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Overcoming Drug Delivery Problems through Advanced Drug Delivery System Design

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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 (31 January 2021) | Viewed by 31090

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Special Issue Editors

Prof. Dr. Sophia G. Antimisiaris

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Guest Editor

1. Laboratory of Pharmaceutical Technology, Department of Pharmacy, School of Health Sciences, University of Patras, 26504 Rio-Patras, Greece
2. Institute for Chemical Engineering Sciences, Foundation for Research and Technology Hellas, FORTH/ICE-HT, Stadiou Street, 26510 Platani-Rio, Greece
Interests: targeted drug delivery; nanomedicines; liposome technology; lipid-based formulations
Special Issues, Collections and Topics in MDPI journals

Dr. Spyridon Mourtas

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Guest Editor

1. Laboratory of Pharmaceutical Technology, Department of Pharmacy, University of Patras, 26510 Rio-Patras, Greece
2. Institute for Chemical Engineering Sciences, Foundation for Research and Technology Hellas, FORTH/ICE-HT, Stadiou Street, 26504 Platani-Rio, Greece
Interests: targeted drug delivery; nanoliposomes; organic chemistry
Special Issues, Collections and Topics in MDPI journals

Dr. Antonia Marazioti

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Guest Editor

Laboratory of Pharmaceutical Technology, Institute for Chemical Engineering Sciences, Foundation for Research and Technology Hellas, FORTH/ICE-HT, Stadiou Street, 26504 Platani-Rio, Greece
Interests: cellular vesicles; bioavailability; drug delivery; anticancer treatment

Special Issue Information

Dear Colleagues,

The scope of this Special Issue: “Overcoming Drug Delivery Problems through Advanced Drug Delivery System Design” is to present and highlight the current developments in the area of advanced drug delivery systems which are designed to help overcome specific drug delivery problems. Such (delivery) problems are encountered in several categories of therapeutics and are usually related to poor properties of the drug molecules, such as permeability, solubility, stability, circulation half-life, and toxicity, which may result in poor absorption and bioavailability at the site of action, need for frequent dosing, exclusion of specific routes of administration or even inability to administer the drug by any route. In other cases, problems are related to difficult-to-reach biological sites, due to existing biological barriers, such as the blood–brain barrier (BBB). To overcome drug delivery problems, several types of nanomedicines have been designed and developed in recent years.

In the current Special Issue, we call for contributions that describe cases where specific problems related to drug properties have been solved by the design of advanced drug delivery systems. Depending on the route of administration and the specific pathology, the usage of nanosized systems may be necessary, as, for instance, in cases of anticancer therapeutics, or when drug delivery across the BBB is attempted. However, microparticulate systems or special types of drug-eluting materials may also be considered for other therapeutic applications. Furthermore, the use of inspiration from biological systems for the design of advanced biomimetic DDSs is also being considered today in many cases. An example is the use of extracellular of cellular-based or -mimicking vesicles for the delivery of drugs. In terms of the administration route used, the scope of this Special Issue is not limited to specific routes; however, it would be desirable to have contributions that use more “topical” routes of administration that are being considered more and more lately for specific pathologies.

This Special Issue serves to highlight all the abovementioned situations, or other cases not mentioned. We invite articles on all aspects of advanced drug delivery systems designed with the aim to overcome drug delivery problems.

Prof. Dr. Sophia G. Antimisiaris
Dr. Spyridon Mourtas
Dr. Antonia Marazioti
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

nanoparticles
liposomes
lipid nanoparticles
targeting
biomimetic
stability
permeability
solubility
topical administration
bioavailability
toxicity
controlled release

Published Papers (8 papers)

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Research

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18 pages, 3119 KiB

Open AccessArticle

pH-Sensitive Alginate/Carboxymethyl Chitosan/Aminated Chitosan Microcapsules for Efficient Encapsulation and Delivery of Diclofenac Sodium

by Ahmed M. Omer, Maha S. Ahmed, Gehan M. El-Subruiti, Randa E. Khalifa and Abdelazeem S. Eltaweil

Pharmaceutics 2021, 13(3), 338; https://doi.org/10.3390/pharmaceutics13030338 - 05 Mar 2021

