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Pharmaceutics
Special Issues
Recent Advances in Oral Biopharmaceutics
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Recent Advances in Oral Biopharmaceutics

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

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 15504

Special Issue Editors

Dr. Mirko Koziolek

E-Mail Website
Guest Editor
Small Molecule CMC Development, AbbVie Deutschland GmbH & Co. KG, 67061 Ludwigshafen, Germany
Interests: oral biopharmaceutics; biorelevant in vitro testing; GI physiology
Dr. Zahari Vinarov

E-Mail Website
Guest Editor
Department of Chemical and Pharmaceutical Engineering, Faculty of Chemistry and Pharmacy, Sofia University, 1164 Sofia, Bulgaria
Interests: oral drug delivery; biopharmaceutics; advanced formulations; in vitro modelling

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to a Pharmaceutics Special Issue on “Recent Advances in Oral Biopharmaceutics”.

This Special Issue aims to showcase recent developments in the understanding of mechanisms and interactions underpinning oral drug release and absorption from conventional and advanced formulations by the use of biopharmaceutical characterization methods. Moreover, we aim to highlight the application of in vitro, in vivo and in silico results for the prediction of oral pharmacokinetics in the context of modern drug product development.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: biorelevant dissolution testing, permeation and drug absorption studies, solubility studies, oral absorption modelling including PBBM, oral drug delivery, and human GI physiology in the context of oral drug delivery.

We look forward to receiving your contributions. The deadline for submission is 31 May 2023.

Dr. Mirko Koziolek
Dr. Zahari Vinarov
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • oral biopharmaceutics
  • biorelevant dissolution
  • permeability
  • solubility
  • advanced oral formulations
  • oral absorption modelling
  • PBPK human GI physiology

Published Papers (9 papers)

