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Pharmaceutics
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The Latest Technology for the Prediction and Improvement of Drug...
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The Latest Technology for the Prediction and Improvement of Drug Absorption

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Biopharmaceutics".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 22083

Special Issue Editors

Prof. Dr. Hiroaki Yuasa

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Guest Editor
Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan
Interests: intestinal absorption; drug transporters; pharmacokinetics; pharmacodynamics
Dr. Masateru Miyake

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Guest Editor
Business Integrity and External Affairs, Otsuka Pharmaceutical Co., Ltd., Shinagawa Grand Central Tower 14F, 2-16-4 Konan, Minato-ku, Tokyo 108-8242, Japan
Interests: transmucosal absorption; absorption enhancement; prediction of intestinal absorption; formulation; IBD; permeability

Special Issue Information

Dear Colleagues,

In the past decade, drugs have been developed to accommodate a wide range of small- (about 500 Da), medium-, and large-molecule candidates. Oral administration is the most convenient way for patients to take medications, and leads to high adherence. To determine the feasibility of developing a candidate as an oral drug, appropriate methods are required for predicting intestinal absorption. First, we focus on methods that use human intestinal tissue. Next, we introduce new findings on co-cultured models that use Caco-2 cells, and on in silico systems. These alternative in vitro methods are not only convenient for predicting intestinal drug absorption, but can also be used in a variety of research locations without strict controls, such as ethical and biosafety assessments. On the other hand, it is necessary to develop an oral absorption improvement technique that enables the intestinal absorption of medium- and large-molecule drugs; such technology should facilitate the development of these drugs. Therefore, we also introduce recent advances in nanocrystal systems.

Prof. Dr. Hiroaki Yuasa
Dr. Masateru Miyake
Guest Editors

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Keywords

  • oral drug delivery
  • in vitro model
  • prediction
  • human intestinal tissue
  • lysosome
  • nanocrystal
  • absorption enhancer
  • inflammatory bowel disease (IBD)

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Published Papers (9 papers)

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Research

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14 pages, 2585 KiB  
Article
Stabilized Astaxanthin Nanoparticles Developed Using Flash Nanoprecipitation to Improve Oral Bioavailability and Hepatoprotective Effects
by Antara Ghosh, Sujan Banik, Kohei Yamada, Shingen Misaka, Robert K. Prud’homme, Hideyuki Sato and Satomi Onoue
Pharmaceutics 2023, 15(11), 2562; https://doi.org/10.3390/pharmaceutics15112562 - 31 Oct 2023
Cited by 3 | Viewed by 1772
Abstract
In this study, we developed stabilized astaxanthin (AX) nanoparticles (sNP/AX) to improve the physicochemical properties, oral bioavailability, and hepatoprotection of AX. A flash nanoprecipitation technique was used with a multi-inlet vortex mixer to prepare the sNP/AX. Vitamins E (VE) and C (VC) were [...] Read more.
In this study, we developed stabilized astaxanthin (AX) nanoparticles (sNP/AX) to improve the physicochemical properties, oral bioavailability, and hepatoprotection of AX. A flash nanoprecipitation technique was used with a multi-inlet vortex mixer to prepare the sNP/AX. Vitamins E (VE) and C (VC) were used as co-stabilizers with poloxamer 407 as a stabilizer to inhibit the oxidative degradation of AX during sNP/AX formation and storage. VC stabilized AX in the aqueous phase during the preparation, whereas VE markedly improved the storage stability of sNP/AX, as evidenced by the AX contents remaining at 94 and 81% after 12 weeks of storage at 4 °C and 25 °C, respectively. The mean sNP/AX diameter was 215 nm, which resulted in higher AX release properties than those of crystalline AX. Rats, orally administered sNP/AX (33.2 mg AX/kg), exhibited higher systemic exposure to AX, whereas oral absorption in the crystalline AX group was negligible. In the rat hepatic injury model, oral pretreatment with sNP/AX (33.2 mg AX/kg) markedly attenuated hepatic damage, as shown by the histopathological analysis and reduced levels of plasma biomarkers for hepatic injury. These findings suggest that strategically including antioxidative additives in the sNP/AX has the potential to improve the physicochemical and nutraceutical properties of AX. Full article
(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)
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14 pages, 3158 KiB  
Article
Caco-2 Cell Sheet Partially Laminated with HT29-MTX Cells as a Novel In Vitro Model of Gut Epithelium Drug Permeability
by Yi Cheng, Chie Watanabe, Yusuke Ando, Satoshi Kitaoka, Yuya Egawa, Tomoya Takashima, Akihiro Matsumoto and Masahiro Murakami
Pharmaceutics 2023, 15(9), 2338; https://doi.org/10.3390/pharmaceutics15092338 - 18 Sep 2023
Cited by 3 | Viewed by 2517
Abstract
The intestinal epithelial Caco-2 cell monolayer is a well-established in vitro model useful for predicting intestinal drug absorption in humans. Coculture models of Caco-2 and goblet-cell-like HT29-MTX cells have been developed to overcome the lack of a mucus layer; however, those models are [...] Read more.
The intestinal epithelial Caco-2 cell monolayer is a well-established in vitro model useful for predicting intestinal drug absorption in humans. Coculture models of Caco-2 and goblet-cell-like HT29-MTX cells have been developed to overcome the lack of a mucus layer; however, those models are much leakier compared to the intestinal epithelium. Here, we developed a partially laminated culture model where HT29-MTX cells were superimposed onto a Caco-2 monolayer to overcome this issue. A morphological study showed that the piled HT29-MTX cells were voluntarily incorporated into the Caco-2 monolayer, and mucus production was confirmed via periodic acid-Schiff and mucin protein 2 staining. Permeability was evaluated in terms of transepithelial electrical resistance (TEER) and the apparent permeability of paracellular markers with different molecular sizes. The partially laminated model maintained the high barrier function of the Caco-2 monolayer, whose permeability appeared adjustable according to the HT29-MTX/Caco-2 cell ratio. In contrast, the coculture models showed abnormally high permeability of those markers, correlated with low TEER. Thus, the partially laminated model enabled in vitro recapitulation of effective mucosal barrier function. Consequently, this novel model may be useful as an in vitro high-throughput evaluation system for enteral mucosal permeability and mucus-penetrating efficiency of drugs and nanocarriers. Full article
(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)
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Review

