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Pharmaceutics
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Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of...
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Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: 30 April 2025 | Viewed by 10260

Special Issue Editors

Dr. Hamdy Abdelkader

E-Mail Website
Guest Editor
Pharmaceutics Department, College of Pharmacy, King Khalid University, Abha 62223, Saudi Arabia
Interests: preformulation studies; cyclodextrins; solubility enhancement; modified release systems; niosomes; ocular delivery; irritation models
Special Issues, Collections and Topics in MDPI journals
Dr. Adel Al-Fatease

E-Mail Website
Guest Editor
Pharmaceutics Department, College of Pharmacy, King Khalid University, Abha 62223, Saudi Arabia
Interests: drug delivery; cancer; pancreatic diseases; bioprinting; biosensor; nanotechnology
Special Issues, Collections and Topics in MDPI journals
Dr. Zimei Wu

E-Mail Website
Guest Editor
School of Pharmacy, Faculty of Medical and Health Sciences, The University of Auckland, Auckland 1142, New Zealand
Interests: cancer nanomedicine; cytoplasmic drug delivery; targeted drug delivery; blood-brain barrier; ligand functionalised nanoparticles; liposomes; exosomes; extracellular vesicles

Special Issue Information

Dear Colleagues,

Conventional pharmaceutical excipients have been used to alter palatability, processing ability, flowability, and compressibility of dosage forms during manufacturing stages for producing elegant pharmaceutical products. Typical examples of these excipients include diluent, disintegrant, binder, lubricant, and glidant. Other pharmaceutical ingredients/excipients have been included to improve the chemical, physical, and microbial stability of the dosage forms.  The literature has reported many drug–excipient incompatibilities and excipients-related side effects such as local irritation, interference at the absorption sites through affecting efflux pumps and g-glycoproteins, and other systemic toxicities.

With the recent advances in pharmaceutical and medical sciences, active pharmaceutical agents have been launched into the market with inherent poor biopharmaceutics properties such as low solubility and limited permeability. Erratic drug absorption, inconsistent bioavailability, irritation, and poor pharmacokinetics may occur, leading to suboptimal efficacy and adverse drug reactions.

Biofunctional excipients have recently emerged, such as smart polymers, lipids, and other safe and natural additives that can alter drug solubility, release characteristics, permeability, and pharmacokinetic profiles. Typical example include in situ forming polymers, amino acids, cyclodextrins, and many more.

The new knowledge obtained from novel research ideas and manuscripts will contribute to improving bioavailability, reducing adverse effects, achieving drug targeting, or promoting better patient treatment adherence.

The focus of this Special Issue is on recent developments in biofunctional non-active ingredients/excipients used to design pharmaceutical formulations and delivery systems (for topical or systemic routes) that could confer targeted drug delivery or modified drug release to enhance efficacy, reduce irritation at the absorption site, and beyond.

We would be much appreciating if you would consider being one of our authors contributing to this Special Issue.  All types of submissions are welcome, including original research articles and comprehensive reviews.

Dr. Hamdy Abdelkader
Dr. Adel Al-Fatease
Dr. Zimei Wu
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

  • excipients
  • in situ forming polymers
  • modified-release
  • cyclodextrins
  • amino acids
  • eye diseases
  • diabetes
  • cancer

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Published Papers (7 papers)

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20 pages, 6644 KiB  
Article
Host–Guest Complexation of Olmesartan Medoxomil by Heptakis(2,6-di-O-methyl)-β-cyclodextrin: Compatibility Study with Excipients
by Dana Emilia Man, Ema-Teodora Nițu, Claudia Temereancă, Laura Sbârcea, Adriana Ledeți, Denisa Ivan, Amalia Ridichie, Minodora Andor, Alex-Robert Jîjie, Paul Barvinschi, Gerlinde Rusu, Renata-Maria Văruţ and Ionuț Ledeți
Pharmaceutics 2024, 16(12), 1557; https://doi.org/10.3390/pharmaceutics16121557 - 4 Dec 2024
Viewed by 344
Abstract
Background: Olmesartan medoxomil (OLM) is the prodrug of olmesartan, an angiotensin II type 1 receptor blocker that has antihypertensive and antioxidant activities and renal protective properties. It exhibits low water solubility, which leads to poor bioavailability and limits its clinical potential. To improve [...] Read more.
Background: Olmesartan medoxomil (OLM) is the prodrug of olmesartan, an angiotensin II type 1 receptor blocker that has antihypertensive and antioxidant activities and renal protective properties. It exhibits low water solubility, which leads to poor bioavailability and limits its clinical potential. To improve the solubility of OLM, a host–guest inclusion complex (IC) between heptakis(2,6-di-O-methyl)-β-cyclodextrin (DMβCD) and the drug substance was obtained. Along with active substances, excipients play a crucial role in the quality, safety, and efficacy of pharmaceutical formulations. Therefore, the compatibility of OLM/DMβCD IC with several pharmaceutical excipients was evaluated. Methods: IC was characterized in both solid and liquid states, employing thermoanalytical techniques, universal-attenuated total reflectance Fourier-transform infrared spectroscopy, powder X-ray diffractometry, UV spectroscopy, and saturation solubility studies. Compatibility studies were carried out using thermal and spectroscopic methods to assess potential physical and chemical interactions. Results: The 1:1 OLM:DMβCD stoichiometry ratio and the value of the apparent stability constant were determined by means of the phase solubility method that revealed an AL-type diagram. The binary system showed different physicochemical characteristics from those of the parent entities, supporting IC formation. The geometry of the IC was thoroughly investigated using molecular modeling. Compatibility studies revealed a lack of interaction between the IC and all studied excipients at ambient conditions and the thermally induced incompatibility of IC with magnesium stearate and α-lactose monohydrate. Conclusions: The results of this study emphasize that OLM/DMβCD IC stands out as a valuable candidate for future research in the development of new pharmaceutical formulations, in which precautions should be considered in choosing magnesium stearate and α-lactose monohydrate as excipients if the manufacture stage requires temperatures above 100 °C. Full article
(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)
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Figure 1