Cited by 58 | Viewed by 3781

Abstract

To develop an effective pH-sensitive drug carrier, alginate (Alg), carboxymethyl chitosan (CMCs), and aminated chitosan (AmCs) derivatives were employed in this study. A simple ionic gelation technique was employed to formulate Alg-CMCs@AmCs dual polyelectrolyte complexes (PECs) microcapsules as a pH-sensitive carrier for efficient encapsulation and release of diclofenac sodium (DS) drug. The developed microcapsules were characterized by Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analyzer (TGA), and scanning electron microscope (SEM). The results clarified that formation of dual PECs significantly protected Alg microcapsules from rapid disintegration at colon conditions (pH 7.4), and greatly reduced their porosity. In addition, the dual PECs microcapsules can effectively encapsulate 95.4% of DS-drug compared to 86.3 and 68.6% for Alg and Alg-CMCs microcapsules, respectively. Higher DS-release values were achieved in simulated colonic fluid [SCF; pH 7.4] compared to those obtained in simulated gastric fluid [SGF; pH 1.2]. Moreover, the drug burst release was prevented and a sustained DS-release was achieved as the AmCs concentration increased. The results confirmed also that the developed microcapsules were biodegradable in the presence of the lysozyme enzyme. These findings emphasize that the formulated pH-sensitive microcapsules could be applied for the delivery of diclofenac sodium. Full article

(This article belongs to the Special Issue Overcoming Drug Delivery Problems through Advanced Drug Delivery System Design)

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23 pages, 3243 KiB

Open AccessArticle

Comprehensive Study of Atorvastatin Nanostructured Lipid Carriers through Multivariate Conceptualization and Optimization

by Heba A. Ghanem, Ali M. Nasr, Tamer H. Hassan, Mahmoud M. Elkhoudary, Reem Alshaman, Abdullah Alattar and Shadeed Gad

Pharmaceutics 2021, 13(2), 178; https://doi.org/10.3390/pharmaceutics13020178 - 28 Jan 2021

Cited by 12 | Viewed by 2339

Abstract

The aim of the current study is to establish a comprehensive experimental design for the screening and optimization of Atorvastatin-loaded nanostructured lipid carriers (AT-NLCs). Initially, combined D-optimal screening design was applied to find the most significant factors affecting AT-NLCs properties. The studied variables included mixtures of solid and liquid lipids, the solid/liquid lipid ratio, surfactant type and concentration, homogenization speed as well as sonication time. Then, the variables homogenization speed (A), the ratio of solid lipid/liquid lipid (B), and concentration of the surfactant (C) were optimized using a central composite design. Particle size, polydispersity index, zeta potential, and entrapment efficiency were chosen as dependent responses. The optimized AT-NLCs demonstrated a nanometric size (83.80 ± 1.13 nm), Polydispersity Index (0.38 ± 0.02), surface charge (−29.65 ± 0.65 mV), and high drug incorporation (93.1 ± 0.04%). Fourier Transform Infrared Spectroscopy (FTIR) analysis showed no chemical interaction between Atorvastatin and the lipid mixture. Differential Scanning Calorimetry (DSC) analysis of the AT-NLCs suggested the transformation of Atorvastatin crystal into an amorphous state. Administration of the optimized AT-NLCs led to a significant reduction (p < 0.001) in serum levels of rats’ total cholesterol, triglycerides, and low-density lipoproteins. This change was histologically validated by reducing the relevant steatosis of the liver. Full article

(This article belongs to the Special Issue Overcoming Drug Delivery Problems through Advanced Drug Delivery System Design)

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32 pages, 6469 KiB

Open AccessArticle

Overcoming the Solubility Barrier of Ibuprofen by the Rational Process Design of a Nanocrystal Formulation

by Andreas Ouranidis, Nikos Gkampelis, Elisavet Vardaka, Anna Karagianni, Dimitrios Tsiptsios, Ioannis Nikolakakis and Kyriakos Kachrimanis

Pharmaceutics 2020, 12(10), 969; https://doi.org/10.3390/pharmaceutics12100969 - 14 Oct 2020

