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Pharmaceutics
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Bioavailability Enhancement of Poorly Water-Soluble Drugs: Biopharmaceutics and Technology
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Bioavailability Enhancement of Poorly Water-Soluble Drugs: Biopharmaceutics and Technology

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (15 December 2019) | Viewed by 30203

Special Issue Editor

Prof. Dr. Beom-Jin Lee

E-Mail Website
Guest Editor
College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea
Interests: controlled bioavailability of poorly soluble and poorly absorbable drugs; solubilization, formulation, and development of patient-centric dosage forms; advanced nano-based delivery systems using fattigation (fatty acid conjugation) and click chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is well-known that approximately 40% of marketed approved drugs and about 90% of molecules in the drug discovery pipeline are poorly water-soluble. In the last decade, emerging trends in combinatorial chemistry and drug design have rendered newly developed drug molecules with higher lipophilicity, larger molecular weight, and poor water solubility. As a result, the majority of new drug development results in failure due to the poor water solubility of the drug molecules. Biopharmaceutics is comprised of the adsorption, distribution, metabolism, and elimination (ADME), as well as the impact, of the physicochemical properties of the drug molecules on their in vivo performance and bioavailability.

The optimization of physicochemical properties of such poorly water-soluble molecules for enhanced solubility, dissolution, and ultimately enhanced bioavailability is the most important prerequisite for pharmaceutical researchers to develop drug products. To overcome the poor water solubility of drugs, various approaches to enhance the dissolution rate include solid dispersion, salt formation, supercritical fluid technology, prodrugs, co-crystal formation, cyclodextrin complexes, lipid-based formulations, and nanoparticle drug delivery systems. The continuous development of the new formulation and pharmaceutical technology for poorly water-soluble drugs is highly desired for faster and better development of new drugs. Furthermore, the convergence of diverse technologies is also recommended for the modulation of the release rate and enhanced bioavailability for better patient adherence.

This Special Issue is aimed at highlighting the latest progress and research of pharmaceutical and biopharmaceutical technologies for the enhanced dissolution and bioavailability of poorly water soluble drugs.

Prof. Dr. Beom-Jin Lee
Guest Editor

Manuscript Submission Information

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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

  • Solubility
  • Dissolution
  • Bioavailability
  • Poorly water soluble
  • Biopharmaceutics
  • Formulation
  • Pharmaceutical technology
  • Patient adherence

Published Papers (6 papers)

