(Sub)micron particles forming in aqueous dispersions of amorphous solid dispersions of the poorly soluble drug ABT-199: A combined particle optical counting and field-flow fractionation study

Bohsen, Mette Sloth; Elvang, Philipp A.; Reder-Hilz, Beate; Lenz, Verena; Rosenberg, Jörg; Brandl, Martin

doi:10.1016/j.ejps.2020.105497

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…There are two distinct small populations: one at approximately 53 nm and another at 33 nm. The first one is present for both the amorphous and crystalline ITZ (without polymer), whereas the latter corresponds to FaSSIF micelles, as observed in a previous study . This smooth shift in size from 33 to 53 nm appears to represent the bile micelle-bound drug.…”

Section: Resultssupporting

confidence: 66%

“…The first one is present for both the amorphous and crystalline ITZ (without polymer), whereas the latter corresponds to FaSSIF micelles, as observed in a previous study. 31 This smooth shift in size from 33 to 53 nm appears to represent the bile micelle-bound drug. These aggregates are commonly known as solubilizing micelles, and although they increase the apparent solubility of the drug, their presence does not correlate with higher permeation rates 46,47 or with performance increase.…”

Section: Resultsmentioning

confidence: 97%

“…Tho et al 12 noticed a spontaneous formation of nanodispersions upon non-sink dissolution of ritonavir ASDs and correlated the presence of these nanostructures with an enhanced bioavailability of the drug. Bohsen et al 31 characterized the colloids formed upon the dissolution of different ASDs, composed by copovidone or HPMCAS, and found that HPMCAS ASDs could attain a higher fraction of the drug in colloids. Indulkar et al 8 and Que et al 19 studied the mechanisms of drug release from ASDs of poorly soluble drugs and copovidone depending on the ASD drug load and linked the congruent release rate of the drug and polymer to the occurrence of LLPS, leading to the formation of drug-rich colloids.…”

Section: Introductionmentioning

confidence: 99%

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Insights into the Release Mechanisms of ITZ:HPMCAS Amorphous Solid Dispersions: The Role of Drug-Rich Colloids

et al. 2021

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Understanding the dissolution mechanisms of amorphous solid dispersions (ASDs) and being able to link enhanced drug exposure with process parameters are key when formulating poorly soluble compounds. Thus, in this study, ASDs composed by itraconazole (ITZ) and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were formulated with different polymer grades and drug loads (DLs) and processed by spray drying with different atomization ratios and outlet temperatures. Their in vitro performance and the ability to form drug-rich colloids were then evaluated by a physiologically relevant dissolution method. In gastric media, drug release followed a diffusion-controlled mechanism and drug-rich colloids were not formed since the solubility of the amorphous API at pH 1.6 was not exceeded. After changing to intestinal media, the API followed a polymer dissolution-controlled release, where the polymer rapidly dissolved, promoting the immediate release of API and thus leading to liquid–liquid phase separation (LLPS) and consequent formation of drug-rich colloids. However, the release of API and polymer was not congruent, so API surface enrichment occurred, which limited the further dissolution of the polymer, leading to a drug-controlled release. ASDs formulated with M-grade showed the highest ability to maintain supersaturation and the lowest tendency for AAPS due to its good balance between acetyl and succinoyl groups, and thus strong interactions with both the hydrophobic drug and the aqueous dissolution medium. The ability to form colloids increased for low DL (15%) and high specific surface area due to the high amount of polymer released until the occurrence of API surface enrichment. Even though congruent release was not observed, all ASDs formed drug-rich colloids that were stable in the solution until the end of the dissolution study (4 h), maintaining the same size distribution (ca. 300 nm). Drug-rich colloids can, in vivo, act as a drug reservoir replenishing the drug while it permeates. Designing ASDs that are prone to form colloids can overcome the solubility constraints of Biopharmaceutics Classification System (BCS) II and IV drugs, posing as a reliable formulation strategy.

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Section: Resultssupporting

confidence: 66%

Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Insights into the Release Mechanisms of ITZ:HPMCAS Amorphous Solid Dispersions: The Role of Drug-Rich Colloids

et al. 2021

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“…When AF4 is preliminary to proteomic analysis, the preservation of the integrity of the corona is of paramount importance, in addition to respecting the conformation and properties of the proteins. The eluent needs to be chosen so as to match the incubation medium, devoid of the macromolecular fraction: for nanoparticles incubated in plasma or serum, PBS or phosphate buffers (PB) are standard choices for the eluent [39,182,183,189], while protein-free intestinal fluid is an option for orally administered drugs [190]. As mentioned above, fractionation carried out with sufficiently mild separation techniques may lead to the retrieval of the corona in its entirety, while harsher conditions would cause the most loosely bound proteins to be washed away.…”

Section: Corona Compositionmentioning

confidence: 99%

Asymmetric flow field-flow fractionation as a multifunctional technique for the characterization of polymeric nanocarriers

Quattrini

Berrecoso

Crecente‐Campo

et al. 2021

Drug Deliv. and Transl. Res.

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The importance of polymeric nanocarriers in the field of drug delivery is ever-increasing, and the accurate characterization of their properties is paramount to understand and predict their behavior. Asymmetric flow field-flow fractionation (AF4) is a fractionation technique that has gained considerable attention for its gentle separation conditions, broad working range, and versatility. AF4 can be hyphenated to a plurality of concentration and size detectors, thus permitting the analysis of the multifunctionality of nanomaterials. Despite this potential, the practical information that can be retrieved by AF4 and its possible applications are still rather unfamiliar to the pharmaceutical scientist. This review was conceived as a primer that clearly states the “do’s and don’ts” about AF4 applied to the characterization of polymeric nanocarriers. Aside from size characterization, AF4 can be beneficial during formulation optimization, for drug loading and drug release determination and for the study of interactions among biomaterials. It will focus mainly on the advances made in the last 5 years, as well as indicating the problematics on the consensus, which have not been reached yet. Methodological recommendations for several case studies will be also included. Graphical abstract

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Application of tiny-TIM as a mechanistic tool to investigate the in vitro performance of different itraconazole formulations under physiologically relevant conditions

Mármol¹,

Fischer²,

Wahl³

et al. 2022

European Journal of Pharmaceutical Sciences

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(Sub)micron particles forming in aqueous dispersions of amorphous solid dispersions of the poorly soluble drug ABT-199: A combined particle optical counting and field-flow fractionation study

Cited by 7 publications

References 26 publications

Insights into the Release Mechanisms of ITZ:HPMCAS Amorphous Solid Dispersions: The Role of Drug-Rich Colloids

Insights into the Release Mechanisms of ITZ:HPMCAS Amorphous Solid Dispersions: The Role of Drug-Rich Colloids

Asymmetric flow field-flow fractionation as a multifunctional technique for the characterization of polymeric nanocarriers

Application of tiny-TIM as a mechanistic tool to investigate the in vitro performance of different itraconazole formulations under physiologically relevant conditions

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