Special Issue "Polymers Enhancing Bioavailability in Drug Delivery"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (20 October 2021).

Special Issue Editors

Dr. Ana Isabel Fernandes
E-Mail Website
Guest Editor
CiiEM, Interdisciplinary Research Centre Egas Moniz, Instituto Universitário Egas Moniz, Quinta da Granja, Monte de Caparica, 2829-511 Caparica, Portugal
Interests: polymers and polymeric systems; protein delivery; formulation in pediatrics; drug solubility enhancement; 3D-printing of pharmaceuticals
Dr. Angela Faustino Jozala
E-Mail Website
Co-Guest Editor
LaMInFE – Laboratory of Industrial Microbiology and Fermentation Process, University of Sorocaba, Sorocaba, SP, Brazil
Interests: microbiology; biopolymers; drug delivery; tissue regeneration; nanotechnology; antimicrobials; bioactive molecules

Special Issue Information

Dear Colleagues,

Currently, many of the drug entities entering the clinic face bioavailability issues, mainly due to poor water solubility and/or permeability, as well as to physicochemical instability or degradation in the body. To overcome biological barriers, drug sensitivity, and formulation problems, the use of several polymers has been considered. Polymers, either natural or synthetic, present an array of different backbones and functional groups, sizes, shapes, as well as mechanical and degradation properties, which have been exploited in drug delivery and targeting. Strategies for bioavailability enhancement using functionalized polymers include: solid amorphous dispersions for improved solubility; chemical modification for extended blood residence and reduced or abrogated immunogenicity and antigenicity; protection from harsh pH or enzymatic degradation; as well as tailored rate and temporal/spatial drug release.

This Special Issue aims to review the specific functional benefits granted by polymers to formulations, which are very much reliant on polymer structure and design, and result in improved drug bioavailability and therapeutic index. You are welcome to submit your research or review papers to the Special Issue, thus contributing to this exciting field of investigation.

Prof. Ana Isabel Fernandes
Dr. Angela Faustino Jozala
Guest Editor

Manuscript Submission Information

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Keywords

  • Polymers
  • Bioavailability enhancement
  • Aqueous solubility enhancement
  • Drug solubilization
  • Improved drug pharmacokinetics
  • Drug delivery and targeting

Published Papers (8 papers)