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Research

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16 pages, 2523 KiB  
Article
New Preclinical Development of a c-Met Inhibitor and Its Combined Anti-Tumor Effect in c-Met-Amplified NSCLC
by Nam Ah Kim, Sungyoul Hong, Ki Hyun Kim, Du Hyung Choi, Joo Seok Kim, Kyung Eui Park, Jun Young Choi, Young Kee Shin and Seong Hoon Jeong
Pharmaceutics 2020, 12(2), 121; https://doi.org/10.3390/pharmaceutics12020121 - 03 Feb 2020
Cited by 5 | Viewed by 2979
Abstract
c-Met is a receptor tyrosine kinase with no commercially available product despite being a pivotal target in cancer progression. Unlike other c-Met inhibitors that fail clinically, ABN401 is a newly synthesized c-Met inhibitor that is not potentially degraded by aldehyde oxidase (AO) in [...] Read more.
c-Met is a receptor tyrosine kinase with no commercially available product despite being a pivotal target in cancer progression. Unlike other c-Met inhibitors that fail clinically, ABN401 is a newly synthesized c-Met inhibitor that is not potentially degraded by aldehyde oxidase (AO) in human liver cytosol. This study aimed to determine the physicochemical stability, pharmacokinetics in beagle dogs, and therapeutic effect of ABN401 in a c-Met-amplified non-small-cell lung cancer (NSCLC) patient-derived xenograft (PDX) model. ABN401 was found to be a weak basic compound, with pKa and log P values of 7.49 and 2.46, respectively. It is poorly water-soluble but soluble at acidic pH. The accelerated storage stability is dependent on temperature, but the purity remains at over 97% after 6 months. The bioavailability is approximately 30% in dogs and it is highly efficient in the PDX model, achieving around 90% tumor growth inhibition in combination with erlotinib. These observations indicate that the compound is acceptable for the next phase of trials. Full article
(This article belongs to the Special Issue Bioavailability Enhancement of Poorly Water-Soluble Drugs: Biopharmaceutics and Technology)
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22 pages, 5316 KiB  
Article
Development of a Resveratrol Nanosuspension Using the Antisolvent Precipitation Method without Solvent Removal, Based on a Quality by Design (QbD) Approach
by Do-Hoon Kuk, Eun-Sol Ha, Dong-Hyun Ha, Woo-Yong Sim, Seon-Kwang Lee, Ji-Su Jeong, Jeong-Soo Kim, In-hwan Baek, Heejun Park, Du Hyung Choi, Jin-Wook Yoo, Seong Hoon Jeong, Sung-Joo Hwang and Min-Soo Kim
Pharmaceutics 2019, 11(12), 688; https://doi.org/10.3390/pharmaceutics11120688 - 17 Dec 2019
Cited by 33 | Viewed by 6262
Abstract
The purpose of this study was to develop a resveratrol nanosuspension with enhanced oral bioavailability, based on an understanding of the formulation and process parameters of nanosuspensions and using a quality by design (QbD) approach. Particularly, the antisolvent method, which requires no solvent [...] Read more.
The purpose of this study was to develop a resveratrol nanosuspension with enhanced oral bioavailability, based on an understanding of the formulation and process parameters of nanosuspensions and using a quality by design (QbD) approach. Particularly, the antisolvent method, which requires no solvent removal and no heating, is newly applied to prepare resveratrol nanosuspension. To ensure the quality of the resveratrol nanosuspensions, a quality target product profile (QTPP) was defined. The particle size (z-average, d90), zeta potential, and drug content parameters affecting the QTPP were selected as critical quality attributes (CQAs). The optimum composition obtained using a 3-factor, 3-level Box–Behnken design was as follows: polyvinylpyrrolidone vinyl acetate (10 mg/mL), polyvinylpyrrolidone K12 (5 mg/mL), sodium lauryl sulfate (1 mg/mL), and diethylene glycol monoethyl ether (DEGEE, 5% v/v) at a resveratrol concentration of 5 mg/mL. The initial particle size (z-average) was 46.3 nm and the zeta potential was −38.02 mV. The robustness of the antisolvent process using the optimized composition conditions was ensured by a full factorial design. The dissolution rate of the optimized resveratrol nanosuspension was significantly greater than that of the resveratrol raw material. An in vivo pharmacokinetic study in rats showed that the area under the plasma concentration versus time curve (AUC0–12h) and the maximum plasma concentration (Cmax) respectively, than those of the resveratrol raw material. Therefore, the prepara values of the resveratrol nanosuspension were approximately 1.6- and 5.7-fold higher,tion of a resveratrol nanosuspension using the QbD approach may be an effective strategy for the development of a new dosage form of resveratrol, with enhanced oral bioavailability. Full article
(This article belongs to the Special Issue Bioavailability Enhancement of Poorly Water-Soluble Drugs: Biopharmaceutics and Technology)
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15 pages, 2875 KiB  
Article
Highly Water-Soluble Solid Dispersions of Honokiol: Preparation, Solubility, and Bioavailability Studies and Anti-Tumor Activity Evaluation
by Li Wang, Weiwei Wu, Lingling Wang, Lu Wang and Xiuhua Zhao
Pharmaceutics 2019, 11(11), 573; https://doi.org/10.3390/pharmaceutics11110573 - 01 Nov 2019
Cited by 7 | Viewed by 3036
Abstract
Honokiol (HK), a well-tolerated natural product, has many multiple pharmacological activities. However, its poor water solubility and low bioavailability limit its clinical application and development. The aim of this research was to prepare the solid dispersion (SD) formulation of honokiol (HK) with poloxamer-188 [...] Read more.
Honokiol (HK), a well-tolerated natural product, has many multiple pharmacological activities. However, its poor water solubility and low bioavailability limit its clinical application and development. The aim of this research was to prepare the solid dispersion (SD) formulation of honokiol (HK) with poloxamer-188 (PLX) as the carrier, thereby improving its solubility and oral bioavailability. Firstly, by investigating the relationship between the addition amount of the PLX and the solubility of HK, and the effects of solid dispersions with different ratios of HK–PLX on the solubility of HK, we determined that the optimum ratio of PLX to HK was (1:4). Then, the HK–PLX (1:4) SD of HK was prepared using the solvent evaporation method. The morphology of the obtained HK–PLX (1:4) SD was different from that of free HK. The HK in the HK–PLX (1:4) SD existed in amorphous form and formed intermolecular hydrogen bonds with PLX. Additionally, the solubility values of the HK–PLX (1:4) SD were about 32.43 ± 0.36 mg/mL and 34.41 ± 0.38 mg/mL in artificial gastric juice (AGJ) and in artificial intestinal juice (AIJ), respectively. Compared with free HK, the release rate and the bioavailability was also substantially improved for HK in its SD form. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay indicated that the HK–PLX (1:4) SD showed higher inhibition of HepG2 cells than free HK. Taken together, the present study suggests that the HK–PLX (1:4) SD could become a new oral drug formulation with high bioavailability and could produce a better response for clinical applications of HK. Full article
