Biorelevant test for supersaturable formulation

Lu, Enxian; Li, Shoufeng; Zhong-qin, Wang

doi:10.1016/j.ajps.2016.10.002

Cited by 23 publications

(13 citation statements)

References 41 publications

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“…It is a common practice to assess the food effect of BCS II drugs by comparing their concentration profiles in the biorelevant media to assess the effect. − This is based on an implicit assumption that the solubilization of the drug would increase the bioavailability. The two-stage dissolution test revealed significantly higher apparent RTV concentrations of ∼180–200 μg/mL in the FeSSIF-V2 (Figure A) as compared to those (∼50 μg/mL) in the FaSSIF-V2 (Figure A), suggesting a food effect with a higher exposure in the fed state.…”

Section: Resultsmentioning

confidence: 99%

“…Diverse two-compartment dissolution methods with pH alteration have been utilized to simulate the dissolution and transit from the gastric compartment to the intestinal compartment in vivo. ,− Representative two-compartment dissolution methods include a transfer model with both donor and acceptor compartments reported by Kostewicz et al, an artificial stomach-duodenum model developed by Hawley et al, − and a gastrointestinal simulator (GIS) incorporates a jejunum compartment as the third chamber reported by Amidon et al − …”

Section: Introductionmentioning

confidence: 99%

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In Vitro Characterization of Ritonavir Drug Products and Correlation to Human in Vivo Performance

Vela

Shi

et al. 2017

Mol. Pharmaceutics

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Ritonavir (RTV) is a weakly basic drug with a pH-dependent solubility. In vitro dissolution and supersatuation behaviors of three Norvir oral products including the tablet, powder, and solution were investigated by two biorelevant dissolution methods with pH alteration: a two-stage dissolution test and a biphasic dissolution-partition test. The two-stage dissolution test revealed a high degree of supersaturation of RTV from these products accompanied by the occurrence of liquid-liquid phase separation (LLPS) in biorelevant dissolution media. Higher, stable apparent RTV concentrations were observed in the FeSSIF-V2 as compared to those in the FaSSIF-V2, which suggested a food effect with higher exposure in the fed state. This is inconsistent with the evaluation in vivo. The biphasic test revealed significantly lower degrees of supersaturation of RTV in the aqueous media from these dosage forms as compared to results of the two-stage dissolution test. RTV concentrations in octanol at 6 h obtained from the tablet and powder with the use of the biorelevant media are consistent with corresponding in vivo AUC and Cmax under the fasting and moderate fat fed (MFF) states and predict the food effect. The underlying mechanisms responsible for the food effect are also proposed. Fractional partition profiles of RTV obtained in octanol from these three Norvir oral products are in agreement with the corresponding fractional absorption profiles in vivo under both the fasting and MFF states. This study reveals a complex interplay among the dissolution, precipitation, and partition processes from these formulations that dictate the oral exposure of RTV.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vitro Characterization of Ritonavir Drug Products and Correlation to Human in Vivo Performance

Vela

Shi

et al. 2017

Mol. Pharmaceutics

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“…Due to the inherent limitations of QC methods, non-sink, tailor-made dissolution approaches along with possibility of including an absorptive interface (i.e., simulating dissolution and permeation simultaneously) integrated with discriminating analytical methods (i.e., solid state characterization) are needed as in-vitro tools to ascertain phase-behavior of ASDs in dissolution media. By careful selection of in-vitro experimental conditions such as the type (i.e., pH, ionic strength, surfactants) and volume of dissolution media, agitation speed, temperature and sampling procedures, the extent of supersaturation and formation of crystalline seeds can be captured [ 90 , 91 ]. Dissolution can be performed in one-, two- or multi-compartment experimental design (to simulate partitioning in the GI and systemic circulation) or in a custom-made technical design, such as TNO intestinal model 1 (TIM-1) or USP II apparatus coupled with peristaltic pumps to simulate flow of different intestinal fluids to the site of drug release and absorption [ 92 ].…”