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Research

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17 pages, 2016 KiB  
Article
Determination of Gastric Water Emptying in Fasted and Fed State Conditions Using a Compression-Coated Tablet and Salivary Caffeine Kinetics
by Theodora Tzakri, Lara Rehenbrock, Stefan Senekowitsch, Adrian Rump, Philipp Schick, Julius Krause, Marie-Luise Kromrey, Michael Grimm and Werner Weitschies
Pharmaceutics 2023, 15(11), 2584; https://doi.org/10.3390/pharmaceutics15112584 - 04 Nov 2023
Viewed by 1718
Abstract
Because of the importance of gastric emptying for pharmacokinetics, numerous methods have been developed for its determination. One of the methods is the salivary tracer technique, which utilizes an ice capsule containing caffeine as a salivary tracer. Despite the ice capsule’s advantage in [...] Read more.
Because of the importance of gastric emptying for pharmacokinetics, numerous methods have been developed for its determination. One of the methods is the salivary tracer technique, which utilizes an ice capsule containing caffeine as a salivary tracer. Despite the ice capsule’s advantage in labeling ingested fluids with caffeine for subsequent salivary detection, its risk of premature melting before swallowing, and its complicated storage and preparation, limit its application, particularly in special populations (e.g., older people). For this reason, here, a compression-coated tablet was developed and validated against the ice capsule in a cross-over clinical trial. The two dosage forms were administered simultaneously to 12 volunteers in an upright position under fasted and fed state conditions. To distinguish the caffeine concentrations in saliva from each dosage form, regular type of caffeine (12C) was added to the tablet, while for the ice capsule 13C3 labelled caffeine was used. The salivary caffeine concentrations showed no statistically significant differences for the pharmacokinetic parameters tmax and AUC0→60 (p > 0.05). Thus, the new formulation is a useful tool for determining gastric emptying that can also be used in special populations. Full article
(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)
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19 pages, 4460 KiB  
Article
Excipient Impact on Fenofibrate Equilibrium Solubility in Fasted and Fed Simulated Intestinal Fluids Assessed Using a Design of Experiment Protocol
by Bayan E. Ainousah, Ibrahim Khadra and Gavin W. Halbert
Pharmaceutics 2023, 15(10), 2484; https://doi.org/10.3390/pharmaceutics15102484 - 17 Oct 2023
Viewed by 1001
Abstract
Solubility is a critical parameter controlling drug absorption after oral administration. For poorly soluble drugs, solubility is influenced by the complex composition of intestinal media and the influence of dosage form excipients, which can cause bioavailability and bioequivalence issues. This study has applied [...] Read more.
Solubility is a critical parameter controlling drug absorption after oral administration. For poorly soluble drugs, solubility is influenced by the complex composition of intestinal media and the influence of dosage form excipients, which can cause bioavailability and bioequivalence issues. This study has applied a small scale design of experiment (DoE) equilibrium solubility approach in order to investigate the impact of excipients on fenofibrate solubility in simulated fasted and fed intestinal media. Seven media parameters (bile salt (BS), phospholipid (PL), fatty acid, monoglyceride, cholesterol, pH and BS/PL ratio) were assessed in the DoE and in excipient-free media, and only pH and sodium oleate in the fasted state had a significant impact on fenofibrate solubility. The impact of excipients were studied at two concentrations, and for polyvinylpyrrolidone (PVP, K12 and K29/32) and hydroxypropylmethylcellulose (HPMC, E3 and E50), two grades were studied. Mannitol had no solubility impact in any of the DoE media. PVP significantly increased solubility in a media-, grade- and concentration-dependent manner, with the biggest change in fasted media. HPMC and chitosan significantly reduced solubility in both fasted and fed states in a media-, grade- and concentration-dependent manner. The results indicate that the impact of excipients on fenofibrate solubility is a complex interplay of media composition in combination with their physicochemical properties and concentration. The results indicate that in vitro solubility studies combining the drug of interest, proposed excipients along with suitable simulated intestinal media recipes will provide interesting information with the potential to guide formulation development. Full article
(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)
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18 pages, 18268 KiB  
Article
A Rational Approach to Predicting Immediate Release Formulation Behavior in Multiple Gastric Motility Patterns: A Combination of a Biorelevant Apparatus, Design of Experiments, and Machine Learning
by Marcela Staniszewska, Michał Romański, Sebastian Polak, Grzegorz Garbacz, Justyna Dobosz, Daria Myslitska, Svitlana Romanova, Jadwiga Paszkowska and Dorota Danielak
Pharmaceutics 2023, 15(8), 2056; https://doi.org/10.3390/pharmaceutics15082056 - 31 Jul 2023
Cited by 2 | Viewed by 1209
Abstract
Gastric mechanical stress often impacts drug dissolution from solid oral dosage forms, but in vitro experiments cannot recreate the substantial variability of gastric motility in a reasonable time. This study, for the first time, combines a novel dissolution apparatus with the design of [...] Read more.