Cited by 13 | Viewed by 3171

Abstract

Wet media milling, coupled with spay drying, is a commonly proposed formulation strategy for the production and solidification of nanosuspensions in order to overcome the solubility barrier of BCS Class II substances. However, the application of mechanically and thermally intensive processes is not straightforward in the cases of ductile and/or low melting point substances that may additionally be susceptible to eutectic formation. Using ibuprofen (IBU) as a model drug with non-favorable mechanical and melting properties, we attempt to rationalize nanocrystal formulation and manufacturing in an integrated approach by implementing Quality by Design (QbD) methodology, particle informatics techniques and computationally assisted process design. Wet media milling was performed in the presence of different stabilizers and co-milling agents, and the nanosuspensions were solidified by spray-drying. The effects of key process parameters (bead diameter, milling time and rotational speed) and formulation variables (stabilizer type and drug/stabilizer ratio) on the critical quality attributes (CQAs), i.e., Z-average size, polydispersity index (PDI), ζ-potential and redispersibility of spray-dried nanosuspensions were evaluated, while possible correlations between IBU free surface energy and stabilizer effectiveness were studied. The fracture mechanism and surface stabilization of IBU were investigated by computer simulation of the molecular interactions at the crystal lattice level. As a further step, process design accounting for mass-energy balances and predictive thermodynamic models were constructed to scale-up and optimize the design space. Contemplating several limitations, our multilevel approach offers insights on the mechanistic pathway applicable to the substances featuring thermosensitivity and eutectic tendency. Full article

(This article belongs to the Special Issue Overcoming Drug Delivery Problems through Advanced Drug Delivery System Design)

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24 pages, 7510 KiB

Open AccessArticle

Enteric Release Essential Oil Prepared by Co-Spray Drying Methacrylate/Polysaccharides—Influence of Starch Type

by Ioannis Partheniadis, Evangelia Zarafidou, Konstantinos E. Litinas and Ioannis Nikolakakis

Pharmaceutics 2020, 12(6), 571; https://doi.org/10.3390/pharmaceutics12060571 - 19 Jun 2020

Cited by 11 | Viewed by 3015

Abstract

Oregano essential oil (EO) enteric release powder was formulated by spray drying feed emulsions stabilized with polysaccharides (PSC) and Eudragit^® L100 (PLM). Different modified starches were used in the PSC component. Spray-dried powders were evaluated for particle size and morphology, dynamic packing, flowability, chemical interactions, reconstitution, and gastric protection. Feed emulsions were stable, indicating the good emulsification ability of the PLM/PSC combination. The presence of polymer in the encapsulating wall neutralized electrostatic charges indicating physical attraction, and FTIR spectra showed peaks of both PLM and PSC without significant shifting. Furthermore, the presence of polymer influenced spray drying, resulting in the elimination of surface cavities and the improvement of powder packing and flowability, which was best when the surface-active, low-viscosity sodium octenyl succinate starch was used (angle of repose 42°). When a PLM/PSC ratio of 80/20 was used in the encapsulating wall, the spray-dried product showed negligible re-emulsification and less than 15% release in pH 1.2 medium for 2 h, confirming gastric protection, whereas at pH 6.8, it provided complete re-emulsification and release. In conclusion, (1) polymer–PSC physical interaction promoted the formation of a smoother particle surface and product with improved technological properties, which is important for further processing, and (2) the gastro protective function of Eudragit^® L100 was not impaired due to the absence of significant chemical interactions. Full article

(This article belongs to the Special Issue Overcoming Drug Delivery Problems through Advanced Drug Delivery System Design)

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18 pages, 2550 KiB

Open AccessArticle

Investigating the Potential of Transmucosal Delivery of Febuxostat from Oral Lyophilized Tablets Loaded with a Self-Nanoemulsifying Delivery System

by Yasir A. Al-Amodi, Khaled M Hosny, Waleed S. Alharbi, Martin K. Safo and Khalid M El-Say

Pharmaceutics 2020, 12(6), 534; https://doi.org/10.3390/pharmaceutics12060534 - 10 Jun 2020

