<i>In Vitro</i>–<i>in Vivo</i> Correlation of the Effect of Supersaturation on the Intestinal Absorption of BCS Class 2 Drugs

Higashino, Haruki; Hasegawa, Tsubasa; Yamamoto, Mari; Matsui, Rie; Masaoka, Yoshie; Kataoka, Makoto; Sakuma, Shinji; Yamashita, Shinji

doi:10.1021/mp400465p

Cited by 52 publications

(31 citation statements)

References 54 publications

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“…In vitro , the rod shaped nanocrystals had a higher dissolution rate, and also in vivo a higher oral bioavailability. The same kind of behavior had been noticed earlier with ketoconazole [ 82 ]. The reason for the differences related to particle shape is that lovastatin is a CYP enzyme substrate and has extensive first pass metabolism after the intestinal uptake.…”

Section: Effect Of Stabilizers On Cell Layers and Drug Transportsupporting

confidence: 80%

Stabilizing Agents for Drug Nanocrystals: Effect on Bioavailability

2016

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Drug nanocrystals are a versatile option for drug delivery purposes, and while the number of poorly soluble drug materials is all the time increasing, more research in this area is performed. Drug nanocrystals have a simple structure—a solid drug core is surrounded by a layer of stabilizing agent. However, despite the considerably simple structure, the selection of an appropriate stabilizer for a certain drug can be challenging. Mostly, the stabilizer selection is based purely on the requirement of physical stability, e.g., maintaining the nanosized particle size as long as possible after the formation of drug nanocrystals. However, it is also worth taking into account that stabilizer can affect the bioavailability in the final formulation via interactions with cells and cell layers. In addition, formation of nanocrystals is only one process step, and for the final formulation, more excipients are often added to the composition. The role of the stabilizers in the final formulation can be more than only stabilizing the nanocrystal particle size. A good example is the stabilizer’s role as cryoprotectant during freeze drying. In this review, the stabilizing effect, role of stabilizers in final nanocrystalline formulations, challenges in reaching in vitro–in vivo correlation with nanocrystalline products, and stabilizers’ effect on higher bioavailability are discussed.

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Section: Effect Of Stabilizers On Cell Layers and Drug Transportsupporting

confidence: 80%

Stabilizing Agents for Drug Nanocrystals: Effect on Bioavailability

2016

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“…78) When the API concentration surpasses its solubility in particular environments, phase separation is induced by precipitation or crystallization of API alone or associated with salts or hydrates 79) (Fig. 1).…”

Section: Solution-mediated Phase Transformation Andmentioning

confidence: 99%

Characterization and Quality Control of Pharmaceutical Cocrystals

Izutsu¹,

Koide²,

Takata

et al. 2016

Chem. Pharm. Bull.

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Recent active research and new regulatory guidance on pharmaceutical cocrystals have increased the rate of their development as promising approaches to improve handling, storage stability, and bioavailability of poorly soluble active pharmaceutical ingredients (APIs). However, their complex structure and the limited amount of available information related to their performance may require development strategies that differ from those of single-component crystals to ensure their clinical safety and efficacy. This article highlights current methods of characterizing pharmaceutical cocrystals and approaches to controlling their quality. Different cocrystal regulatory approaches between regions are also discussed. The physical characterization of cocrystals should include elucidating the structure of their objective crystal form as well as their possible variations (e.g., polymorphs, hydrates). Some solids may also contain crystals of individual components. Multiple processes to prepare pharmaceutical cocrystals (e.g., crystallization from solutions, grinding) vary in their applicable ingredients, scalability, and characteristics of resulting solids. The choice of the manufacturing method affects the quality control of particular cocrystals and their formulations. In vitro evaluation of the properties that govern clinical performance is attracting increasing attention in the development of pharmaceutical cocrystals. Understanding and mitigating possible factors perturbing the dissolution and/ or dissolved states, including solution-mediated phase transformation (SMPT) and precipitation from supersaturated solutions, are important to ensure the bioavailability of orally administrated lower-solubility APIs. The effect of polymer excipients on the performance of APIs emphasizes the relevance of formulation design for appropriate use.

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“…This study raised questions regarding the dissolution system used to predict in vivo performance and the likely discrepancy between in vitro and in vivo dissolution. The in vivo dissolution profiles of BCS class IIb drugs, weak base drugs in BCS class II such as ketoconazole, have been also evaluated (Dressman and Reppas, 2000;Higashino et al, 2014;Taneri et al, 2010;Zhou et al, 2005). Those drugs will quickly dissolve at gastric pH but will not dissolve at intestinal pH, exhibiting totally opposite dissolution profiles to BCS class IIa drugs.…”

Section: Introductionmentioning

confidence: 99%