Gastric mechanical stress often impacts drug dissolution from solid oral dosage forms, but in vitro experiments cannot recreate the substantial variability of gastric motility in a reasonable time. This study, for the first time, combines a novel dissolution apparatus with the design of experiments (DoE) and machine learning (ML) to overcome this obstacle. The workflow involves the testing of soft gelatin capsules in a set of fasted-state biorelevant dissolution experiments created with DoE. The dissolution results are used by an ML algorithm to build the classification model of the capsule’s opening in response to intragastric stress (IS) within the physiological space of timing and magnitude. Next, a random forest algorithm is used to model the further drug dissolution. The predictive power of the two ML models is verified with independent dissolution tests, and they outperform a polynomial-based DoE model. Moreover, the developed tool reasonably simulates over 50 dissolution profiles under varying IS conditions. Hence, we prove that our method can be utilized for the simulation of dissolution profiles related to the multiplicity of individual gastric motility patterns. In perspective, the developed workflow can improve virtual bioequivalence trials and the patient-centric development of immediate-release oral dosage forms. Full article
(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)
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20 pages, 5232 KiB  
Article
Advanced In Vivo Prediction by Introducing Biphasic Dissolution Data into PBPK Models
by Alexander Denninger, Tim Becker, Ulrich Westedt and Karl G. Wagner
Pharmaceutics 2023, 15(7), 1978; https://doi.org/10.3390/pharmaceutics15071978 - 19 Jul 2023
Cited by 2 | Viewed by 1530
Abstract
Coupling biorelevant in vitro dissolution with in silico physiological-based pharmacokinetic (PBPK) tools represents a promising method to describe and predict the in vivo performance of drug candidates in formulation development including non-passive transport, prodrug activation, and first-pass metabolism. The objective of the present [...] Read more.
Coupling biorelevant in vitro dissolution with in silico physiological-based pharmacokinetic (PBPK) tools represents a promising method to describe and predict the in vivo performance of drug candidates in formulation development including non-passive transport, prodrug activation, and first-pass metabolism. The objective of the present study was to assess the predictability of human pharmacokinetics by using biphasic dissolution results obtained with the previously established BiPHa+ assay and PBPK tools. For six commercial drug products, formulated by different enabling technologies, the respective organic partitioning profiles were processed with two PBPK in silico modeling tools, namely PK-Sim and GastroPlus®, similar to extended-release dissolution profiles. Thus, a mechanistic dissolution/precipitation model of the assessed drug products was not required. The developed elimination/distribution models were used to simulate the pharmacokinetics of the evaluated drug products and compared with available human data. In essence, an in vitro to in vivo extrapolation (IVIVE) was successfully developed. Organic partitioning profiles obtained from the BiPHa+ dissolution analysis enabled highly accurate predictions of the pharmacokinetic behavior of the investigated drug products. In addition, PBPK models of (pro-)drugs with pronounced first-pass metabolism enabled adjustment of the solely passive diffusion predicting organic partitioning profiles, and increased prediction accuracy further. Full article
(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)
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23 pages, 2316 KiB  
Article
Projection of Target Drug Particle Size in Oral Formulations Using the Refined Developability Classification System (rDCS)
by Kristian Beran, Eline Hermans, René Holm, Kia Sepassi and Jennifer Dressman
Pharmaceutics 2023, 15(7), 1909; https://doi.org/10.3390/pharmaceutics15071909 - 08 Jul 2023
Viewed by 1975
Abstract
Dissolution limitations to oral absorption can occur if the time required for dissolution is longer than the transit time across the small intestine and/or if dissolution is slower than the drug’s permeation through the gut wall. These limitations most often occur for poorly [...] Read more.
Dissolution limitations to oral absorption can occur if the time required for dissolution is longer than the transit time across the small intestine and/or if dissolution is slower than the drug’s permeation through the gut wall. These limitations most often occur for poorly soluble drugs. A standard method for overcoming dissolution issues is to reduce the particle size of the (solid) drug. Building on the refined Developability Classification System (rDCS), this work establishes a novel set of equations with which the appropriate degree of particle size reduction needed to mitigate dissolution limitations to absorption can be calculated. According to the type of data available, the appropriate equation(s) for each situation can be applied. Three case examples are used to illustrate implementation of the equations: voriconazole, lemborexant and istradefylline. Although for voriconazole (rDCS Class I) target radius (rtarget) estimates indicate that particle size reduction is unnecessary, for lemborexant (rDCS Class I) a radius of ≤20 µm would be required to improve absorption. For istradefylline (rDCS Class IIb) the rtarget was approximately 12 µm. Results are commensurate with literature information for these three drugs, signaling that the equations are suitable for application to a wide variety of drug substances. Full article
(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)
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20 pages, 11940 KiB  
Article
Characterization of Aspirated Duodenal Fluids from Parkinson’s Disease Patients
by Tom de Waal, Joachim Brouwers, Philippe Berben, Talia Flanagan, Jan Tack, Wim Vandenberghe, Tim Vanuytsel and Patrick Augustijns
Pharmaceutics 2023, 15(4), 1243; https://doi.org/10.3390/pharmaceutics15041243 - 14 Apr 2023
Cited by 1 | Viewed by 1636
Abstract
Parkinson’s disease, one of the most common neurodegenerative diseases, may not only affect the motor system, but also the physiology of the gastrointestinal tract. Delayed gastric emptying, impaired motility and altered intestinal bacteria are well-established consequences of the disease, which can have a [...] Read more.