Figure 1
<p>Chemical structures of OLM (<b>a</b>) and DMβCD (<b>b</b>).</p> Full article ">Figure 2
<p>Phase solubility diagram of OLM with DMβCD in 0.1 M phosphate buffer, pH 7.4.</p> Full article ">Figure 3
<p>OLM/DMβCD IC simulation for 1:1 molar ratio. Images (<b>a</b>,<b>b</b>) show the supramolecular entity from the secondary face of the DMβCD cavity. OLM is represented as sticks colored by element, and DMβCD is represented by red/green/white dots (<b>a</b>); OLM is shown as spheres colored by element, and DMβCD is shown as sticks in red/green/white (<b>b</b>). Polar/hydrophobic contacts between OLM and DMβCD, where OLM is represented as sticks colored by element, and DMβCD is represented as lines (<b>c</b>). H-bond surface interaction of OLM/DMβCD (<b>d</b>).</p> Full article ">Figure 4
<p>TG/DTG/DSC thermoanalytical curves of OLM (<b>a</b>); DMβCD (<b>b</b>); OLM/DMβCD PM (<b>c</b>); and KP (<b>d</b>) in air atmosphere.</p> Full article ">Figure 5
<p>FTIR spectra of OLM, DMβCD, OLM/DMβCD PM, and KP.</p> Full article ">Figure 6
<p>Diffraction profiles of OLM, DMβCD, and OLM/DMβCD binary systems PM and KP.</p> Full article ">Figure 7
<p>UV spectra of DMβCD 150.0 µg mL<sup>−1</sup> and OLM 27.0 µg mL<sup>−1</sup> in 0.1 M phosphate buffer, pH 7.4, at 25 °C.</p> Full article ">Figure 8
<p>TG (<b>a</b>,<b>b</b>), DTG (<b>c</b>,<b>d</b>), and DSC (<b>e</b>,<b>f</b>) curves of OLM/DMβCD IC and its mixture with pharmaceutical excipients TA and STA (<b>a</b>,<b>c</b>,<b>e</b>), and Mg STR and LA (<b>b</b>,<b>d</b>,<b>f</b>) in synthetic air atmosphere.</p> Full article ">Figure 9
<p>UATR-FTIR spectra of (<b>a</b>) OLM/DMβCD IC, TA, STA, and the physical mixture of IC with TA and STA; (<b>b</b>) OLM/DMβCD IC, MgSTR, LA, and the mixture of IC with MgSTR and LA, recorded at ambient temperature.</p> Full article ">Figure 10
<p>PXRD diffraction patterns of (<b>a</b>) OLM/DMβCD IC, TA, and their corresponding physical mixtures—main image; OLM/DMβCD KP + TA with 2θ values of diffraction peaks corresponding to KP—inset image; and OLM/DMβCD KP, excipients, and their mixture. (<b>b</b>) STA. (<b>c</b>) MgSTR. (<b>d</b>) LA.</p> Full article ">Figure 10 Cont.
<p>PXRD diffraction patterns of (<b>a</b>) OLM/DMβCD IC, TA, and their corresponding physical mixtures—main image; OLM/DMβCD KP + TA with 2θ values of diffraction peaks corresponding to KP—inset image; and OLM/DMβCD KP, excipients, and their mixture. (<b>b</b>) STA. (<b>c</b>) MgSTR. (<b>d</b>) LA.</p> Full article ">
20 pages, 14709 KiB  
Article
Characterizing Extracellular Vesicles Generated from the Integra CELLine Culture System and Their Endocytic Pathways for Intracellular Drug Delivery
by Tianjiao Geng, Lei Tian, Song Yee Paek, Euphemia Leung, Lawrence W. Chamley and Zimei Wu
Pharmaceutics 2024, 16(9), 1206; https://doi.org/10.3390/pharmaceutics16091206 - 13 Sep 2024
Viewed by 991
Abstract
Extracellular vesicles (EVs) have attracted great attention as promising intracellular drug delivery carriers. While the endocytic pathways of small EVs (sEVs, <200 nm) have been reported, there is limited understanding of large EVs (lEVs, >200 nm), despite their potential applications for drug delivery. [...] Read more.
Extracellular vesicles (EVs) have attracted great attention as promising intracellular drug delivery carriers. While the endocytic pathways of small EVs (sEVs, <200 nm) have been reported, there is limited understanding of large EVs (lEVs, >200 nm), despite their potential applications for drug delivery. Additionally, the low yield of EVs during isolation remains a major challenge in their application. Herein, we aimed to compare the endocytic pathways of sEVs and lEVs using MIA PaCa-2 pancreatic cancer cell-derived EVs as models and to explore the efficiency of their production. The cellular uptake of EVs by MIA PaCa-2 cells was assessed and the pathways were investigated with the aid of endocytic inhibitors. The yield and protein content of sEVs and lEVs from the Integra CELLine culture system and the conventional flasks were compared. Our findings revealed that both sEVs and lEVs produced