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Pharmaceutics
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Advanced Pharmaceutical Science and Technology in Israel
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Advanced Pharmaceutical Science and Technology in Israel

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: 10 January 2025 | Viewed by 12840

Special Issue Editor

Dr. Arik Dahan

E-Mail Website
Guest Editor
Department of Clinical Pharmacology, School of Pharmacy, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
Interests: oral drug absorption; intestinal permeability; drug solubility; drug dissolution; biopharmaceutics classification system (BCS); drug delivery and targeting

Special Issue Information

Dear Colleagues,

In recent decades, pharmaceutical sciences and engineering have undergone rapid growth and development, both globally and in Israel alone. This Special Issue aims to provide an overview of the ongoing progress in this field in Israel. Scientists from academia, the pharma/biotech industry, and healthcare institutions are encouraged to submit research or review articles focused on, but not limited to, drug delivery, drug targeting, preformulation/formulation, biopharmaceutics/pharmacokinetics, nanopharmaceutics, pharmaceutics biotechnology, personalized medicine, and other related topics.

The aim of this Special Issue is to highlight high-quality articles that present exceptional pharmaceutical research performed in Israel, in line with its 75th anniversary. Of particular interest is the presentation of novel results and the establishment of future research directions. Moreover, it is hoped that this Special Issue will contribute to multidisciplinary discussions on these exciting topics and prompt new scientific collaborations, further advancing pharmaceutical sciences and engineering in Israel and globally.

Dr. Arik Dahan
Guest Editor

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

  • drug delivery and targeting
  • drug discovery and development
  • preformulation/formulation
  • biopharmaceutics
  • molecular pharmaceutics
  • pharmacokinetics
  • nanopharmaceutics
  • pharmaceutical biotechnology
  • drug manufacturing sciences
  • material sciences

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Related Special Issue

Published Papers (9 papers)