Parkinson’s disease, one of the most common neurodegenerative diseases, may not only affect the motor system, but also the physiology of the gastrointestinal tract. Delayed gastric emptying, impaired motility and altered intestinal bacteria are well-established consequences of the disease, which can have a pronounced effect on the absorption of orally administered drugs. In contrast, no studies have been performed into the composition of intestinal fluids. It is not unlikely that Parkinson’s disease also affects the composition of intestinal fluids, a critical factor in the in vitro and in silico simulation of drug dissolution, solubilization and absorption. In the current study, duodenal fluids were aspirated from Parkinson’s disease (PD) patients and age-matched healthy controls (healthy controls, HC) consecutively in fasted and fed conditions. The fluids were then characterized for pH, buffer capacity, osmolality, total protein, phospholipids, bile salts, cholesterol and lipids. In a fasted state, the intestinal fluid composition was highly similar in PD patients and healthy controls. In general, the same was true for fed-state fluids, apart from a slightly slower and less pronounced initial change in factors directly affected by the meal (i.e., buffer capacity, osmolality, total protein and lipids) in PD patients. The absence of a fast initial increase for these factors immediately after meal intake, as was observed in healthy controls, might result from slower gastric emptying in PD patients. Irrespective of the prandial state, a higher relative amount of secondary bile salts was observed in PD patients, potentially indicating altered intestinal bacterial metabolism. Overall, the data from this study indicate that only minor disease-specific adjustments in small intestinal fluid composition should be considered when simulating intestinal drug absorption in PD patients. Full article
(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)
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20 pages, 2023 KiB  
Article
Development and Application of a Dissolution-Transfer-Partitioning System (DTPS) for Biopharmaceutical Drug Characterization
by Christian Jede, Laura J. Henze, Kirstin Meiners, Malte Bogdahn, Marcel Wedel and Valeria van Axel
Pharmaceutics 2023, 15(4), 1069; https://doi.org/10.3390/pharmaceutics15041069 - 26 Mar 2023
Cited by 2 | Viewed by 1528
Abstract
A variety of in vitro dissolution and gastrointestinal transfer models have been developed aiming to predict drug supersaturation and precipitation. Further, biphasic, one-vessel in vitro systems are increasingly applied to simulate drug absorption in vitro. However, to date, there is a lack of [...] Read more.
A variety of in vitro dissolution and gastrointestinal transfer models have been developed aiming to predict drug supersaturation and precipitation. Further, biphasic, one-vessel in vitro systems are increasingly applied to simulate drug absorption in vitro. However, to date, there is a lack of combining the two approaches. Therefore, the first aim of this study was to develop a dissolution-transfer-partitioning system (DTPS) and, secondly, to assess its biopredictive power. In the DTPS, simulated gastric and intestinal dissolution vessels are connected via a peristaltic pump. An organic layer is added on top of the intestinal phase, serving as an absorptive compartment. The predictive power of the novel DTPS was assessed to a classical USP II transfer model using a BCS class II weak base with poor aqueous solubility, MSC-A. The classical USP II transfer model overestimated simulated intestinal drug precipitation, especially at higher doses. By applying the DTPS, a clearly improved estimation of drug supersaturation and precipitation and an accurate prediction of the in vivo dose linearity of MSC-A were observed. The DTPS provides a useful tool taking both dissolution and absorption into account. This advanced in vitro tool offers the advantage of streamlining the development process of challenging compounds. Full article
(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)
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19 pages, 3999 KiB  
Article
Intragastric Carbon Dioxide Release Prolongs the Gastric Residence Time of Postprandially Administered Caffeine
by Stefan Senekowitsch, Constantin Foja, Toni Wildgrube, Philipp Schick, Christoph Rosenbaum, Julius Krause, Friederike Brokmann, Marie-Luise Kromrey, Stefan Engeli, Werner Weitschies and Michael Grimm
Pharmaceutics 2023, 15(3), 1012; https://doi.org/10.3390/pharmaceutics15031012 - 22 Mar 2023
Cited by 2 | Viewed by 1567
Abstract
Sparkling water is said to increase gastric motility by the release of carbon dioxide, thereby potentially affecting the pharmacokinetics of orally administered drugs. The hypothesis of the present work was that the induction of gastric motility by intragastric release of carbon dioxide from [...] Read more.
Sparkling water is said to increase gastric motility by the release of carbon dioxide, thereby potentially affecting the pharmacokinetics of orally administered drugs. The hypothesis of the present work was that the induction of gastric motility by intragastric release of carbon dioxide from effervescent granules could promote the mixing of drugs into the chyme under postprandial conditions, resulting in a prolonged drug absorption. For this purpose, an effervescent and a non-effervescent granule formulation of caffeine as a marker for gastric emptying were developed. In a three-way crossover study with twelve healthy volunteers, the salivary caffeine pharmacokinetics, after administration of the effervescent granules with still water and the administration of the non-effervescent granules with still and sparkling water, were investigated after intake of a standard meal. While the administration of the effervescent granules with 240 mL of still water led to a significantly prolonged gastric residence of the substance compared to the administration of the non-effervescent granules with 240 mL still water, the application of the non-effervescent granules with 240 mL sparkling water did not prolong gastric residence via mixing into caloric chyme. Overall, the mixing of caffeine into the chyme following the administration of the effervescent granules did not seem to be a motility mediated process. Full article
(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)
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Review