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Research

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Article
Oromucosal Alginate Films with Zein Nanoparticles as a Novel Delivery System for Digoxin
by , , , , and
Pharmaceutics 2021, 13(12), 2030; https://doi.org/10.3390/pharmaceutics13122030 (registering DOI) - 29 Nov 2021
Abstract
Digoxin is a hydrophobic drug used for the treatment of heart failure that possesses a narrow therapeutic index, which raises safety concerns for toxicity. This is of utmost relevance in specific populations, such as the elderly. This study aimed to demonstrate the potential [...] Read more.
Digoxin is a hydrophobic drug used for the treatment of heart failure that possesses a narrow therapeutic index, which raises safety concerns for toxicity. This is of utmost relevance in specific populations, such as the elderly. This study aimed to demonstrate the potential of the sodium alginate films as buccal drug delivery system containing zein nanoparticles incorporated with digoxin to reduce the number of doses, facilitating the administration with a quick onset of action. The film was prepared using the solvent casting method, whereas nanoparticles by the nanoprecipitation method. The nanoparticles incorporated with digoxin (0.25 mg/mL) exhibited a mean size of 87.20 ± 0.88 nm, a polydispersity index of 0.23 ± 0.00, and a zeta potential of 21.23 ± 0.07 mV. Digoxin was successfully encapsulated into zein nanoparticles with an encapsulation efficiency of 91% (±0.00). Films with/without glycerol and with different concentrations of ethanol were produced. The sodium alginate (SA) films with 10% ethanol demonstrated good performance for swelling (maximum of 1474%) and mechanical properties, with a mean tensile strength of 0.40 ± 0.04 MPa and an elongation at break of 27.85% (±0.58), compatible with drug delivery application into the buccal mucosa. The current study suggests that SA films with digoxin-loaded zein nanoparticles can be an effective alternative to the dosage forms available on the market for digoxin administration. Full article
(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)
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Article
PEG-Modified tert-Octylcalix[8]arenes as Drug Delivery Nanocarriers of Silibinin
Pharmaceutics 2021, 13(12), 2025; https://doi.org/10.3390/pharmaceutics13122025 (registering DOI) - 27 Nov 2021
Viewed by 130
Abstract
The hepatoprotective properties of silibinin, as well its therapeutic potential as an anticancer and chemo-preventive agent, have failed to progress towards clinical development and commercialization due to this material’s unfavorable pharmacokinetics and physicochemical properties, low aqueous solubility, and chemical instability. The present contribution [...] Read more.
The hepatoprotective properties of silibinin, as well its therapeutic potential as an anticancer and chemo-preventive agent, have failed to progress towards clinical development and commercialization due to this material’s unfavorable pharmacokinetics and physicochemical properties, low aqueous solubility, and chemical instability. The present contribution is focused on the feasibility of using PEGylated calixarene, in particular polyoxyethylene-derivatized tert-octylcalix[8]arene, to prepare various platforms for the delivery of silibinin, such as inclusion complexes and supramolecular aggregates thereof. The inclusion complex is characterized by various instrumental methods. At concentrations exceeding the critical micellization concentration of PEGylated calixarene, the tremendous solubility increment of silibinin is attributed to the additional solubilization and hydrophobic non-covalent interactions of the drug with supramolecular aggregates. PEG-modified tert-octylcalix[8]arenes, used as drug delivery carriers for silibinin, were additionally investigated for cytotoxicity against human tumor cell lines. Full article
(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)
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Article
Optimization and Development of Selective Histone Deacetylase Inhibitor (MPT0B291)-Loaded Albumin Nanoparticles for Anticancer Therapy
Pharmaceutics 2021, 13(10), 1728; https://doi.org/10.3390/pharmaceutics13101728 - 19 Oct 2021
Viewed by 468
Abstract
Histone deacetylase (HDAC) inhibitors have emerged as a new class of antitumor agent for various types of tumors. MPT0B291, a novel selective inhibitor of HDAC6, demonstrated significant antiproliferative activity in various human cancer cell types. However, MPT0B291 has very low water solubility, which [...] Read more.
Histone deacetylase (HDAC) inhibitors have emerged as a new class of antitumor agent for various types of tumors. MPT0B291, a novel selective inhibitor of HDAC6, demonstrated significant antiproliferative activity in various human cancer cell types. However, MPT0B291 has very low water solubility, which limits its clinical use for cancer therapy. In the current study, MPT0B291 was encapsulated in human serum albumin (HSA), and its anticancer activities were investigated. Nanoparticles (NPs) were prepared using two-stage emulsification resulting in 100~200-nm NPs with a fine size distribution (polydispersity index of <0.3). The in vitro drug release profiles of MPT0B291-loaded HSA NPs presented sustained-release properties. The cytotoxic effect on MIA PaCa-2 human pancreatic carcinoma cells was found to be similar to MPT0B291-loaded HSA NPs and the free-drug group. The albumin-based formulation provided a higher maximum tolerated dose than that of a drug solution with reduced toxicity toward normal cells. Furthermore, in vivo pharmacokinetic studies demonstrated an effective increase (5~8-fold) in the bioavailability of NPs containing MPT0B291 loaded in HSA compared to the free-drug solution with an extended circulation time (t1/2) leading to significantly enhanced efficacy of anticancer treatment. Full article
(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)
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Article
Dual-Acting Zeta-Potential-Changing Micelles for Optimal Mucus Diffusion and Enhanced Cellular Uptake after Oral Delivery
Pharmaceutics 2021, 13(7), 974; https://doi.org/10.3390/pharmaceutics13070974 - 27 Jun 2021
Viewed by 793
Abstract
Context: Overcoming the intestinal mucosal barrier can be a challenge in drug delivery. Nanoemulsions with negative zeta potentials can effectively permeate the mucus layer, but those with positive zeta potentials are better taken up by cells; a nanoemulsion with capricious zeta potential from [...] Read more.
Context: Overcoming the intestinal mucosal barrier can be a challenge in drug delivery. Nanoemulsions with negative zeta potentials can effectively permeate the mucus layer, but those with positive zeta potentials are better taken up by cells; a nanoemulsion with capricious zeta potential from negative to positive can achieve both good permeation and high uptake. Objective: This study aimed to develop dual-acting zeta-potential-amphoteric micelles enabling optimal muco-permeation and enhancement of cellular uptake. Methods: A micellar pre-concentrate was prepared from 15% Labrasol, 15% Kolliphor EL, 30% Kolliphor RH 40, and 40% dimethylsulfoxide. The micellar pre-concentrate was loaded with anionic stearic acid (SA), forming ionic complexes with cationic polymers at a ratio of 25:1 with Eudragit RS 100 and Eudragit RL 100. Blank micelles and those containing complexes were separately diluted in physiological buffers and examined for their droplet sizes, polydispersity indices (PDIs), zeta potentials, and cytotoxicity. The SA release from the micellar complexes was evaluated in 0.1 mM phosphate buffer (pH 6.8) containing 0.001% fluorescein, thereby enabling an instant decrease in fluorescence. Finally, the micelles were loaded with the model drug fluorescein diacetate (FDA) and evaluated for their muco-permeation behavior and cellular uptake. Results: The micellar dilutions formed micelles at the critical micelle concentration (CMC) of 312 µg/mL and showed a uniform average droplet size of 14.2 nm, with a PDI < 0.1. Micellar dilutions were non-cytotoxic when used at 1:100 in a physiological medium. Micelles loaded with ionic complexes achieved a sustained release of 95.5 ± 3.7% of the SA in 180 min. Moreover, the zeta potential of the complex-loaded micelles shifted from −5.4 to +1.8 mV, whereas the blank micelles showed a stabilized zeta potential of −10 mV. Furthermore, the negatively charged blank and complex-loaded micelles exhibited comparable muco-permeation, with an overall average of 58.2 ± 3.7% diffusion of FDA. The complex-loaded micellar droplets, however, provided a significantly higher cellular uptake of the model drug FDA (2.2-fold, p ≤ 0.01) Conclusion: Due to undergoing a shift in zeta potential, the modified micelles significantly enhanced cellular uptake while preserving mucus-permeating properties. Full article