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Research

11 pages, 4900 KiB  
Communication
Differential Effect of Simulated Microgravity on the Cellular Uptake of Small Molecules
by Odelia Tepper-Shimshon, Nino Tetro, Roa’a Hamed, Natalia Erenburg, Emmanuelle Merquiol, Gourab Dey, Agam Haim, Tali Dee, Noa Duvdevani, Talin Kevorkian, Galia Blum, Eylon Yavin and Sara Eyal
Pharmaceutics 2024, 16(9), 1211; https://doi.org/10.3390/pharmaceutics16091211 - 14 Sep 2024
Viewed by 842
Abstract
The space environment can affect the function of all physiological systems, including the properties of cell membranes. Our goal in this study was to explore the effect of simulated microgravity (SMG) on the cellular uptake of small molecules based on reported microgravity-induced changes [...] Read more.
The space environment can affect the function of all physiological systems, including the properties of cell membranes. Our goal in this study was to explore the effect of simulated microgravity (SMG) on the cellular uptake of small molecules based on reported microgravity-induced changes in membrane properties. SMG was applied to cultured cells using a random-positioning machine for up to three hours. We assessed the cellular accumulation of compounds representing substrates of uptake and efflux transporters, and of compounds not shown to be transported by membrane carriers. Exposure to SMG led to an increase of up to 60% (p < 0.01) in the cellular uptake of efflux transporter substrates, whereas a glucose transporter substrate showed a decrease of 20% (p < 0.05). The uptake of the cathepsin activity-based probe GB123 (MW, 1198 g/mol) was also enhanced (1.3-fold, p < 0.05). Cellular emission of molecules larger than ~3000 g/mol was reduced by up to 50% in SMG (p < 0.05). Our findings suggest that short-term exposure to SMG could differentially affect drug distribution across membranes. Longer exposure to microgravity, e.g., during spaceflight, may have distinct effects on the cellular uptake of small molecules. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Israel)
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12 pages, 2862 KiB  
Article
Development of Clarstatin, a Novel Drug Lead for the Therapy of Autoimmune Uveitis
by Shira Merzbach, Amnon Hoffman, Philip Lazarovici, Chaim Gilon and Radgonde Amer
Pharmaceutics 2024, 16(6), 723; https://doi.org/10.3390/pharmaceutics16060723 - 27 May 2024
Viewed by 905
Abstract
We describe the design, synthesis, and activity of a potent thiourea-bridged backbone cyclic peptidomimetic known as Clarstatin, comprising a 5-amino acid sequence (Q/D)1-(R/K)2-X3-X4-A5-(Gln/Asp)1-(Arg/Lys)2-AA3-AA4-Ala5-based [...] Read more.
We describe the design, synthesis, and activity of a potent thiourea-bridged backbone cyclic peptidomimetic known as Clarstatin, comprising a 5-amino acid sequence (Q/D)1-(R/K)2-X3-X4-A5-(Gln/Asp)1-(Arg/Lys)2-AA3-AA4-Ala5-based on a motif called “shared epitope (SE)”, specifically present in specific alleles of the HLA-DRB1 gene. This SE binds to a particular site within the proline reach domain (P-domain) of the cell surface-calreticulin (CS-CRT). CS-CRT is a multifunctional endoplasmic reticulum (ER) calcium-binding protein that is located on the cell surface of T cells and triggers innate immune signaling, leading to the development of inflammatory autoimmune diseases. The development of Clarstatin was based on the parent peptide W-G-D1-K2-S3-G4-A5- derived from the active region of the SE. Following the design based on the cycloscan method, the synthesis of Clarstatin was performed by the Fmoc solid phase peptide synthesis (SPPS) method, purified by HPLC to 96% homogeneity, and its structure was confirmed by LC-MS. Clarstatin reduced calcium levels in Jurkat lymphocyte cultures, ameliorated uveitis in vivo in the experimental autoimmune uveitis (EAU) mice model, and was safe upon acute toxicity evaluation. These findings identify Clarstatin as a promising lead compound for future drug development as a novel class of therapeutic agents in the therapy of uveitis. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Israel)
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14 pages, 2287 KiB  
Communication
Safety of Repeated Administration of Xenogeneic Human Apoptotic State (Allocetra-OTS) in Sprague Dawley Rats
by Chen Ankri, Oren Hershkovitz, Liat Hershkovitz, Meital Brami, Ronnie Levy, Hadar Sarig, Einat Souli, Barak Reicher, Veronique Amor-Baroukh, Dror Mevorach and Abraham Nyska
Pharmaceutics 2024, 16(3), 426; https://doi.org/10.3390/pharmaceutics16030426 - 20 Mar 2024
Viewed by 1122
Abstract
Apoptotic cells possess immunomodulatory effects that can be utilized to treat imbalanced immune conditions. Information on the preclinical safety of such treatment is sparse. In this study, the safety of apoptotic cells (Allocetra-OTS) was assessed in a GLP toxicological study on Sprague Dawley [...] Read more.
Apoptotic cells possess immunomodulatory effects that can be utilized to treat imbalanced immune conditions. Information on the preclinical safety of such treatment is sparse. In this study, the safety of apoptotic cells (Allocetra-OTS) was assessed in a GLP toxicological study on Sprague Dawley rats. Three doses of Allocetra-OTS or vehicle were administered intravenously (IV) for 3 consecutive days. Animals in the main study were sacrificed on day 4, while animals from the recovery groups were kept for 14 or 28 days. Allocetra-OTS was well tolerated, and no adverse effects were observed in terms of body weight, clinical signs, food consumption, or ophthalmologic observation. Thus, the No Observed Adverse Effect Level (NOAEL) dose was determined as the highest dose administered. An observed elevation in immune cells was suspected to be due to Allocetra-OTS, similarly to other clinical chemistry parameters; however, it was resolved in the recovery phases. Splenomegaly and dose-related extramedullary hematopoiesis (EMH) in the red pulp were observed, with no adverse events, and were considered to be a normal and expected reaction following the IV administration of cell-based therapies. In conclusion, under the conditions of this study, Allocetra-OTS was concluded to be safe, further supporting its potential candidacy for clinical studies. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Israel)