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27 pages, 5769 KiB  
Review
Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs
by Daigo Asano, Hideo Takakusa and Daisuke Nakai
Pharmaceutics 2024, 16(1), 47; https://doi.org/10.3390/pharmaceutics16010047 - 28 Dec 2023
Cited by 3 | Viewed by 4105
Abstract
To meet unmet medical needs, middle-to-large molecules, including peptides and oligonucleotides, have emerged as new therapeutic modalities. Owing to their middle-to-large molecular sizes, middle-to-large molecules are not suitable for oral absorption, but there are high expectations around orally bioavailable macromolecular drugs, since oral [...] Read more.
To meet unmet medical needs, middle-to-large molecules, including peptides and oligonucleotides, have emerged as new therapeutic modalities. Owing to their middle-to-large molecular sizes, middle-to-large molecules are not suitable for oral absorption, but there are high expectations around orally bioavailable macromolecular drugs, since oral administration is the most convenient dosing route. Therefore, extensive efforts have been made to create bioavailable middle-to-large molecules or develop absorption enhancement technology, from which some successes have recently been reported. For example, Rybelsus® tablets and Mycapssa® capsules, both of which contain absorption enhancers, were approved as oral medications for type 2 diabetes and acromegaly, respectively. The oral administration of Rybelsus and Mycapssa exposes their pharmacologically active peptides with molecular weights greater than 1000, namely, semaglutide and octreotide, respectively, into systemic circulation. Although these two medications represent major achievements in the development of orally absorbable peptide formulations, the oral bioavailability of peptides after taking Rybelsus and Mycapssa is still only around 1%. In this article, we review the approaches and recent advances of orally bioavailable middle-to-large molecules and discuss challenges for improving their oral absorption. Full article
(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)
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13 pages, 239 KiB  
Review
Recent Advances in the Gastrointestinal Complex in Vitro Model for ADME Studies
by Kazuyoshi Michiba, Kengo Watanabe, Tomoki Imaoka and Daisuke Nakai
Pharmaceutics 2024, 16(1), 37; https://doi.org/10.3390/pharmaceutics16010037 - 27 Dec 2023
Cited by 1 | Viewed by 1603
Abstract
Intestinal absorption is a complex process involving the permeability of the epithelial barrier, efflux transporter activity, and intestinal metabolism. Identifying the key factors that govern intestinal absorption for each investigational drug is crucial. To assess and predict intestinal absorption in humans, it is [...] Read more.
Intestinal absorption is a complex process involving the permeability of the epithelial barrier, efflux transporter activity, and intestinal metabolism. Identifying the key factors that govern intestinal absorption for each investigational drug is crucial. To assess and predict intestinal absorption in humans, it is necessary to leverage appropriate in vitro systems. Traditionally, Caco-2 monolayer systems and intestinal Ussing chamber studies have been considered the ‘gold standard’ for studying intestinal absorption. However, these methods have limitations that hinder their universal use in drug discovery and development. Recently, there has been an increasing number of reports on complex in vitro models (CIVMs) using human intestinal organoids derived from intestinal tissue specimens or iPSC-derived enterocytes plated on 2D or 3D in microphysiological systems. These CIVMs provide a more physiologically relevant representation of key ADME-related proteins compared to conventional in vitro methods. They hold great promise for use in drug discovery and development due to their ability to replicate the expressions and functions of these proteins. This review highlights recent advances in gut CIVMs employing intestinal organoid model systems compared to conventional methods. It is important to note that each CIVM should be tailored to the investigational drug properties and research questions at hand. Full article
(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)
15 pages, 608 KiB  
Review
Intestinal Membrane Function in Inflammatory Bowel Disease
by Daisuke Nakai and Masateru Miyake
Pharmaceutics 2024, 16(1), 29; https://doi.org/10.3390/pharmaceutics16010029 - 25 Dec 2023
Cited by 2 | Viewed by 1918
Abstract
Inflammatory bowel disease is a set of chronic inflammatory diseases that mainly develop in the gastrointestinal mucosa, including ulcerative colitis and Crohn’s disease. Gastrointestinal membrane permeability is an important factor influencing the pharmacological effects of pharmaceuticals administered orally for treating inflammatory bowel disease [...] Read more.