(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)
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Article
The Preparation of a Novel Poly(Lactic Acid)-Based Sustained H2S Releasing Microsphere for Rheumatoid Arthritis Alleviation
Pharmaceutics 2021, 13(5), 742; https://doi.org/10.3390/pharmaceutics13050742 - 18 May 2021
Cited by 2 | Viewed by 799
Abstract
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that mainly erodes joints and surrounding tissues, and if it is not treated in time, it can cause joint deformities and loss of function. S-propargyl-cysteine (SPRC) is an excellent endogenous hydrogen sulfide donor which [...] Read more.
Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease that mainly erodes joints and surrounding tissues, and if it is not treated in time, it can cause joint deformities and loss of function. S-propargyl-cysteine (SPRC) is an excellent endogenous hydrogen sulfide donor which can relieve the symptoms of RA through the promotion of H2S release via the CSE/H2S pathway in vivo. However, the instant release of H2S in vivo could potentially limit its further clinical use. To solve this problem, in this study, a SPRC-loaded poly(lactic acid) (PLA) microsphere ([email protected]) was prepared, which could release SPRC in vitro in a sustained manner, and further promote sustained in vivo H2S release. Furthermore, its therapeutical effect on RA in rats was also studied. A spherical-like [email protected] was successfully prepared with a diameter of approximately 31.61 μm, yielding rate of 50.66%, loading efficiency of 6.10% and encapsulation efficiency of 52.71%. The [email protected] showed significant prolonged in vitro SPRC release, to 4 days, and additionally, an in vivo H2S release around 3 days could also be observed. In addition, a better therapeutical effect and prolonged administration interval toward RA rats was also observed in the [email protected] group. Full article
(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)
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Article
Synthesis and Evaluation of Thiol-Conjugated Poloxamer and Its Pharmaceutical Applications
Pharmaceutics 2021, 13(5), 693; https://doi.org/10.3390/pharmaceutics13050693 - 11 May 2021
Viewed by 653
Abstract
The current study was designed to convert the poloxamer (PLX) into thiolated poloxamer (TPLX), followed by its physicochemical, biocompatibilities studies, and applications as a pharmaceutical excipient in the development of tacrolimus (TCM)-containing compressed tablets. Thiolation was accomplished by using thiourea as a thiol [...] Read more.
The current study was designed to convert the poloxamer (PLX) into thiolated poloxamer (TPLX), followed by its physicochemical, biocompatibilities studies, and applications as a pharmaceutical excipient in the development of tacrolimus (TCM)-containing compressed tablets. Thiolation was accomplished by using thiourea as a thiol donor and hydrochloric acid (HCl) as a catalyst in the reaction. Both PLX and TPLX were evaluated for surface morphology based on SEM, the crystalline or amorphous nature of the particles, thiol contents, micromeritics, FTIR, and biocompatibility studies in albino rats. Furthermore, the polymers were used in the development of compressed tablets. Later, they were also characterized for thickness, diameter, hardness, weight variation, swelling index, disintegration time, mucoadhesion, and in vitro drug release. The outcomes of the study showed that the thiolation process was accomplished successfully, which was confirmed by FTIR, where a characteristic peak was noticed at 2695.9968 cm−1 in the FTIR scan of TPLX. Furthermore, the considerable concentration of the thiol constituents (20.625 µg/g of the polymer), which was present on the polymeric backbone, also strengthened the claim of successful thiolation. A mucoadhesion test illustrated the comparatively better mucoadhesion strength of TPLX compared to PLX. The in vitro drug release study exhibited that the TPLX-based formulation showed a more rapid (p < 0.05) release of the drug in 1 h compared to the PLX-based formulation. The in vivo toxicity studies confirmed that both PLX and TPLX were safe when they were administered to the albino rats. Conclusively, the thiolation of PLX made not only the polymer more mucoadhesive but also capable of improving the dissolution profile of TCM. Full article
(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)
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Article
The Impact of an Efflux Pump Inhibitor on the Activity of Free and Liposomal Antibiotics against Pseudomonas aeruginosa
Pharmaceutics 2021, 13(4), 577; https://doi.org/10.3390/pharmaceutics13040577 - 18 Apr 2021
Viewed by 687
Abstract
The eradication of Pseudomonas aeruginosa in cystic fibrosis patients has become continuously difficult due to its increased resistance to treatments. This study assessed the efficacy of free and liposomal gentamicin and erythromycin, combined with Phenylalanine arginine beta-naphthylamide (PABN), a broad-spectrum efflux pump inhibitor, [...] Read more.
The eradication of Pseudomonas aeruginosa in cystic fibrosis patients has become continuously difficult due to its increased resistance to treatments. This study assessed the efficacy of free and liposomal gentamicin and erythromycin, combined with Phenylalanine arginine beta-naphthylamide (PABN), a broad-spectrum efflux pump inhibitor, against P. aeruginosa isolates. Liposomes were prepared and characterized for their sizes and encapsulation efficiencies. The antimicrobial activities of formulations were determined by the microbroth dilution method. Their activity on P. aeruginosa biofilms was assessed, and the effect of sub-inhibitory concentrations on bacterial virulence factors, quorum sensing (QS) signals and bacterial motility was also evaluated. The average diameters of liposomes were 562.67 ± 33.74 nm for gentamicin and 3086.35 ± 553.95 nm for erythromycin, with encapsulation efficiencies of 13.89 ± 1.54% and 51.58 ± 2.84%, respectively. Liposomes and PABN combinations potentiated antibiotics by reducing minimum inhibitory and bactericidal concentrations by 4–32 fold overall. The formulations significantly inhibited biofilm formation and differentially attenuated virulence factor production as well as motility. Unexpectedly, QS signal production was not affected by treatments. Taken together, the results indicate that PABN shows potential as an adjuvant of liposomal macrolides and aminoglycosides in the management of lung infections in cystic fibrosis patients. Full article
(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)
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Review