Cited by 13 | Viewed by 3416

Abstract

Gout is the most familiar inflammatory arthritis condition caused by the elevation of uric acid in the bloodstream. Febuxostat (FBX) is the latest drug approved by the United States Food and Drug Administration (US FDA) for the treatment of gout and hyperuricemia. FBX is characterized by low solubility resulting in poor gastrointestinal bioavailability. This study aimed at improving the oral bioavailability of FBX by its incorporation into self-nanoemulsifying delivery systems (SNEDS) with minimum globule size and maximum stability index. The SNEDS-incorporated FBX was loaded into a carrier substrate with a large surface area and lyophilized with other excipients to produce a fluffy, porous-like structure tablet for the transmucosal delivery of FBX. The solubility of FBX was studied in various oils, surfactants, and cosurfactants. Extreme vertices design was utilized to optimize FBX-SNEDS, and subsequently loaded into lyophilized tablets along with suitable excipients. The percentages of the main tablet excipients were optimized using a Box–Behnken design to develop self-nanoemulsifying lyophilized tablets (SNELTs) with minimum disintegration time and maximum drug release. The pharmacokinetics parameters of the optimized FBX-SNELTs were tested in healthy human volunteers in comparison with the marketed FBX tablets. The results revealed that the optimized FBX-SNELTs increased the maximum plasma concentration (C_max) and decreased the time to reach C_max (T_max) with a large area under the curve (AUC) as a result of the enhanced relative oral bioavailability of 146.4%. The significant enhancement of FBX bioavailability is expected to lead to reduced side effects and frequency of administration during the treatment of gout. Full article

(This article belongs to the Special Issue Overcoming Drug Delivery Problems through Advanced Drug Delivery System Design)

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22 pages, 2490 KiB

Open AccessArticle

Quality by Design for the Development and Analysis of Enhanced In-Situ Forming Vesicles for the Improvement of the Bioavailability of Fexofenadine HCl In Vitro and In Vivo

by Ali M. Nasr, Mona K. Qushawy, Mahmoud M. Elkhoudary, Aya Y. Gawish, Sameh S. Elhady and Shady A. Swidan

Pharmaceutics 2020, 12(5), 409; https://doi.org/10.3390/pharmaceutics12050409 - 29 Apr 2020

Cited by 15 | Viewed by 3577

Abstract

Drug absorption from the gastrointestinal tract (GIT) is one of the major problems affecting the bioavailability of orally absorbed drugs. This work aims to enhance Fexofenadine HCl oral bioavailability in vivo, the drug used for allergic rhinitis. In this study, novel spray-dried lactose-based enhanced in situ forming vesicles were prepared using different absorption enhancer by the slurry method. Full factorial design was used to obtain an optimized formulation, while central composite design was used to develop economic, environment-friendly analysis method of Fexofenadine HCl in plasma of rabbits. The optimized formulation containing Capryol 90 as absorption enhancer has a mean particle size 202.6 ± 3.9 nm and zeta potential −31.6 ± 0.9 mV. It achieved high entrapment efficiency of the drug 73.7 ± 1.7% and rapid Q3h release reaches 71.5 ± 2.7%. The design-optimized HPLC assay method in rabbit plasma could separate Fexofenadine HCl from endogenous plasma compounds in less than 3.7 min. The pharmacokinetic study and the pharmacological effect of the fexofenadine-loaded optimized formulation showed a significant increase in blood concentration and significantly higher activity against compound 48/80 induced systemic anaphylaxis-like reactions in mice. Therefore, enhanced in situ forming vesicles were effective nanocarriers for the entrapment and delivery of Fexofenadine HCl. Full article

(This article belongs to the Special Issue Overcoming Drug Delivery Problems through Advanced Drug Delivery System Design)

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19 pages, 2207 KiB

Open AccessArticle

Preparation, Physicochemical Properties, and In Vitro Toxicity towards Cancer Cells of Novel Types of Arsonoliposomes

by Paraskevi Zagana, Spyridon Mourtas, Anastasia Basta and Sophia G. Antimisiaris

Pharmaceutics 2020, 12(4), 327; https://doi.org/10.3390/pharmaceutics12040327 - 06 Apr 2020