by the Integra CELLine system entered their parental cells via multiple routes, including caveolin-mediated endocytosis, clathrin-mediated endocytosis, and actin-dependent phagocytosis or macropinocytosis. Notably, caveolin- and clathrin-mediated endocytosis were more prominent in the uptake of sEVs, while actin-dependent phagocytosis and macropinocytosis were significant for both sEVs and lEVs. Compared with conventional flasks, the Integra CELLine system demonstrated a 9-fold increase in sEVs yield and a 6.5-fold increase in lEVs yield, along with 3- to 4-fold higher protein content per 1010 EVs. Given that different endocytic pathways led to distinct intracellular trafficking routes, this study highlights the unique potentials of sEVs and lEVs for intracellular cargo delivery. The Integra CELLine proves to be a highly productive and cost-effective system for generating EVs with favourable properties for drug delivery. Full article
(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Schematic illustration of the Integra CELLine culture system (<b>A</b>) and conventional flasks (<b>B</b>) and the set-up to generate EVs. With the Integra CELLine culture system, cells can be continuously used for up to 300 days while medium containing EVs was collected twice per week. However, conventional flasks only can be used for one week and medium containing EVs was collected once.</p> Full article ">Figure 2
<p>The structure of sulfo-cyanine5 NHS ester (Cy5) (MW 777.49 g/mol), a red fluorescent dye for EVs labelling. Labelling of EVs was achieved through covalent coupling between NHS ester groups and amine groups on proteins within the EVs. Excitation maximum ~646 nm; emission maximum ~662 nm.</p> Full article ">Figure 3
<p>The EVs yield from the Integra CELLine culture system compared with that from conventional flasks. Data are expressed as EVs number per mL medium (<b>A</b>) and EVs protein (μg) per mL medium (<b>B</b>) (mean ± SD, <span class="html-italic">n</span> = 3). ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.005, **** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 4
<p>Characterisation of EVs isolated from the Integra CELLine culture system. Nanoparticle tracking analysis (NTA) measurement of sEVs (<b>A</b>) and lEVs (<b>B</b>) isolated from MIA PaCa-2 cells. Size distribution of sEVs (<b>C</b>) and lEVs (<b>D</b>) measured by dynamic light scattering (DLS). Representative EVs samples in tubes (black arrows) and cryogenic transmission electron microscopic (cryo-TEM) micrographs of sEVs (<b>E</b>) and lEVs (red arrows) (<b>F</b>). Scale bars: 200 nm.</p> Full article ">Figure 5
<p>The cellular uptake of Cy5- or PKH67-labelled sEVs and lEVs by their donor MIA PaCa-2 cells. (<b>A</b>) Fluorescence intensity of Cy5 (relative fluorescence units, RFU) in sEVs and lEVs cellular uptake at different time points measured by a fluorescence plate reader. Fluorescence images of sEVs (<b>B</b>) and lEVs (<b>C</b>) labelled by PKH67 internalised by MIA PaCa-2 cells for 1 h and 2 h, respectively. Scale bars: 20 μm. Cells were exposed to the same number of EVs in both experiments. Data represent the means ± SD, and <span class="html-italic">n</span> = 3 cells each data point. ** <span class="html-italic">p</span> &lt; 0.01. For clarity cells within the red boxed areas are highlighted in the upper panels and the arrows show that internalized EVs were prone to being entrapped in organelles.</p> Full article ">Figure 6
<p>The effect of inhibitors concentrations on MIA PaCa-2 cells viability. Left: Images showing cell morphology after 3 h pre-treatment under light microscope (40×). Right: An MTT assay was carried out to evaluate the cell viability in the presence of inhibitors with different concentrations (mean ± SD, <span class="html-italic">n</span> = 3 batches). * <span class="html-italic">p</span> &lt; 0.05, **** <span class="html-italic">p</span> &lt; 0.001, ns = nonsignificant.</p> Full article ">Figure 7