Inflammatory bowel disease is a set of chronic inflammatory diseases that mainly develop in the gastrointestinal mucosa, including ulcerative colitis and Crohn’s disease. Gastrointestinal membrane permeability is an important factor influencing the pharmacological effects of pharmaceuticals administered orally for treating inflammatory bowel disease and other diseases. Understanding the presence or absence of changes in pharmacokinetic properties under a disease state facilitates effective pharmacotherapy. In this paper, we reviewed the gastrointestinal membrane function in ulcerative colitis and Crohn’s disease from the perspective of in vitro membrane permeability and electrophysiological parameters. Information on in vivo permeability in humans is summarized. We also overviewed the inflammatory bowel disease research using gut-on-a-chip, in which some advances have recently been achieved. It is expected that these findings will be exploited for the development of therapeutic drugs for inflammatory bowel disease and the optimization of treatment options and regimens. Full article
(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)
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20 pages, 3650 KiB  
Review
Simultaneous Prediction Method for Intestinal Absorption and Metabolism Using the Mini-Ussing Chamber System
by Satoshi Kondo and Masateru Miyake
Pharmaceutics 2023, 15(12), 2732; https://doi.org/10.3390/pharmaceutics15122732 - 5 Dec 2023
Viewed by 1552
Abstract
Many evaluation tools for predicting human absorption are well-known for using cultured cell lines such as Caco-2, MDCK, and so on. Since the combinatorial chemistry and high throughput screening system, pharmacological assay, and pharmaceutical profiling assay are mainstays of drug development, PAMPA has [...] Read more.
Many evaluation tools for predicting human absorption are well-known for using cultured cell lines such as Caco-2, MDCK, and so on. Since the combinatorial chemistry and high throughput screening system, pharmacological assay, and pharmaceutical profiling assay are mainstays of drug development, PAMPA has been used to evaluate human drug absorption. In addition, cultured cell lines from iPS cells have been attracting attention because they morphologically resemble human intestinal tissues. In this review, we used human intestinal tissues to estimate human intestinal absorption and metabolism. The Ussing chamber uses human intestinal tissues to directly assay a drug candidate’s permeability and determine the electrophysiological parameters such as potential differences (PD), short circuit current (Isc), and resistance (R). Thus, it is an attractive tool for elucidating human intestinal permeability and metabolism. We have presented a novel prediction method for intestinal absorption and metabolism by utilizing a mini-Ussing chamber using human intestinal tissues and animal intestinal tissues, based on the transport index (TI). The TI value was calculated by taking the change in drug concentrations on the apical side due to precipitation and the total amounts accumulated in the tissue (Tcorr) and transported to the basal side (Xcorr). The drug absorbability in rank order, as well as the fraction of dose absorbed (Fa) in humans, was predicted, and the intestinal metabolism of dogs and rats was also predicted, although it was not quantitative. However, the metabolites formation index (MFI) values, which are included in the TI values, can predict the evaluation of intestinal metabolism and absorption by using ketoconazole. Therefore, the mini-Ussing chamber, equipped with human and animal intestinal tissues, would be an ultimate method to predict intestinal absorption and metabolism simultaneously. Full article
(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)
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16 pages, 3137 KiB  
Review
Advances in the Evaluation of Gastrointestinal Absorption Considering the Mucus Layer
by Kaori Miyazaki, Akira Sasaki and Hiroshi Mizuuchi
Pharmaceutics 2023, 15(12), 2714; https://doi.org/10.3390/pharmaceutics15122714 - 30 Nov 2023
Cited by 4 | Viewed by 1874
Abstract
Because of the increasing sophistication of formulation technology and the increasing polymerization of compounds directed toward undruggable drug targets, the influence of the mucus layer on gastrointestinal drug absorption has received renewed attention. Therefore, understanding the complex structure of the mucus layer containing [...] Read more.
Because of the increasing sophistication of formulation technology and the increasing polymerization of compounds directed toward undruggable drug targets, the influence of the mucus layer on gastrointestinal drug absorption has received renewed attention. Therefore, understanding the complex structure of the mucus layer containing highly glycosylated glycoprotein mucins, lipids bound to the mucins, and water held by glycans interacting with each other is critical. Recent advances in cell culture and engineering techniques have led to the development of evaluation systems that closely mimic the ecological environment and have been applied to the evaluation of gastrointestinal drug absorption while considering the mucus layer. This review provides a better understanding of the mucus layer components and the gastrointestinal tract’s biological defense barrier, selects an assessment system for drug absorption in the mucus layer based on evaluation objectives, and discusses the overview and features of each assessment system. Full article