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13 pages, 2134 KiB  
Article
The Complexity of Bariatric Patient’s Pharmacotherapy: Sildenafil Biopharmaceutics and Pharmacokinetics before vs. after Gastric Sleeve/Bypass
by Daniel Porat, Oleg Dukhno, Sandra Cvijić and Arik Dahan
Pharmaceutics 2023, 15(12), 2795; https://doi.org/10.3390/pharmaceutics15122795 - 18 Dec 2023
Viewed by 1680
Abstract
Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is [...] Read more.
Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1–5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Israel)
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16 pages, 4033 KiB  
Article
Assessment of Bioprotect’s Biodegradable Balloon System as a Rectal Spacer in Radiotherapy: An Animal Study on Tissue Response and Biocompatibility
by Yuval Ramot, Tal Levin-Harrus, Adva Ezratty, Michal Steiner, Nati Ezov, Abraham J. Domb, Muhammad Abdel-Haq, Shaul Shohat, Liron Aperman, Lee Adler, Oleg Dolkart and Abraham Nyska
Pharmaceutics 2023, 15(12), 2744; https://doi.org/10.3390/pharmaceutics15122744 - 7 Dec 2023
Viewed by 1178
Abstract
Prostate cancer is a significant health concern for men, emphasizing the need for effective treatment strategies. Dose-escalated external beam radiotherapy shows promise in improving outcomes but presents challenges due to radiation effects on nearby structures, such as the rectum. Innovative techniques, including rectal [...] Read more.
Prostate cancer is a significant health concern for men, emphasizing the need for effective treatment strategies. Dose-escalated external beam radiotherapy shows promise in improving outcomes but presents challenges due to radiation effects on nearby structures, such as the rectum. Innovative techniques, including rectal spacers, have emerged to mitigate these effects. This study comprehensively assessed tissue responses following the implantation of the Bioprotect biodegradable fillable balloon as a rectal spacer in a rat model. Evaluation occurred at multiple time points (4, 26, and 52 weeks) post-implantation. Results revealed localized tissue responses consistent with the expected reaction to biodegradable materials, characterized by mild to moderate fibrotic reactions and encapsulation, underscoring the safety and biocompatibility of the balloon. Importantly, no other adverse events occurred, and the animals remained healthy throughout the study. These findings support its potential clinical utility in radiotherapy treatments to enhance patient outcomes and minimize long-term implant-related complications, serving as a benchmark for future similar studies and offering valuable insights for researchers in the field. In conclusion, the findings from this study highlight the safety, biocompatibility, and potential clinical applicability of the Bioprotect biodegradable fillable balloon as a promising rectal spacer in mitigating radiation-induced complications during prostate cancer radiotherapy. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Israel)
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14 pages, 5394 KiB  
Article
A Multivariate Meta-Analysis for Optimizing Cell Counts When Using the Mechanical Processing of Lipoaspirate for Regenerative Applications
by Gershon Zinger, Nia Kepes, Ron Kenett, Amos Peyser and Racheli Sharon-Gabbay
Pharmaceutics 2023, 15(12), 2737; https://doi.org/10.3390/pharmaceutics15122737 - 6 Dec 2023
Viewed by 1259
Abstract
Lipoaspirate has become the preferred source for regenerative cells. The mechanical processing of lipoaspirate has advantages over enzymatic processing but has a lower yield of regenerative cells. A review of the literature shows different techniques of extraction, but the ideal method or combination [...] Read more.
Lipoaspirate has become the preferred source for regenerative cells. The mechanical processing of lipoaspirate has advantages over enzymatic processing but has a lower yield of regenerative cells. A review of the literature shows different techniques of extraction, but the ideal method or combination has not been determined. Methods: A comprehensive literature search was focused on the mechanical processing of lipoaspirate, without the use of enzymes. Data from the articles were integrated by utilizing a multivariate meta-analysis approach and used to create a statistical-based predictive model for a combination of multiple variables. Results: Starting with 10,000 titles, 159 articles were reviewed, and 6 met the criteria for inclusion and exclusion. The six studies included data on 117 patients. Sixteen factors were analyzed and six were identified as significant. The predictive profilers indicated that the optimal combination to maximize the cell yield was: a centrifuge force of 2000× g, a centrifuge time of 10 min, a cannula diameter of 2 mm, and an intra-syringe number of passes of 30. The optimal patient factors were a higher BMI and younger age. Conclusions: The novelty of the method used here was in combining data across different studies to understand the effect of the individual factors and in the optimization of their combination for mechanical lipoaspirate processing. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Israel)
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19 pages, 5625 KiB  
Article
Towards Effective Antiviral Oral Therapy: Development of a Novel Self-Double Emulsifying Drug Delivery System for Improved Zanamivir Intestinal Permeability
by Sapir Ifrah, Arik Dahan and Nir Debotton
Pharmaceutics 2023, 15(10), 2518; https://doi.org/10.3390/pharmaceutics15102518 - 23 Oct 2023
Cited by 1 | Viewed by 1627
Abstract
Self-double emulsifying drug delivery systems have the potential to enhance the intestinal permeability of drugs classified under the Biopharmaceutics Classification System (BCS) class III. One such example is the antiviral agent zanamivir, exhibiting suboptimal oral absorption (with a bioavailability range of 1–5%). To [...] Read more.