<p>Representative fluorescence images of MIA PaCa-2 cells treated with MIA PaCa-2 cell-derived sEVs (<b>A</b>) or lEVs (<b>C</b>) for 1 h and 2 h in the presence of genistein (50 μg/mL), CPZ (10 μg/mL), or CytoD (10 μg/mL). Representative cells within the red boxed area are displayed in the upper panels for clarity. The cellular uptake (% of control) was measured by Fiji software (<b>B</b>,<b>D</b>) (data are presented as means ± SD, <span class="html-italic">n</span> = 3 cells in each case). Cells without pre-treatment with inhibitors were used as controls. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.005, **** <span class="html-italic">p</span> &lt; 0.001. Scale bars: 20 μm. Images of the control groups were also used in <a href="#pharmaceutics-16-01206-f005" class="html-fig">Figure 5</a> as they were captured at the same time as those from the other groups.</p> Full article ">Figure 7 Cont.
<p>Representative fluorescence images of MIA PaCa-2 cells treated with MIA PaCa-2 cell-derived sEVs (<b>A</b>) or lEVs (<b>C</b>) for 1 h and 2 h in the presence of genistein (50 μg/mL), CPZ (10 μg/mL), or CytoD (10 μg/mL). Representative cells within the red boxed area are displayed in the upper panels for clarity. The cellular uptake (% of control) was measured by Fiji software (<b>B</b>,<b>D</b>) (data are presented as means ± SD, <span class="html-italic">n</span> = 3 cells in each case). Cells without pre-treatment with inhibitors were used as controls. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.005, **** <span class="html-italic">p</span> &lt; 0.001. Scale bars: 20 μm. Images of the control groups were also used in <a href="#pharmaceutics-16-01206-f005" class="html-fig">Figure 5</a> as they were captured at the same time as those from the other groups.</p> Full article ">Figure 8
<p>Schematic representation of the pathways of cellular internalisation of EVs based on their size. This includes phagocytosis, macropinocytosis, clathrin-mediated endocytosis, and caveolin-mediated endocytosis.</p> Full article ">
18 pages, 2802 KiB  
Article
Enhancing Oral Bioavailability of Simvastatin Using Uncoated and Polymer-Coated Solid Lipid Nanoparticles
by Amira E. Abd-Elghany, Omar El-Garhy, Adel Al Fatease, Ali H. Alamri and Hamdy Abdelkader
Pharmaceutics 2024, 16(6), 763; https://doi.org/10.3390/pharmaceutics16060763 - 4 Jun 2024
Cited by 1 | Viewed by 1380
Abstract
Simvastatin (SVA) is a well-prescribed drug for treating cardiovascular and hypercholesterolemia. Due to the extensive hepatic first-pass metabolism and poor solubility, its oral bioavailability is 5%. Solid lipid nanoparticles (SLNs) and hydrogel-coated SLNs were investigated to overcome the limited bioavailability of SVA. Four [...] Read more.
Simvastatin (SVA) is a well-prescribed drug for treating cardiovascular and hypercholesterolemia. Due to the extensive hepatic first-pass metabolism and poor solubility, its oral bioavailability is 5%. Solid lipid nanoparticles (SLNs) and hydrogel-coated SLNs were investigated to overcome the limited bioavailability of SVA. Four different lipids used alone or in combination with two stabilizers were employed to generate 13 SLNs. Two concentrations of chitosan (CS) and alginate (AL) were coating materials. SLNs were studied for particle size, zeta potential, in vitro release, rheology, and bioavailability. The viscosities of both the bare and coated SLNs exhibited shear-thinning behavior. The viscosity of F11 (Chitosan 1%) at 20 and 40 rpm were 424 and 168 cp, respectively. F11 had a particle size of 260.1 ± 3.72 nm with a higher release; the particle size of F11-CS at 1% was 524.3 ± 80.31 nm. In vivo studies illustrated that F11 had the highest plasma concentration when compared with the SVA suspension and coated chitosan (F11 (Chitosan 1%)). Greater bioavailability is measured as (AUC0→24), as compared to uncoated ones. The AUC for F11, F11-CS 1%, and the SVA suspension were 1880.4, 3562.18, and 272 ng·h/mL, respectively. Both bare and coated SLNs exhibited a significantly higher relative bioavailability when compared to that from the control SVA. Full article
(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)
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Figure 1

