Special Issue "Novel Strategies for Enhancing Oral Bioavailability and/or Biopharmaceutics-Related Research"

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

Deadline for manuscript submissions: 31 October 2021.

Special Issue Editors

Prof. Dr. Han-Joo Maeng
E-Mail Website
Guest Editor
College of Pharmacy, Gachon University, Incheon, Korea
Interests: biopharmaceutics (ADME and regulation on drug transporters and enzymes by vitamin D receptor); pharmacokinetics; nanoparticles; oral formulations
Prof. Dr. In-Soo Yoon
E-Mail Website
Guest Editor
Biopharmaceutics and Pharmacokinetics Laboratory, College of Pharmacy, Pusan National University, Geumjeong, Busan 46241, Korea
Interests: bioanalysis; biopharmaceutics; food/herb–drug interaction; pharmacokinetics
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Poor oral absorption is likely due to low aqueous or gastrointestinal solubility and poor intestinal membrane permeability. Additionally, drug candidates are often optimized with respect to intestinal and/or hepatic metabolic stability in the drug discovery and development stage, suggesting that the first-pass effect can govern oral bioavailability (BA) in vivo.

Thus, strategies to enhance the oral bioavailability of new drug candidates and prescription drugs are necessary. Various oral formulation technologies have been developed for poorly water-soluble drugs, such as nanosuspensions, solid dispersions, self-nanoemulsifying drug delivery systems (SNEDDSs), and so on. In addition, research on intestinal absorption to avoid efflux transporters such as P-glycoprotein, breast cancer resistance protein (BCRP), and multidrug-resistance-associated proteins (MRPs), using specific inhibitors; to utilize absorption-mediated influx transporters; and to increase passive diffusion via paracellular pathways by various formulations and/or nontoxic surfactants are scientifically meaningful to understand the mechanisms related to absorption.

This Special Issue focuses on novel strategies for enhancing oral bioavailability, such as oral formulations and/or biopharmaceutics-related approaches, to elucidate possible mechanisms responsible for poor oral bioavailability. We would like to invite original and review articles of novel and innovative research on drugs, drug candidates, nutrients, and other natural products in the fields of Pharmaceutics and Biopharmaceutics.

Prof. Dr. Han-Joo Maeng
Prof. Dr. In-Soo Yoon
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 papers will be 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 2200 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 absorption
  • poorly water-soluble
  • bioavailability
  • permeability
  • solid dispersions
  • nanosuspension
  • self-nanoemulsifying drug delivery system
  • oral formulation technology
  • transporters
  • natural products
  • nutrients
  • first pass effect
  • biopharmaceutics

Published Papers (7 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

Article
Pharmacokinetic Comparison between Methotrexate-Loaded Nanoparticles and Nanoemulsions as Hard- and Soft-Type Nanoformulations: A Population Pharmacokinetic Modeling Approach
Pharmaceutics 2021, 13(7), 1050; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13071050 - 09 Jul 2021
Viewed by 594
Abstract
The purpose of this study was to identify and explore the differences in pharmacokinetics between different nanoformulations. This was done by comparing the pharmacokinetics of methotrexate-loaded nanoparticles [poly(lactic-co-glycolic acid); size of 163.70 ± 10.25 nm] and nanoemulsions (olive oil and Labrasol; size of [...] Read more.
The purpose of this study was to identify and explore the differences in pharmacokinetics between different nanoformulations. This was done by comparing the pharmacokinetics of methotrexate-loaded nanoparticles [poly(lactic-co-glycolic acid); size of 163.70 ± 10.25 nm] and nanoemulsions (olive oil and Labrasol; size of 173.77 ± 5.76 nm), which represent hard- and soft-type nanoformulations, respectively. In addition, the population pharmacokinetic modeling approach as a useful tool for the comparison of pharmacokinetics between nanoformulations was newly proposed through this study. Significant pharmacokinetic differences were identified between nanoformulations through the new population pharmacokinetic modeling approach. As a result, the formulation type was explored as a significant covariate. The clearance and bioavailability of methotrexate-loaded nanoemulsions tended to decrease by 99% and increase by 19%, respectively, compared to those of the nanoparticles. The exploration of significant pharmacokinetic differences between drug formulations and their correlations presented in this study provide new perspectives on the development of nanoformulations. Full article
Show Figures