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Review
Potential Applications of Chitosan-Based Nanomaterials to Surpass the Gastrointestinal Physiological Obstacles and Enhance the Intestinal Drug Absorption
Pharmaceutics 2021, 13(6), 887; https://doi.org/10.3390/pharmaceutics13060887 - 15 Jun 2021
Viewed by 804
Abstract
The small intestine provides the major site for the absorption of numerous orally administered drugs. However, before reaching to the systemic circulation to exert beneficial pharmacological activities, the oral drug delivery is hindered by poor absorption/metabolic instability of the drugs in gastrointestinal (GI) [...] Read more.
The small intestine provides the major site for the absorption of numerous orally administered drugs. However, before reaching to the systemic circulation to exert beneficial pharmacological activities, the oral drug delivery is hindered by poor absorption/metabolic instability of the drugs in gastrointestinal (GI) tract and the presence of the mucus layer overlying intestinal epithelium. Therefore, a polymeric drug delivery system has emerged as a robust approach to enhance oral drug bioavailability and intestinal drug absorption. Chitosan, a cationic polymer derived from chitin, and its derivatives have received remarkable attention to serve as a promising drug carrier, chiefly owing to their versatile, biocompatible, biodegradable, and non-toxic properties. Several types of chitosan-based drug delivery systems have been developed, including chemical modification, conjugates, capsules, and hybrids. They have been shown to be effective in improving intestinal assimilation of several types of drugs, e.g., antidiabetic, anticancer, antimicrobial, and anti-inflammatory drugs. In this review, the physiological challenges affecting intestinal drug absorption and the effects of chitosan on those parameters impacting on oral bioavailability are summarized. More appreciably, types of chitosan-based nanomaterials enhancing intestinal drug absorption and their mechanisms, as well as potential applications in diabetes, cancers, infections, and inflammation, are highlighted. The future perspective of chitosan applications is also discussed. Full article
(This article belongs to the Special Issue Polymers Enhancing Bioavailability in Drug Delivery)
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