Cited by 8 | Viewed by 2490

Abstract

Arsonoliposomes (ARSL) are liposomes that incorporate arsonolipids (ARS) in their membranes. They have demonstrated significant toxicity towards cancer cells, while being less toxic towards normal cells. In this study, we sought to investigate the possibility to prepare novel types of arsonoliposomes (ARSL) by incorporating a lipidic derivative of curcumin (TREG) in their membrane, and/or by loading the vesicles with doxorubicin (DOX). The final aim of our studies is to develop novel types of ARSL with improved pharmacokinetics/targeting potential and anticancer activity. TREG was incorporated in ARSL and their integrity during incubation in buffer and serum proteins was studied by monitoring calcein latency. After evaluation of TREG-ARSL stability, the potential to load DOX into ARSL and TREG-ARSL, using the active loading protocol, was studied. Loading was performed at two temperatures (40 °C and 60 °C) and different time periods of co-incubation (of empty vesicles with DOX). Calculation of DOX entrapment efficiency (%) was based on initial and final drug/lipid ratios. The cytotoxic activity of DOX-ARSL was tested towards B16F10 cells (mouse melanoma cells), LLC (Lewis Lung carcinoma cells), and HEK-293 (Human embryonic kidney cells). Results show that TREG-ARSL have slightly larger size but similar surface charge with ARSL and that they are both highly stable during storage at 4 °C for 56 d. Interestingly, the inclusion of TREG in ARSL conferred increased stability to the vesicles towards disruptive effects of serum proteins. The active-loading protocol succeeded to encapsulate high amounts of DOX into ARSL as well as TREG-LIP and TREG-ARSL, while the release profile of DOX from the novel liposome types was similar to that demonstrated by DOX-LIP. The cytotoxicity study results are particularly encouraging, since DOX-ARSL were less toxic towards the (normal) HEK cells compared to the two cancer cell-types. Furthermore, DOX-ARSL demonstrated lower toxicities (at all concentrations tested) for HEK cells, compared to that of the corresponding mixtures of free DOX and empty ARSL, while the opposite was true for the cancer cells (in most cases). The current results justify further in vivo exploitation of DOX-ARSL, as well as TREGARSL as anticancer therapeutic systems. Full article

(This article belongs to the Special Issue Overcoming Drug Delivery Problems through Advanced Drug Delivery System Design)

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Review

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29 pages, 3812 KiB

Open AccessReview

Naringenin Nano-Delivery Systems and Their Therapeutic Applications

by Mohammed Bhia, Mahzad Motallebi, Banafshe Abadi, Atefeh Zarepour, Miguel Pereira-Silva, Farinaz Saremnejad, Ana Cláudia Santos, Ali Zarrabi, Ana Melero, Seid Mahdi Jafari and Mehdi Shakibaei

Pharmaceutics 2021, 13(2), 291; https://doi.org/10.3390/pharmaceutics13020291 - 23 Feb 2021

Cited by 90 | Viewed by 7947

Abstract

Naringenin (NRG) is a polyphenolic phytochemical belonging to the class of flavanones and is widely distributed in citrus fruits and some other fruits such as bergamot, tomatoes, cocoa, and cherries. NRG presents several interesting pharmacological properties, such as anti-cancer, anti-oxidant, and anti-inflammatory activities. However, the therapeutic potential of NRG is hampered due to its hydrophobic nature, which leads to poor bioavailability. Here, we review a wide range of nanocarriers that have been used as delivery systems for NRG, including polymeric nanoparticles, micelles, liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), nanosuspensions, and nanoemulsions. These nanomedicine formulations of NRG have been applied as a potential treatment for several diseases, using a wide range of in vitro, ex vivo, and in vivo models and different routes of administration. From this review, it can be concluded that NRG is a potential therapeutic option for the treatment of various diseases such as cancer, neurological disorders, liver diseases, ocular disorders, inflammatory diseases, skin diseases, and diabetes when formulated in the appropriate nanocarriers. Full article

(This article belongs to the Special Issue Overcoming Drug Delivery Problems through Advanced Drug Delivery System Design)

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