Graphical abstract

Article
Improved Hygroscopicity and Bioavailability of Solid Dispersion of Red Ginseng Extract with Silicon Dioxide
Pharmaceutics 2021, 13(7), 1022; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13071022 - 04 Jul 2021
Cited by 2 | Viewed by 823
Abstract
This study aims to develop a powder formulation for the Korean red ginseng extract (RGE) and to evaluate its in vitro and in vivo formulation characteristics. The solid dispersion of RGE was prepared with hydrophilic carriers using a freeze-drying method. After conducting the [...] Read more.
This study aims to develop a powder formulation for the Korean red ginseng extract (RGE) and to evaluate its in vitro and in vivo formulation characteristics. The solid dispersion of RGE was prepared with hydrophilic carriers using a freeze-drying method. After conducting the water sorption–desorption isothermogram (relative humidity between 30 and 70% RH), differential scanning calorimetry thermal behavior, dissolution test, and intestinal permeation study, a solid dispersion formulation of RGE and silicon dioxide (RGE-SiO2) was selected. RGE-SiO2 formulation increased intestinal permeability of ginsenoside Rb1 (GRb1), GRb2, GRc, and GRd by 1.6-fold in rat jejunal segments as measured by the Ussing chamber system. A 1.6- to 1.8-fold increase in plasma exposure of GRb1, GRb2, GRc, and GRd in rats was observed following oral administration of RGE-SiO2 (375 mg/kg as RGE). No significant difference was observed in the time to reach maximum concentration (Tmax) and half-life in comparison to those in RGE administered rats (375 mg/kg). In conclusion, formulating solid dispersion of RGE with amorphous SiO2, the powder formulation of RGE was successfully formulated with improved hygroscopicity, increased intestinal permeability, and enhanced oral bioavailability and is therefore suitable for processing solid formulations of RGE product. Full article
Show Figures

Figure 1

Article
Comparison of Pharmacokinetics and Anti-Pulmonary Fibrosis-Related Effects of Sulforaphane and Sulforaphane N-acetylcysteine
Pharmaceutics 2021, 13(7), 958; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13070958 - 25 Jun 2021
Viewed by 602
Abstract
Sulforaphane (SFN), belonging to the isothiocyanate family, has received attention owing to its beneficial activities, including chemopreventive and antifibrotic effects. As sulforaphane N-acetylcysteine (SFN-NAC), a major sulforaphane metabolite, has presented similar pharmacological activities to those of SFN, it is crucial to simultaneously [...] Read more.
Sulforaphane (SFN), belonging to the isothiocyanate family, has received attention owing to its beneficial activities, including chemopreventive and antifibrotic effects. As sulforaphane N-acetylcysteine (SFN-NAC), a major sulforaphane metabolite, has presented similar pharmacological activities to those of SFN, it is crucial to simultaneously analyze the pharmacokinetics and activities of SFN and SFN-NAC, to comprehensively elucidate the efficacy of SFN-containing products. Accordingly, the anti-pulmonary fibrotic effects of SFN and SFN-NAC were assessed, with simultaneous evaluation of permeability, metabolic stability, and in vivo pharmacokinetics. Both SFN and SFN-NAC decreased the levels of transforming growth factor-β1-induced fibronectin, alpha-smooth muscle actin, and collagen, which are major mediators of fibrosis, in MRC-5 fibroblast cells. Regarding pharmacokinetics, SFN and SFN-NAC were metabolically unstable, especially in the plasma. SFN-NAC degraded considerably faster than SFN in plasma, with SFN being formed from SFN-NAC. In rats, SFN and SFN-NAC showed a similar clearance when administered intravenously; however, SFN showed markedly superior absorption when administered orally. Although the plasma SFN-NAC concentration was low owing to poor absorption following oral administration, SFN-NAC was converted to SFN in vivo, as in plasma. Collectively, these data suggest that SFN-NAC could benefit a prodrug formulation strategy, possibly avoiding the gastrointestinal side effects of SFN, and with improved SFN-NAC absorption. Full article
Show Figures