Figure 1
<p>Photographs of the four different bare SLNs with milky dispersion textures.</p> Full article ">Figure 2
<p>Representative SEM micrographs of F6 and F11 SLNs at different magnifications.</p> Full article ">Figure 3
<p>Rheological profiles (viscosity (cp) versus shear rates (rpm) for selected bare SLNs; Data points represent means; n = 3.</p> Full article ">Figure 4
<p>Rheological profiles (viscosity vs. shear rates) of bare and alginate coated SLNs; (<b>A</b>) and (<b>B</b>) were bare and alginate coated F6 and F11; respectively. Data points represent means ± SD, n = 3.</p> Full article ">Figure 5
<p>Rheological profiles (viscosity vs. shear rates) of bare and chitosan-coated SLNs; (<b>A</b>,<b>B</b>) were bare and chitosan-coated F6 and F11, respectively. Data points represent means ± SD, n = 3.</p> Full article ">Figure 6
<p>In vitro drug release profile of simvastatin suspension, bare F6 and F11 (<b>A</b>); and bare F11, coated F11 with alginate (1%) and chitosan (1%) (<b>B</b>) at pH 1.2 and pH 6.8. Data points represent means, n = 3.</p> Full article ">Figure 7
<p>Plasma concentrations versus time curve for simvastatin suspension (the control for a conventional release system), bare SLNs (F11), and coated F11 (chitosan 1%). Data points represent means ± SD, n = 3.</p> Full article ">
18 pages, 4654 KiB  
Article
Polymeric Amorphous Solid Dispersions of Dasatinib: Formulation and Ecotoxicological Assessment
by Katarina Sokač, Martina Miloloža, Dajana Kučić Grgić and Krunoslav Žižek
Pharmaceutics 2024, 16(4), 551; https://doi.org/10.3390/pharmaceutics16040551 - 18 Apr 2024
Viewed by 2006
Abstract
Dasatinib (DAS), a potent anticancer drug, has been subjected to formulation enhancements due to challenges such as significant first-pass metabolism, poor absorption, and limited oral bioavailability. To improve its release profile, DAS was embedded in a matrix of the hydrophilic polymer polyvinylpyrrolidone (PVP). [...] Read more.
Dasatinib (DAS), a potent anticancer drug, has been subjected to formulation enhancements due to challenges such as significant first-pass metabolism, poor absorption, and limited oral bioavailability. To improve its release profile, DAS was embedded in a matrix of the hydrophilic polymer polyvinylpyrrolidone (PVP). Drug amorphization was induced in a planetary ball mill by solvent-free co-grinding, facilitating mechanochemical activation. This process resulted in the formation of amorphous solid dispersions (ASDs). The ASD capsules exhibited a notable enhancement in the release rate of DAS compared to capsules containing the initial drug. Given that anticancer drugs often undergo limited metabolism in the body with unchanged excretion, the ecotoxicological effect of the native form of DAS was investigated as well, considering its potential accumulation in the environment. The highest ecotoxicological effect was observed on the bacteria Vibrio fischeri, while other test organisms (bacteria Pseudomonas putida, microalgae Chlorella sp., and duckweed Lemna minor) exhibited negligible effects. The enhanced drug release not only contributes to improved oral absorption but also has the potential to reduce the proportion of DAS that enters the environment through human excretion. This comprehensive approach highlights the significance of integrating advances in drug development while considering its environmental implications. Full article
(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>DSC thermograms of the initial drug, polymer, and obtained solid dispersions.</p> Full article ">Figure 2
<p>FTIR spectra of the initial drug and polymer.</p> Full article ">Figure 3
<p>FTIR spectra of obtained solid dispersions.</p> Full article ">Figure 4
<p>Diffractograms of the initial drug and polymer.</p> Full article ">Figure 5
<p>Diffractograms of obtained solid dispersions.</p> Full article ">Figure 6
<p>Drug release profiles of capsules containing solid dispersions (obtained under various conditions) and initial DAS.</p> Full article ">Figure 7
<p>Concentration–response curve for DAS concentration in the range 25–150 µg L<sup>−1</sup> obtained by ecotoxicity tests with marine bacterium <span class="html-italic">Vibrio fischeri</span>.</p> Full article ">Figure 8
<p>Concentration–response curve for DAS concentration in the range 25–150 µg L<sup>−1</sup> obtained by ecotoxicity tests with saprophytic bacterium <span class="html-italic">Pseudomonas putida</span>.</p> Full article ">Figure 9