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38 pages, 4754 KiB  
Review
Challenges in Permeability Assessment for Oral Drug Product Development
by Mirko Koziolek, Patrick Augustijns, Constantin Berger, Rodrigo Cristofoletti, David Dahlgren, Janneke Keemink, Pär Matsson, Fiona McCartney, Marco Metzger, Mario Mezler, Janis Niessen, James E. Polli, Maria Vertzoni, Werner Weitschies and Jennifer Dressman
Pharmaceutics 2023, 15(10), 2397; https://doi.org/10.3390/pharmaceutics15102397 - 28 Sep 2023
Cited by 1 | Viewed by 2025
Abstract
Drug permeation across the intestinal epithelium is a prerequisite for successful oral drug delivery. The increased interest in oral administration of peptides, as well as poorly soluble and poorly permeable compounds such as drugs for targeted protein degradation, have made permeability a key [...] Read more.
Drug permeation across the intestinal epithelium is a prerequisite for successful oral drug delivery. The increased interest in oral administration of peptides, as well as poorly soluble and poorly permeable compounds such as drugs for targeted protein degradation, have made permeability a key parameter in oral drug product development. This review describes the various in vitro, in silico and in vivo methodologies that are applied to determine drug permeability in the human gastrointestinal tract and identifies how they are applied in the different stages of drug development. The various methods used to predict, estimate or measure permeability values, ranging from in silico and in vitro methods all the way to studies in animals and humans, are discussed with regard to their advantages, limitations and applications. A special focus is put on novel techniques such as computational approaches, gut-on-chip models and human tissue-based models, where significant progress has been made in the last few years. In addition, the impact of permeability estimations on PK predictions in PBPK modeling, the degree to which excipients can affect drug permeability in clinical studies and the requirements for colonic drug absorption are addressed. Full article
(This article belongs to the Special Issue Recent Advances in Oral Biopharmaceutics)
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