Figure 1

Article
Investigation of the Factors Responsible for the Poor Oral Bioavailability of Acacetin in Rats: Physicochemical and Biopharmaceutical Aspects
Pharmaceutics 2021, 13(2), 175; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13020175 - 28 Jan 2021
Cited by 2 | Viewed by 570
Abstract
Acacetin, an important ingredient of acacia honey and a component of several medicinal plants, exhibits therapeutic effects such as antioxidative, anticancer, anti-inflammatory, and anti-plasmodial activities. However, to date, studies reporting a systematic investigation of the in vivo fate of orally administered acacetin are [...] Read more.
Acacetin, an important ingredient of acacia honey and a component of several medicinal plants, exhibits therapeutic effects such as antioxidative, anticancer, anti-inflammatory, and anti-plasmodial activities. However, to date, studies reporting a systematic investigation of the in vivo fate of orally administered acacetin are limited. Moreover, the in vitro physicochemical and biopharmaceutical properties of acacetin in the gastrointestinal (GI) tract and their pharmacokinetic impacts remain unclear. Therefore, in this study, we aimed to systematically investigate the oral absorption and disposition of acacetin using relevant rat models. Acacetin exhibited poor solubility (≤119 ng/mL) and relatively low stability (27.5–62.0% remaining after 24 h) in pH 7 phosphate buffer and simulated GI fluids. A major portion (97.1%) of the initially injected acacetin dose remained unabsorbed in the jejunal segments, and the oral bioavailability of acacetin was very low at 2.34%. The systemic metabolism of acacetin occurred ubiquitously in various tissues (particularly in the liver, where it occurred most extensively), resulting in very high total plasma clearance of 199 ± 36 mL/min/kg. Collectively, the poor oral bioavailability of acacetin could be attributed mainly to its poor solubility and low GI luminal stability. Full article
Show Figures

Graphical abstract

Article
Improved Bioavailability and High Photostability of Methotrexate by Spray-Dried Surface-Attached Solid Dispersion with an Aqueous Medium
Pharmaceutics 2021, 13(1), 111; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13010111 - 16 Jan 2021
Cited by 10 | Viewed by 1511
Abstract
Low aqueous solubility and poor bioavailability are major concerns in the development of oral solid-dosage drug forms. In this study, we fabricated surface-attached solid dispersion (SASD) to enhance the solubility, bioavailability, and photostability of methotrexate (MTX), a highly lipophilic and photo-unstable drug. Several [...] Read more.
Low aqueous solubility and poor bioavailability are major concerns in the development of oral solid-dosage drug forms. In this study, we fabricated surface-attached solid dispersion (SASD) to enhance the solubility, bioavailability, and photostability of methotrexate (MTX), a highly lipophilic and photo-unstable drug. Several MTX-loaded SASD formulations were developed for spray-drying using water as the solvent, and were investigated for their aqueous solubility and dissolution kinetics. An optimized ternary SASD formulation composed of MTX/ sodium carboxymethyl cellulose (Na-CMC)/sodium lauryl sulfate (SLS) at 3/0.5/0.5 (w/w) had 31.78-fold and 1.88-fold higher solubility and dissolution, respectively, than MTX powder. For SASD, the in vivo pharmacokinetic parameters AUC and Cmax were 2.90- and 3.41-fold higher, respectively, than for the MTX powder. Solid-state characterizations by differential scanning calorimetry and X-ray diffraction revealed that MTX exists in its crystalline state within the spray-dried SASD. The MTX-loaded SASD formulation showed few physical changes with photostability testing. Overall, the results indicate that the spray-dried MTX-loaded SASD formulation without organic solvents enhances the solubility and oral bioavailability of MTX without a significant deterioration of its photochemical stability. Full article
Show Figures