<p>Concentration–response curve for DAS concentration in the range 25–150 µg L<sup>−1</sup> obtained by ecotoxicity tests with microalgae <span class="html-italic">Chlorella</span> sp.</p> Full article ">Figure 10
<p>Changes of specific growth rate (<b>A</b>), average root length (<b>B</b>), and average concentration of chlorophyll (<b>C</b>) obtained after 7 days of exposure of duckweed <span class="html-italic">Lemna minor</span> to the concentration of DAS in the range 25–150 µg L<sup>−1</sup> compared to control.</p> Full article ">
19 pages, 1877 KiB  
Article
Conjugated Linoleic Acid–Carboxymethyl Chitosan Polymeric Micelles to Improve the Solubility and Oral Bioavailability of Paclitaxel
by Iqra Mubeen, Ghulam Abbas, Shahid Shah and Abdullah A Assiri
Pharmaceutics 2024, 16(3), 342; https://doi.org/10.3390/pharmaceutics16030342 - 28 Feb 2024
Cited by 2 | Viewed by 1443
Abstract
Oral delivery, the most common method of therapeutic administration, has two significant obstacles: drug solubility and permeability. The challenges of current oral medicine delivery are being tackled through an emerging method that uses structures called polymeric micelles. In the present study, polymeric micelles [...] Read more.
Oral delivery, the most common method of therapeutic administration, has two significant obstacles: drug solubility and permeability. The challenges of current oral medicine delivery are being tackled through an emerging method that uses structures called polymeric micelles. In the present study, polymeric micelles were developed using conjugates of linoleic acid–carboxymethyl chitosan (LA-CMCS) for the oral delivery of paclitaxel (PCL). The developed micelles were evaluated by particle size, zeta potential, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). When PCL was contained within micelles, its solubility increased by almost 13.65 times (around 60 µg/mL). The micelles’ zeta potentials were −29 mV, their polydispersity indices were 0.023, and their particle diameters were 93 nm. Micelles showed PCL loading and entrapment efficiencies of 67% and 61%, respectively. The sustained release qualities of the PCL release data from micelles were good. In comparison to the pure PCL suspension, the permeability of the PCL from micelles was 2.2 times higher. The pharmacokinetic data revealed that PCL with LA-CMCS micelles had a relative bioavailability of 239.17%, which was much greater than the PCL in the suspension. The oral bioavailability of PCL was effectively increased by LA-CMCS micelles according to an in vivo study on animals. The polymer choice, maybe through improved permeability, plays an essential role when assessing oral bioavailability enhancement and solubility improvement (13.65 times). The outcomes demonstrated that PCL’s solubility and pharmacokinetics were improved in the micelles of the LA-CMCS conjugate. Full article
(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Chemical scheme for the synthesis of LA-CMCS conjugate in the presence of coupling agents (EDC and NHS).</p> Full article ">Figure 2
<p>FTIR spectra (<b>A</b>), DSC thermograms (<b>B</b>), and TGA (<b>C</b>) of PCL, CMCS, LA, LA-CMCS conjugate, blank, and PCL-loaded micelles formulation LA-CMCS2.</p> Full article ">Figure 3
<p>Release of PCL from LA-CMCS micelles in SGF with pepsin (<b>A</b>), SGF without pepsin (<b>B</b>), SIF with pancreatin (<b>C</b>), and SIF without pancreatin (<b>D</b>) for a period of 72 h.</p> Full article ">Figure 4
<p>Biological studies of the micelles of LA-CMCS conjugates, cell viability (<b>A</b>), haemolysis test (<b>B</b>), permeability of PCL (<b>C</b>), and gene expression of epithelial and mesenchymal markers by qPCR, where epithelial marker like E-cadherin were found to be higher, while mesenchymal markers (Slug, Vimentin, and N-cadherin) were lower in cancer cells compared to the control (<b>D</b>).</p> Full article ">Figure 5
<p>Western blot (<b>A</b>) and analysis of pharmacokinetics (<b>B</b>) of PCL from LA-CMCS2 and PCL suspension in albino rats.</p> Full article ">
20 pages, 8957 KiB  
Article
Exploring the Ocular Absorption Pathway of Fasudil Hydrochloride towards Developing a Nanoparticulate Formulation with Improved Performance
by Barzan Osi, Ali A. Al-Kinani, Zinah K. Al-Qaysi, Mouhamad Khoder and Raid G. Alany
Pharmaceutics 2024, 16(1), 112; https://doi.org/10.3390/pharmaceutics16010112 - 15 Jan 2024
Cited by 2 | Viewed by 1606
Abstract