(This article belongs to the Special Issue Bioavailability Enhancement of Poorly Water-Soluble Drugs: Biopharmaceutics and Technology)
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18 pages, 3176 KiB  
Article
Enhanced Oral Bioavailability of Celecoxib Nanocrystalline Solid Dispersion based on Wet Media Milling Technique: Formulation, Optimization and In Vitro/In Vivo Evaluation
by Zhuang Ding, Lili Wang, Yangyang Xing, Yanna Zhao, Zhengping Wang and Jun Han
Pharmaceutics 2019, 11(7), 328; https://doi.org/10.3390/pharmaceutics11070328 - 11 Jul 2019
Cited by 42 | Viewed by 4166
Abstract
Celecoxib (CLX), a selective COX-2 inhibitor, is a biopharmaceutics classification system (BCS) class II drug with its bioavailability being limited by thepoor aqueoussolubility. The purpose of this study was to develop and optimize CLX nanocrystalline(CLX-NC) solid dispersion prepared by the wet medium millingtechnique [...] Read more.
Celecoxib (CLX), a selective COX-2 inhibitor, is a biopharmaceutics classification system (BCS) class II drug with its bioavailability being limited by thepoor aqueoussolubility. The purpose of this study was to develop and optimize CLX nanocrystalline(CLX-NC) solid dispersion prepared by the wet medium millingtechnique combined with lyophilizationto enhance oral bioavailability. In formulation screening, the resulting CLX-NC usingpolyvinylpyrrolidone (PVP) VA64 and sodiumdodecyl sulfate (SDS) as combined stabilizers showed the minimum particle size and a satisfactory stability. The formulation and preparation processwere further optimized by central composite experimentaldesign with PVP VA64 concentration (X1), SDS concentration (X2) and milling times (X3) as independent factors and particle size (Y1), polydispersity index (PDI, Y2) and zeta potential (Y3) as response variables. The optimal condition was determined as a combination of 0.75% PVP VA64, 0.11% SDS with milling for 90 min.The particle size, PDI and zeta potential of optimized CLX-NC were found to be 152.4 ± 1.4 nm, 0.191 ± 0.012 and −34.4 ± 0.6 mV, respectively. The optimized formulation showed homogeneous rod-like morphology as observed by scanning electron microscopy and was in a crystalline state as determined by differential scanning calorimetry and powder X-ray diffraction. In a storage stability study, optimized CLX-NC exhibited an excellent physical stability during six months’ storage at both the refrigeration and room conditions. In vivo pharmacokinetic research in Sprague-Dawley ratsdisplayed that Cmax and AUC0–∞ of CLX-NC were increased by 2.9 and 3.1 fold, compared with physical mixture. In this study, the screening and optimizing strategy of CLX-NC formulation represents a commercially viable approach forenhancing the oral bioavailability of CLX. Full article
(This article belongs to the Special Issue Bioavailability Enhancement of Poorly Water-Soluble Drugs: Biopharmaceutics and Technology)
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14 pages, 3451 KiB  
Article
Development of a Ternary Solid Dispersion Formulation of LW6 to Improve the In Vivo Activity as a BCRP Inhibitor: Preparation and In Vitro/In Vivo Characterization
by Rajiv Bajracharya, Sang Hoon Lee, Jae Geun Song, Minkyoung Kim, Kyeong Lee and Hyo-Kyung Han
Pharmaceutics 2019, 11(5), 206; https://doi.org/10.3390/pharmaceutics11050206 - 01 May 2019
Cited by 17 | Viewed by 4081
Abstract
LW6 (3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester) is a potent inhibitor of drug efflux by the breast cancer resistance protein (BCRP). However, its poor aqueous solubility leads to low bioavailability, which currently limits in vivo applications. Therefore, the present study aimed to develop ternary solid [...] Read more.
LW6 (3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-4-hydroxy-benzoic acid methyl ester) is a potent inhibitor of drug efflux by the breast cancer resistance protein (BCRP). However, its poor aqueous solubility leads to low bioavailability, which currently limits in vivo applications. Therefore, the present study aimed to develop ternary solid dispersion (SD) formulations in order to enhance the aqueous solubility and dissolution rate of LW6. Various SDs of LW6 were prepared using a solvent evaporation method with different drug/excipient ratios. The solubility and dissolution profiles of LW6 in different SDs were examined, and F8-SD which is composed of LW6, poloxamer 407, and povidone K30 at a weight ratio of 1:5:8 was selected as the optimal SD. The structural characteristics of F8-SD were also examined using Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and scanning electron microscopy (SEM). In the acidic to neutral pH range, F8-SD achieved rapid dissolution with a drug release of 76–81% within 20 min, while the dissolution of pure LW6 was negligible. The XRPD patterns indicated that F8-SD probably enhanced the solubility and dissolution of LW6 by changing the drug crystallinity to an amorphous state, in addition to the solubilizing effect of the hydrophilic carriers. Furthermore, F8-SD significantly improved the oral bioavailability of topotecan, which is a BCRP substrate, in rats. The systemic exposure of topotecan was enhanced approximately 10-fold by the concurrent use of F8-SD. In conclusion, the ternary SD formulation of LW6 with povidone K30 and poloxamer 407 appeared to be effective at improving the dissolution and in vivo effects of LW6 as a BCRP inhibitor. Full article
(This article belongs to the Special Issue Bioavailability Enhancement of Poorly Water-Soluble Drugs: Biopharmaceutics and Technology)
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Review