Graphical abstract

Article
Enhanced Intestinal Absorption and Pharmacokinetic Modulation of Berberine and Its Metabolites through the Inhibition of P-Glycoprotein and Intestinal Metabolism in Rats Using a Berberine Mixed Micelle Formulation
Pharmaceutics 2020, 12(9), 882; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12090882 - 17 Sep 2020
Cited by 11 | Viewed by 1163
Abstract
We aimed to develop a berberine formulation to enhance the intestinal absorption and plasma concentrations of berberine through the inhibition of P-glycoprotein (P-gp)-mediated efflux and the intestinal metabolism of berberine in rats. We used pluronic P85 (P85) and tween 80, which have the [...] Read more.
We aimed to develop a berberine formulation to enhance the intestinal absorption and plasma concentrations of berberine through the inhibition of P-glycoprotein (P-gp)-mediated efflux and the intestinal metabolism of berberine in rats. We used pluronic P85 (P85) and tween 80, which have the potential to inhibit P-gp and cytochrome P450s (i.e., CYP1A2, 2C9, 2C19, 2D6, and 3A4). A berberine-loaded mixed micelle formulation with ratios of berberine: P85: tween 80 of 1:5:0.5 (w/w/w) was developed. This berberine mixed micelle formulation had a mean size of 12 nm and increased the cellular accumulation of digoxin via P-gp inhibition. It also inhibited berberine metabolism in rat intestinal microsomes, without significant cytotoxicity, up to a berberine concentration of 100 μM. Next, we compared the pharmacokinetics of berberine and its major metabolites in rat plasma following the oral administration of the berberine formulation (50 mg/kg) in rats with the oral administration of berberine alone (50 mg/kg). The plasma exposure of berberine was significantly greater in rats administered the berberine formulation compared to rats administered only berberine, which could be attributed to the increased berberine absorption by inhibiting the P-gp-mediated berberine efflux and intestinal berberine metabolism by berberine formulation. In conclusion, we successfully prepared berberine mixed micelle formulation using P85 and tween 80 that has inhibitory potential for P-gp and CYPs (CYP2C19, 2D6, and 3A4) and increased the berberine plasma exposure. Therefore, a mixed micelle formulation strategy with P85 and tween 80 for drugs with high intestinal first-pass effects could be applied to increase the oral absorption and plasma concentrations of the drugs. Full article
Show Figures

Graphical abstract

Review

Jump to: Research

Review
Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability
by , and
Pharmaceutics 2021, 13(7), 1103; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics13071103 - 20 Jul 2021
Cited by 3 | Viewed by 1233
Abstract
P-glycoprotein (P-gp) is crucial in the active transport of various substrates with diverse structures out of cells, resulting in poor intestinal permeation and limited bioavailability following oral administration. P-gp inhibitors, including small molecule drugs, natural constituents, and pharmaceutically inert excipients, have been exploited [...] Read more.
P-glycoprotein (P-gp) is crucial in the active transport of various substrates with diverse structures out of cells, resulting in poor intestinal permeation and limited bioavailability following oral administration. P-gp inhibitors, including small molecule drugs, natural constituents, and pharmaceutically inert excipients, have been exploited to overcome P-gp efflux and enhance the oral absorption and bioavailability of many P-gp substrates. The co-administration of small molecule P-gp inhibitors with P-gp substrates can result in drug–drug interactions and increased side effects due to the pharmacological activity of these molecules. On the other hand, pharmaceutically inert excipients, including polymers, surfactants, and lipid-based excipients, are safe, pharmaceutically acceptable, and are not absorbed from the gut. Notably, they can be incorporated in pharmaceutical formulations to enhance drug solubility, absorption, and bioavailability due to the formulation itself and the P-gp inhibitory effects of the excipients. Different formulations with inherent P-gp inhibitory activity have been developed. These include micelles, emulsions, liposomes, solid lipid nanoparticles, polymeric nanoparticles, microspheres, dendrimers, and solid dispersions. They can bypass P-gp by different mechanisms related to their properties. In this review, we briefly introduce P-gp and P-gp inhibitors, and we extensively summarize the current development of oral drug delivery systems that can bypass and inhibit P-gp to improve the oral absorption and bioavailability of P-gp substrates. Since many drugs are limited by P-gp-mediated efflux, this review is helpful for designing suitable formulations of P-gp substrates to enhance their oral absorption and bioavailability. Full article
Show Figures

Figure 1

Back to TopTop