Essential Medicines“ neu hinzugefügt wurden. Neun von 16 untersuchten Wirkstoffen, die in feste, perorale Arzneimittel formuliert werden können, sind im Hinblick auf ihre BCS Klasse für das eine Zulassung per BCS-Biowaiver geeignet. Eine umfangreichere Empfehlung könnte im Rahmen einer Biowaiver Monografie gegeben werden. Die experimentelle Bestimmung der Löslichkeit über einen pH-Wert-Bereich von 1-6,8 war essenzieller Bestandteil beider Projekte, da Literaturdaten zur Löslichkeit der Wirkstoffe nicht oder nur unvollständig vorlagen. Die entwickelte Methode basiert auf einer im Kleinmaßstab angesetzten „Shake-Flask“-Methode zur Bestimmung der thermodynamischen Löslichkeit, wird jedoch in einem Zeitrahmen von 24 Stunden durchgeführt. Sie nutzt die höchste Dosis der Wirkstoffe als Substanzmenge, um zu bestimmen, ob dieser „hochlöslich“ gemäß den BCS-Biowaiver Richtlinien ist oder nicht. Die Methode bzw. das dazugehörige Studienprotokoll beinhalten Empfehlungen zu den einzelnen Schritten der Durchführung, der Auswahl der Medien und Herausforderungen wie Präzipitation (Fallbeispiel: Proguanilhydrochlorid) und Zersetzungsreaktionen (Fallbeispiel: Cefalexinmonohydrat). Löslichkeitsdaten, die mit dieser Methode erhoben werden, können für eine Zulassung per BCS-Biowaiver bei den Gesundheitsbehörden eingereicht werden, aber auch für ein Vorab-Screening genutzt werden, dass „hochlösliche“ Arzneistoffe aus einer Vielzahl von Substanzen herauszufiltern soll, um nähere Untersuchungen im Rahmen einer Biowaiver Monografie anzuschließen.

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IVIVC Revised

Alimpertis,

Simitopoulos,

Tsekouras

et al. 2024

Pharm Res

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Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Proguanil Hydrochloride

Cited by 6 publications

References 39 publications

In silico investigation of the therapeutic and prophylactic potential of medicinal substances bearing guanidine moieties against COVID-19

In silico investigation of the therapeutic and prophylactic potential of medicinal substances bearing guanidine moieties against COVID-19

Optimization of solubility studies performed in the context of BCS biowaiver monographs

IVIVC Revised

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