Section: Product Development Strategymentioning

confidence: 99%

“…Regardless of the dissolution design, a single dissolution media or different media can be used during dissolution test to simulate shifts in pH and fluid composition in the GI tract with the possibility of including bile salts and/or surfactants. In addition, oil-like media can be included on top of an aqueous buffer to sustain quasi-sink conditions or a semi-permeable membrane (i.e., PAMPA membranes, CaCo-2 cell monolayers, microFlux system) can be included to simulate the absorption barrier [ 91 ]. A review of recent publications on analytical and dissolution techniques including those from FDA database and bio-relevant dissolution methods to assess solid dispersion formulations is presented in Table 2 below along with a summary of the composition of solid dispersion and preparation process.…”

Section: Product Development Strategymentioning

confidence: 99%

Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development

Iyer¹,

Jovanovska

Berginc

et al. 2021

Pharmaceutics

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Poorly water-soluble drugs pose a significant challenge to developability due to poor oral absorption leading to poor bioavailability. Several approaches exist that improve the oral absorption of such compounds by enhancing the aqueous solubility and/or dissolution rate of the drug. These include chemical modifications such as salts, co-crystals or prodrugs and physical modifications such as complexation, nanocrystals or conversion to amorphous form. Among these formulation strategies, the conversion to amorphous form has been successfully deployed across the pharmaceutical industry, accounting for approximately 30% of the marketed products that require solubility enhancement and making it the most frequently used technology from 2000 to 2020. This article discusses the underlying scientific theory and influence of the active compound, the material properties and manufacturing processes on the selection and design of amorphous solid dispersion (ASD) products as marketed products. Recent advances in the analytical tools to characterize ASDs stability and ability to be processed into suitable, patient-centric dosage forms are also described. The unmet need and regulatory path for the development of novel ASD polymers is finally discussed, including a description of the experimental data that can be used to establish if a new polymer offers sufficient differentiation from the established polymers to warrant advancement.

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“…A systematic and quantitative synopsis of the knowledge about SDDS has recently been published by Fong and colleagues (Fong et al, 2016). As an extensively and publicly debated topic, there are some important aspects that should be considered in order to gain valuable information about the biorelevant supersaturated concentrations and precipitated amounts of the administered drug (Bevernage et al, 2013;Lu et al, 2017;Sun et al, 2016;Sun and Lee, 2013). There are multiple in vitro models described in the literature that are frequently applied to evaluate supersaturation and precipitation for oral drug products; some of these models are more simple and static while other models are more complex and dynamic (Kostewicz et al, 2014b).…”

Section: Introductionmentioning

confidence: 99%

Evaluation and optimized selection of supersaturating drug delivery systems of posaconazole (BCS class 2b) in the gastrointestinal simulator (GIS): An in vitro-in silico-in vivo approach

Hens

Bermejo

Tsume

et al. 2018

European Journal of Pharmaceutical Sciences

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Supersaturating drug delivery systems (SDDS) have been put forward in the recent decades in order to circumvent the issue of low aqueous solubility. Prior to the start of clinical trials, these enabling formulations should be adequately explored in in vitro/in silico studies in order to understand their in vivo performance and to select the most appropriate and effective formulation in terms of oral bioavailability and therapeutic outcome. The purpose of this work was to evaluate the in vivo performance of four different oral formulations of posaconazole (categorized as a biopharmaceutics classification system (BCS) class 2b compound) based on the in vitro concentrations in the gastrointestinal simulator (GIS), coupled with an in silico pharmacokinetic model to predict their systemic profiles. Recently published intraluminal and systemic concentrations of posaconazole for these formulations served as a reference to validate the in vitro and in silico results. Additionally, the morphology of the formed precipitate of posaconazole was visualized and characterized by optical microscopy studies and thermal analysis. This multidisciplinary work demonstrates an in vitro-in silico-in vivo approach that provides a scientific basis for screening SDDS by a user-friendly formulation predictive dissolution (fPD) device in order to rank these formulations towards their in vivo performance.

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Biorelevant test for supersaturable formulation

Cited by 23 publications

References 41 publications

In Vitro Characterization of Ritonavir Drug Products and Correlation to Human in Vivo Performance

In Vitro Characterization of Ritonavir Drug Products and Correlation to Human in Vivo Performance

Amorphous Solid Dispersions (ASDs): The Influence of Material Properties, Manufacturing Processes and Analytical Technologies in Drug Product Development

Evaluation and optimized selection of supersaturating drug delivery systems of posaconazole (BCS class 2b) in the gastrointestinal simulator (GIS): An in vitro-in silico-in vivo approach

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