(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)
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20 pages, 1049 KiB  
Review
Recent Advancements in the Development of Nanocarriers for Mucosal Drug Delivery Systems to Control Oral Absorption
by Hideyuki Sato, Kohei Yamada, Masateru Miyake and Satomi Onoue
Pharmaceutics 2023, 15(12), 2708; https://doi.org/10.3390/pharmaceutics15122708 - 30 Nov 2023
Cited by 6 | Viewed by 1953
Abstract
Oral administration of active pharmaceutical ingredients is desirable because it is easy, safe, painless, and can be performed by patients, resulting in good medication adherence. The mucus layer in the gastrointestinal (GI) tract generally acts as a barrier to protect the epithelial membrane [...] Read more.
Oral administration of active pharmaceutical ingredients is desirable because it is easy, safe, painless, and can be performed by patients, resulting in good medication adherence. The mucus layer in the gastrointestinal (GI) tract generally acts as a barrier to protect the epithelial membrane from foreign substances; however, in the absorption process after oral administration, it can also disturb effective drug absorption by trapping it in the biological sieve structured by mucin, a major component of mucus, and eliminating it by mucus turnover. Recently, functional nanocarriers (NCs) have attracted much attention due to their immense potential and effectiveness in the field of oral drug delivery. Among them, NCs with mucopenetrating and mucoadhesive properties are promising dosage options for controlling drug absorption from the GI tracts. Mucopenetrating and mucoadhesive NCs can rapidly deliver encapsulated drugs to the absorption site and/or prolong the residence time of NCs close to the absorption membrane, providing better medications than conventional approaches. The surface characteristics of NCs are important factors that determine their functionality, owing to the formation of various kinds of interactions between the particle surface and mucosal components. Thus, a deeper understanding of surface modifications on the biopharmaceutical characteristics of NCs is necessary to develop the appropriate mucosal drug delivery systems (mDDS) for the treatment of target diseases. This review summarizes the basic information and functions of the mucosal layer, highlights the recent progress in designing functional NCs for mDDS, and discusses their performance in the GI tract. Full article
(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)
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30 pages, 654 KiB  
Review
The Trends and Future Prospective of In Silico Models from the Viewpoint of ADME Evaluation in Drug Discovery
by Hiroshi Komura, Reiko Watanabe and Kenji Mizuguchi
Pharmaceutics 2023, 15(11), 2619; https://doi.org/10.3390/pharmaceutics15112619 - 12 Nov 2023
Cited by 15 | Viewed by 3676
Abstract
Drug discovery and development are aimed at identifying new chemical molecular entities (NCEs) with desirable pharmacokinetic profiles for high therapeutic efficacy. The plasma concentrations of NCEs are a biomarker of their efficacy and are governed by pharmacokinetic processes such as absorption, distribution, metabolism, [...] Read more.
Drug discovery and development are aimed at identifying new chemical molecular entities (NCEs) with desirable pharmacokinetic profiles for high therapeutic efficacy. The plasma concentrations of NCEs are a biomarker of their efficacy and are governed by pharmacokinetic processes such as absorption, distribution, metabolism, and excretion (ADME). Poor ADME properties of NCEs are a major cause of attrition in drug development. ADME screening is used to identify and optimize lead compounds in the drug discovery process. Computational models predicting ADME properties have been developed with evolving model-building technologies from a simplified relationship between ADME endpoints and physicochemical properties to machine learning, including support vector machines, random forests, and convolution neural networks. Recently, in the field of in silico ADME research, there has been a shift toward evaluating the in vivo parameters or plasma concentrations of NCEs instead of using predictive results to guide chemical structure design. Another research hotspot is the establishment of a computational prediction platform to strengthen academic drug discovery. Bioinformatics projects have produced a series of in silico ADME models using free software and open-access databases. In this review, we introduce prediction models for various ADME parameters and discuss the currently available academic drug discovery platforms. Full article
(This article belongs to the Special Issue The Latest Technology for the Prediction and Improvement of Drug Absorption)
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