Rho-kinase (ROCK) inhibitors represent a new category of anti-glaucoma medications. Among them, Fasudil hydrochloride, a selective ROCK inhibitor, has demonstrated promising outcomes in glaucoma treatment. It works by inhibiting the ROCK pathway, which plays a crucial role in regulating the trabecular meshwork and [...] Read more.
Rho-kinase (ROCK) inhibitors represent a new category of anti-glaucoma medications. Among them, Fasudil hydrochloride, a selective ROCK inhibitor, has demonstrated promising outcomes in glaucoma treatment. It works by inhibiting the ROCK pathway, which plays a crucial role in regulating the trabecular meshwork and canal of Schlemm’s aqueous humor outflow. This study aims to investigate the ocular absorption pathway of Fasudil hydrochloride and, subsequently, develop a nanoparticle-based delivery system for enhanced corneal absorption. Employing the ionic gelation method and statistical experimental design, the factors influencing chitosan nanoparticle (Cs NP) characteristics and performance were explored. Fasudil in vitro release and ex vivo permeation studies were performed, and Cs NP ocular tolerability and cytotoxicity on human lens epithelial cells were evaluated. Permeation studies on excised bovine eyes revealed significantly higher Fasudil permeation through the sclera compared to the cornea (370.0 μg/cm2 vs. 96.8 μg/cm2, respectively). The nanoparticle size (144.0 ± 15.6 nm to 835.9 ± 23.4 nm) and entrapment efficiency range achieved (17.2% to 41.4%) were predominantly influenced by chitosan quantity. Cs NPs showed a substantial improvement in the permeation of Fasudil via the cornea, along with slower release compared to the Fasudil aqueous solution. The results from the Hen’s Egg Test Chorioallantoic Membrane (HET-CAM) and Bovine Corneal Opacity and Permeability (BCOP) tests indicated good conjunctival and corneal biocompatibility of the formulated chitosan nanoparticles, respectively. Lens epithelial cells displayed excellent tolerance to low concentrations of these nanoparticles (>94% cell viability). To the best of our knowledge, this is the first report on the ocular absorption pathway of topically applied Fasudil hydrochloride where the cornea has been identified as a potential barrier that could be overcome using Cs NPs. Full article
(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)
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<p>Chemical structure of Fasudil hydrochloride.</p> Full article ">Figure 2
<p>Ex vivo permeation study of Fasudil from Fasudil simple solution through excised bovine cornea and sclera for 6 h. Results are expressed (n = 3 ± SD), <span class="html-italic">t</span>-test was performed.</p> Full article ">Figure 3
<p>Response surface representing the effect of independent variables, including Cs concentration (mg/mL), Cs:TPP mass ratio, and sonication time (s), on the dependent variables: (<b>a</b>) particle size (nm), (<b>b</b>) PDI, (<b>c</b>) zeta potential (mV), and (<b>d</b>) entrapment efficiency (EE%).</p> Full article ">Figure 4
<p>Scanning electron micrographs of optimized Cs nanoparticles loaded with Fasudil hydrochloride.</p> Full article ">Figure 5
<p>Cumulative release of Fasudil loaded into Cs NPs and Fasudil solution (control) in simulated tear fluid (STF). Results are presented as mean ± SD, n = 3.</p> Full article ">Figure 6
<p>Trans-corneal permeation profiles of Fasudil from Cs NPs and Fasudil solution (mean ± SD, n = 3).</p> Full article ">Figure 7
<p>Images displaying the irritant effects of substances applied to the CAMs over a 5 min period: (A) NaOH 0.5 M (strong irritant), (B) propylene glycol (PG) (moderate irritant), (C) normal saline (negative control), and (D) Cs NPs formulation.</p> Full article ">Figure 8
<p>Cumulative scores of the HET-CAM assay results and subsequent classification for the controls and Cs NPs. Results are expressed as mean values ± SD, n = 3.</p> Full article ">Figure 9
<p>Bovine corneal opacity (upper row) and permeability assay (lower row). The corneas were subjected to controls (<b>a</b>–<b>c</b>) and Cs NPs (<b>d</b>) and examined for opacity and permeability under bright light and a cobalt blue filter, respectively.</p> Full article ">Figure 10
<p>Cumulative scores of the BCOP assay and subsequent irritation classification for the controls and Cs NPs. Results are expressed as mean values ± SD, n = 3.</p> Full article ">Figure 11
<p>Cell viability (%) evaluated by NRU assay after 24 h of exposure of HLEC cells to different concentrations of Cs NPs. Hydrogen peroxide and treatment medium are used as positive and negative controls, respectively. Results are expressed as mean values ± SD from three independent experiments. One-way analysis of variance (ANOVA) followed by Bonferroni post hoc test was used with * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">
