Mechanistic Study of Belinostat Oral Absorption From Spray-Dried Dispersions

Stewart, Aaron M.; Yates, I.C.; Mudie, Deanna M.; Pivette, Perrine; Goodwin, Aaron K.; Sarmiento, Alyssa; Winter, Marcus; Morgen, Michael M.; Vodak, David T.

doi:10.1016/j.xphs.2018.09.031

Cited by 18 publications

(19 citation statements)

References 45 publications

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“…In literature, different examples of GLPS (Mosquera-Giraldo & Taylor, 2015;Mosquera-Giraldo et al, 2018b), and LLPS (Ilevbare & Taylor, 2013;Indulkar et al, 2016;Saboo et al, 2019) (together referred to as ALPS in this review) evolving during ASD dissolution were reported. As already pointed out in Section 4, from a physicochemical point of view, ALPS only occurs if supersaturated drug concentration exceeds the amorphous solubility (Taylor & Zhang, 2016;Baghel et al, 2018;Stewart et al, 2019). However, beyond the formation of ALPS based on phase separation from pure API-solvent mixtures, polymers play an important role in the formation of ALPS-particles.…”

Section: Api In Amorphous-liquid Phase Separationmentioning

confidence: 89%

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

2019

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Amorphous solid dispersions (ASDs) can increase the oral bioavailability of poorly soluble drugs. However, their use in drug development is comparably rare due to a lack of basic understanding of mechanisms governing drug liberation and absorption in vivo. Furthermore, the lack of a unified nomenclature hampers the interpretation and classification of research data. In this review, we therefore summarize and conceptualize mechanisms covering the dissolution of ASDs, formation of supersaturated ASD solutions, factors responsible for solution stabilization, drug uptake from ASD solutions, and drug distribution within these complex systems as well as effects of excipients. Furthermore, we discuss the importance of these findings on the development of ASDs. This improved overall understanding of these mechanisms will facilitate a rational ASD formulation development and will serve as a basis for further mechanistic research on drug delivery by ASDs.

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Section: Api In Amorphous-liquid Phase Separationmentioning

confidence: 89%

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

2019

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“…In silico PK simulations are emerging tools for ASD formulation development, since they can simulate many dynamic physiological factors that impact ASD bioperformance [ 13 , 38 , 39 , 40 ]. Simulations using physiologically-based pharmacokinetic (PBPK) modeling software such as GastroPlus can help design and optimize in vivo studies with respect to dose, prandial state, or pH modification (i.e., selecting ARAs for pH effect study) to maximize the likelihood of achieving desired ASD in vivo performance.…”

Section: Discussionmentioning

confidence: 99%

“…A polymer screening test of seven different polymers was performed using a solvent shift method to assess the polymers’ abilities to sustain acalabrutinib supersaturated drug concentrations [ 12 , 13 ]. The polymers tested included HPMCAS-H, HPMCAS-M, HPMCAS-L, Eudragit L100, HPMC E3, PVP K30, and PVP-VA64.…”

Section: Methodsmentioning

confidence: 99%

“…Solubilities of amorphous acalabrutinib dosed as the 50/50 ( w/w ) acalabrutinib/HPMCAS-H ASD were determined in different HCl molarities (pH 4.0, 4.5, 5.0, and 6.0) containing 34 mM NaCl. This approach was used rather than measuring amorphous solubility in the absence of polymer, since polymer has been shown to impact the apparent amorphous solubility [ 13 , 31 ]. After dosing the 50/50 ( w/w ) acalabrutinib/HPMCAS-H ASD to each medium, HCl was automatically titrated to maintain the target starting pH during dissolution using a Metrohm Titrado apparatus (Metohm, Tampa, FL, USA).…”

Section: Methodsmentioning

confidence: 99%

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In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets

et al. 2021

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Amorphous solid dispersion (ASD) dosage forms can improve the oral bioavailability of poorly water-soluble drugs, enabling the commercialization of new chemical entities and improving the efficacy and patient compliance of existing drugs. However, the development of robust, high-performing ASD dosage forms can be challenging, often requiring multiple formulation iterations, long timelines, and high cost. In a previous study, acalabrutinib/hydroxypropyl methylcellulose acetate succinate (HPMCAS)-H grade ASD tablets were shown to overcome the pH effect of commercially marketed Calquence in beagle dogs. This study describes the streamlined in vitro and in silico approach used to develop those ASD tablets. HPMCAS-H and -M grade polymers provided the longest acalabrutinib supersaturation sustainment in an initial screening study, and HPMCAS-H grade ASDs provided the highest in vitro area under the curve (AUC) in gastric to intestinal transfer dissolution tests at elevated gastric pH. In silico simulations of the HPMCAS-H ASD tablet and Calquence capsule provided good in vivo study prediction accuracy using a bottom–up approach (absolute average fold error of AUC0-inf < 2 except for Calquence + famotidine ≈ 3). This streamlined approach combined an understanding of key drug, polymer, and gastrointestinal properties with in vitro and in silico tools to overcome the acalabrutinib pH effect without the need for reformulation or multiple studies, showing promise for reducing time and costs to develop ASD drug products.

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“…In addition, potential impacts of excipients and dosage form design on drug release were not considered. For example, any acidic or basic excipients present in the formulation could impact the GI region/pH at which the drug is released and modulate bulk and surface pH (29)(30)(31). Therefore, recommendations are most applicable to IR dosage forms containing standard tableting excipients.…”

Section: Dissolution Medium Selection Methodology Introductionmentioning

confidence: 99%

Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties

Mudie

Samiei

Marshall

et al. 2020

AAPS J

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The rate and extent of drug dissolution in the gastrointestinal (GI) tract are highly dependent upon drug physicochemical properties and GI fluid properties. Biorelevant dissolution media (BDM), which aim to facilitate in vitro prediction of in vivo dissolution performance, have evolved with our understanding of GI physiology. However, BDM with a variety of properties and compositions are available, making the choice of dissolution medium challenging. In this tutorial, we describe a simple and quantitative methodology for selecting practical, yet physiologically relevant BDM representative of fasted humans for evaluating dissolution of immediate release formulations. Specifically, this methodology describes selection of pH, buffer species, and concentration and evaluates the importance of including bile salts and phospholipids in the BDM based upon drug substance log D, pKa, and intrinsic solubility. The methodology is based upon a mechanistic understanding of how three main factors affect dissolution, including (1) drug ionization at gastrointestinal pH, (2) alteration of surface pH by charged drug species, and (3) drug solubilization in mixed lipidic aggregates comprising bile salts and phospholipids. Assessment of this methodology through testing and comparison with literature reports showed that the recommendations correctly identified when a biorelevant buffer capacity or the addition of bile salts and phospholipids to the medium would appreciably change the drug dissolution profile. This methodology can enable informed decisions about when a time, complexity, and/or cost-saving buffer is expected to lead to physiologically meaningful in vitro dissolution testing, versus when a more complex buffer would be required.

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Mechanistic Study of Belinostat Oral Absorption From Spray-Dried Dispersions

Cited by 18 publications

References 45 publications

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

Mechanisms of increased bioavailability through amorphous solid dispersions: a review

In Vitro-In Silico Tools for Streamlined Development of Acalabrutinib Amorphous Solid Dispersion Tablets

Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties

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