Self-double emulsifying drug delivery systems have the potential to enhance the intestinal permeability of drugs classified under the Biopharmaceutics Classification System (BCS) class III. One such example is the antiviral agent zanamivir, exhibiting suboptimal oral absorption (with a bioavailability range of 1–5%). To address this challenge, we have developed an innovative oral formulation for zanamivir: a self-double nanoemulsifying Winsor delivery system (SDNE-WDS) consisting of the microemulsion, which subsequently yields final double nanoemulsion (W1/O/W2) upon interaction with water. Two distinct formulations were prepared: SDNE-WDS1, classified as a W/O microemulsion, and SDNE-WDS2, discovered to be a bicontinuous microemulsion. The inner microemulsions displayed a consistent radius of gyration, with an average size of 35.1 ± 2.1 nm. Following self-emulsification, the resultant zanamivir-loaded nanoemulsion droplets for zSDNE-WDS1 and zSDNE-WDS2 measured 542.1 ± 36.1 and 174.4 ± 3.4 nm, respectively. Both types of emulsions demonstrated the ability to enhance the transport of zanamivir across a parallel artificial membrane. Additionally, in situ rat intestinal perfusion studies involving drug-loaded SDNE-WDSs revealed a significantly increased permeability of zanamivir through the small intestinal wall. Notably, both SDNE-WDS formulations exhibited effective permeability (Peff) values that were 3.5–5.5-fold higher than those of the low/high permeability boundary marker metoprolol. This research emphasizes the success of SDNE-WDSs in overcoming intestinal permeability barriers and enabling the effective oral administration of zanamivir. These findings hold promise for advancing the development of efficacious oral administration of BCS class III drugs. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Israel)
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12 pages, 3906 KiB  
Article
Controlling Microparticle Morphology in Melt-Jet Printing of Active Pharmaceutical Ingredients through Surface Phenomena
by Shachar Bornstein, Almog Uziel and Dan Y. Lewitus
Pharmaceutics 2023, 15(8), 2026; https://doi.org/10.3390/pharmaceutics15082026 - 26 Jul 2023
Viewed by 1288
Abstract
Achieving homogeneity and reproducibility in the size, shape, and morphology of active pharmaceutical ingredient (API) particles is crucial for their successful manufacturing and performance. Herein, we describe a new method for API particle engineering using melt-jet printing technology as an alternative to the [...] Read more.
Achieving homogeneity and reproducibility in the size, shape, and morphology of active pharmaceutical ingredient (API) particles is crucial for their successful manufacturing and performance. Herein, we describe a new method for API particle engineering using melt-jet printing technology as an alternative to the current solvent-based particle engineering methods. Paracetamol, a widely used API, was melted and jetted as droplets onto various surfaces to solidify and form microparticles. The influence of different surfaces (glass, aluminum, polytetrafluoroethylene, and polyethylene) on particle shape was investigated, revealing a correlation between substrate properties (heat conduction, surface energy, and roughness) and particle sphericity. Higher thermal conductivity, surface roughness, and decreased surface energy contributed to larger contact angles and increased sphericity, reaching a near-perfect micro-spherical shape on an aluminum substrate. The integrity and polymorphic form of the printed particles were confirmed through differential scanning calorimetry and X-ray diffraction. Additionally, high-performance liquid chromatography analysis revealed minimal degradation products. The applicability of the printing process to other APIs was demonstrated by printing carbamazepine and indomethacin on aluminum surfaces, resulting in spherical microparticles. This study emphasizes the potential of melt-jet printing as a promising approach for the precise engineering of pharmaceutical particles, enabling effective control over their physiochemical properties. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Israel)
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17 pages, 2472 KiB  
Article
Cannabidiol-Loaded Nanoparticles Based on Crosslinked Starch: Anti-Inflammatory Activity and Improved Nose-to-Brain Delivery
by Ilya Eydelman, Na’ama Zehavi, Valeria Feinshtein, Dinesh Kumar, Shimon Ben-Shabat and Amnon C. Sintov
Pharmaceutics 2023, 15(7), 1803; https://doi.org/10.3390/pharmaceutics15071803 - 23 Jun 2023
Cited by 3 | Viewed by 1739
Abstract
Cannabidiol (CBD) has previously been shown to inhibit inflammatory cytokine production in both in vitro and in vivo studies of neurodegenerative diseases. To date, the CBD treatment of these diseases by quantitative targeting directly to the brain is one of the greatest challenges. [...] Read more.
Cannabidiol (CBD) has previously been shown to inhibit inflammatory cytokine production in both in vitro and in vivo studies of neurodegenerative diseases. To date, the CBD treatment of these diseases by quantitative targeting directly to the brain is one of the greatest challenges. In this paper, we present a new particulate system capable of delivering CBD into the brain via the intranasal route. Intranasal administration of CBD-loaded starch nanoparticles resulted in higher levels of cannabidiol in the brain compared to an identically administered cannabidiol solution. The production and the characterization of starch-based nanoparticles was reported, as well as the evaluation of their penetration and anti-inflammatory activity in cells. Cannabidiol-loaded starch nanoparticles were prepared by crosslinking with divanillin, using the nanoprecipitation method. Evaluation of the anti-inflammatory activity in vitro was performed using the BV2 microglia cell line. The starch nanoparticles appeared under electron microscopy in clusters sized approximately 200 nm in diameter. In cultures of lipopolysaccharide-induced inflamed BV2 cells, the cannabidiol-loaded starch nanoparticles demonstrated low toxicity while effectively reducing nitric oxide production and IL-6 levels. The anti-inflammatory effect was comparable to that of a glucocorticoid. Starch-based nanoparticle formulations combined with intranasal administration may provide a suitable platform for efficacious cannabidiol delivery and activity in the central nervous system. Full article
(This article belongs to the Special Issue Advanced Pharmaceutical Science and Technology in Israel)
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