19 pages, 4607 KiB  
Article
Effect of Phenolics from Aeonium arboreum on Alpha Glucosidase, Pancreatic Lipase, and Oxidative Stress; a Bio-Guided Approach
by Marwah M. Alfeqy, Seham S. El-Hawary, Ali M. El-Halawany, Mohamed A. Rabeh, Saad A. Alshehri, Aya M. Serry, Heba A. Fahmy and Marwa. I. Ezzat
Pharmaceutics 2023, 15(11), 2541; https://doi.org/10.3390/pharmaceutics15112541 - 27 Oct 2023
Cited by 1 | Viewed by 1455
Abstract
Metabolic syndrome (MetS) is a global issue affecting over a billion people, raising the risk of diabetes, cardiovascular disorders, and other ailments. It is often characterized by hypertension, dyslipidemia and/or obesity, and hyperglycemia. Chemical investigation of Aeonium arboreum (L.) Webb & Berthel led [...] Read more.
Metabolic syndrome (MetS) is a global issue affecting over a billion people, raising the risk of diabetes, cardiovascular disorders, and other ailments. It is often characterized by hypertension, dyslipidemia and/or obesity, and hyperglycemia. Chemical investigation of Aeonium arboreum (L.) Webb & Berthel led to the isolation of six compounds, viz. β-sitosterol, β-sitosterol glucoside, myricetin galactoside, quercetin rhamnoside, kaempferol rhamnoside, and myricetin glucoside. Interestingly, A. arboreum’s dichloromethane (DCM), 100 and 50% MeOH Diaion fractions and the isolated compound (quercetin-3-rhamnoside) revealed potent α-glucosidase inhibitory activity, especially 50% Diaion fraction. In addition, they also showed very potent antioxidant potential, especially the polar fractions, using DPPH, ABTS, FRAP, ORAC, and metal chelation assays. Notably, the 50% Diaion fraction had the highest antioxidant potential using DPPH and ORAC assays, while the 100% Diaion fraction and quercetin-3-rhamnoside showed the highest activity using ABTS, FRAP, and metal chelation assays. Also, quercetin-3-rhamnoside showed a good docking score of −5.82 kcal/mol in comparison to acarbose. In addition, molecular dynamic stimulation studies illustrated high stability of compound binding to pocket of protein. Such potent activities present A. arboreum as a complementary safe approach for the management of diabetes mellitus as well as MetS. Full article
(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)
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<p>Scheme for <span class="html-italic">A. arboreum</span> extraction, fractionation, and isolation of compounds.</p> Full article ">Figure 2
<p>Chemical composition of isolated <span class="html-italic">A. arboreum</span> compounds.</p> Full article ">Figure 3
<p>Antioxidant potential (DPPH (2,2-Diphenyl-1-picrylhydrazyl), ABTS (2,2′-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), FRAP (Ferric Reducing Antioxidant Power), ORAC (Oxygen Radical Absorbance Capacity), and metal chelation) of plant fractions (Total MeOH extract, DCM (Dichloromethane) Fraction, 100% and 50% Diaion fractions) and quercetin-3-rhamnoside. **** Significantly different at <span class="html-italic">p</span> &lt; 0.0001, ***/**/* significantly different at <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 4
<p>Two-dimensional interactions of acarbose with hMGAM (human intestinal maltase-glucoamylase α-glucosidase enzyme).</p> Full article ">Figure 5
<p>Redocking of acarbose showing perfect superimposition.</p> Full article ">Figure 6
<p>The 2D and 3D interactions of quercetin rhamnoside with the key amino acids of hMGAM (human intestinal maltase-glucoamylase α-glucosidase enzyme).</p> Full article ">Figure 6 Cont.
<p>The 2D and 3D interactions of quercetin rhamnoside with the key amino acids of hMGAM (human intestinal maltase-glucoamylase α-glucosidase enzyme).</p> Full article ">Figure 7
<p>Quercetin rhamnoside/hMGAM complex molecular dynamics simulation via the iMODS server. Deformability, B-factor values, eigenvalues, and covariance model are listed in order from (<b>A</b>–<b>D</b>).</p> Full article ">Figure 7 Cont.
<p>Quercetin rhamnoside/hMGAM complex molecular dynamics simulation via the iMODS server. Deformability, B-factor values, eigenvalues, and covariance model are listed in order from (<b>A</b>–<b>D</b>).</p> Full article ">Figure 8
<p>Representation of Swiss-ADME results of quercetin rhamnoside.</p> Full article ">
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