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30 pages, 3047 KiB  
Review
Liposomes for Enhanced Bioavailability of Water-Insoluble Drugs: In Vivo Evidence and Recent Approaches
by Mi-Kyung Lee
Pharmaceutics 2020, 12(3), 264; https://doi.org/10.3390/pharmaceutics12030264 - 13 Mar 2020
Cited by 158 | Viewed by 8596
Abstract
It has been known that a considerable number of drugs in clinical use or under development are water-insoluble drugs with poor bioavailability (BA). The liposomal delivery system has drawn attention as one of the noteworthy approaches to increase dissolution and subsequently absorption in [...] Read more.
It has been known that a considerable number of drugs in clinical use or under development are water-insoluble drugs with poor bioavailability (BA). The liposomal delivery system has drawn attention as one of the noteworthy approaches to increase dissolution and subsequently absorption in the gastrointestinal (GI) tract because of its biocompatibility and ability to encapsulate hydrophobic molecules in the lipid domain. However, there have been several drawbacks, such as structural instability in the GI tract and poor permeability across intestinal epithelia because of its relatively large size. In addition, there have been no liposomal formulations approved for oral use to date, despite the success of parenteral liposomes. Nevertheless, liposomal oral delivery has resurged with the rapid increase of published studies in the last decade. However, it is discouraging that most of this research has been in vitro studies only and there have not been many water-insoluble drugs with in vivo data. The present review focused on the in vivo evidence for the improved BA of water-insoluble drugs using liposomes to resolve doubts raised concerning liposomal oral delivery and attempted to provide insight by highlighting the approaches used for in vivo achievements. Full article
(This article belongs to the Special Issue Bioavailability Enhancement of Poorly Water-Soluble Drugs: Biopharmaceutics and Technology)
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