Pharmaceutics

22 pages, 6720 KiB

Open AccessEditor’s ChoiceArticle

Archaeosomes for Oral Drug Delivery: From Continuous Microfluidics Production to Powdered Formulations

by Ivan Vidakovic, Karin Kornmueller, Daniela Fiedler, Johannes Khinast, Eleonore Fröhlich, Gerd Leitinger, Christina Horn, Julian Quehenberger, Oliver Spadiut and Ruth Prassl

Pharmaceutics 2024, 16(6), 694; https://doi.org/10.3390/pharmaceutics16060694 - 23 May 2024

Cited by 1 | Viewed by 1153

Abstract

Archaeosomes were manufactured from natural archaeal lipids by a microfluidics-assisted single-step production method utilizing a mixture of di- and tetraether lipids extracted from Sulfolobus acidocaldarius. The primary aim of this study was to investigate the exceptional stability of archaeosomes as potential carriers for [...] Read more.

Archaeosomes were manufactured from natural archaeal lipids by a microfluidics-assisted single-step production method utilizing a mixture of di- and tetraether lipids extracted from Sulfolobus acidocaldarius. The primary aim of this study was to investigate the exceptional stability of archaeosomes as potential carriers for oral drug delivery, with a focus on powdered formulations. The archaeosomes were negatively charged with a size of approximately 100 nm and a low polydispersity index. To assess their suitability for oral delivery, the archaeosomes were loaded with two model drugs: calcein, a fluorescent compound, and insulin, a peptide hormone. The archaeosomes demonstrated high stability in simulated intestinal fluids, with only 5% of the encapsulated compounds being released after 24 h, regardless of the presence of degrading enzymes or extremely acidic pH values such as those found in the stomach. In a co-culture cell model system mimicking the intestinal barrier, the archaeosomes showed strong adhesion to the cell membranes, facilitating a slow release of contents. The archaeosomes were loaded with insulin in a single-step procedure achieving an encapsulation efficiency of approximately 35%. These particles have been exposed to extreme manufacturing temperatures during freeze-drying and spray-drying processes, demonstrating remarkable resilience under these harsh conditions. The fabrication of stable dry powder formulations of archaeosomes represents a promising advancement toward the development of solid dosage forms for oral delivery of biological drugs. Full article

(This article belongs to the Special Issue Advances in Oral Administration)

► Show Figures

Graphical abstract

13 pages, 1872 KiB

Open AccessEditor’s ChoiceArticle

Population Pharmacokinetic Analysis and Simulation of Alternative Dosing Regimens for Biosimilars to Adalimumab and Etanercept in Patients with Rheumatoid Arthritis

by Stephanie F. Ling, Kayode Ogungbenro, Adam S. Darwich, Amirah Binti Mohammad Ariff, Nisha Nair, James Bluett, Ann W. Morgan, John D. Isaacs, Anthony G. Wilson, Kimme L. Hyrich, Anne Barton and Darren Plant

Pharmaceutics 2024, 16(6), 702; https://doi.org/10.3390/pharmaceutics16060702 - 23 May 2024

Viewed by 1170

Abstract

Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient’s circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to [...] Read more.

Efficacy to biologics in rheumatoid arthritis (RA) patients is variable and is likely influenced by each patient’s circulating drug levels. Using modelling and simulation, the aim of this study was to investigate whether adalimumab and etanercept biosimilar dosing intervals can be altered to achieve therapeutic drug levels at a faster/similar time compared to the recommended interval. RA patients starting subcutaneous Amgevita or Benepali (adalimumab and etanercept biosimilars, respectively) were recruited and underwent sparse serum sampling for drug concentrations. Drug levels were measured using commercially available kits. Pharmacokinetic data were analysed using a population approach (popPK) and potential covariates were investigated in models. Models were compared using goodness-of-fit criteria. Final models were selected and used to simulate alternative dosing intervals. Ten RA patients starting the adalimumab biosimilar and six patients starting the etanercept biosimilar were recruited. One-compartment PK models were used to describe the popPK models for both drugs; no significant covariates were found. Typical individual parameter estimates were used to simulate altered dosing intervals for both drugs. A simulation of dosing the etanercept biosimilar at a lower rate of every 10 days reached steady-state concentrations earlier than the usual dosing rate of every 7 days. Simulations of altered dosing intervals could form the basis for future personalised dosing studies, potentially saving costs whilst increasing efficacy. Full article

(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)

► Show Figures

Figure 1

17 pages, 13618 KiB

Open AccessEditor’s ChoiceArticle

Cytotoxic and Immunomodulatory Effects of Hypericin as a Photosensitizer in Photodynamic Therapy Used on Skin Cell Cultures

by Magdalena Krupka-Olek, Andrzej Bożek, Zenon P. Czuba, Małgorzata Kłósek, Grzegorz Cieślar and Aleksandra Kawczyk-Krupka

Pharmaceutics 2024, 16(6), 696; https://doi.org/10.3390/pharmaceutics16060696 - 23 May 2024

Viewed by 1122

Abstract

Determination of the hypericin–photodynamic (HY–PDT) effect on the secretion of cytokines secreted by the skin cells, may be the basis for using the immunomodulatory effect of photodynamic action in the treatment of inflammatory skin diseases. The study aimed to evaluate the cytotoxic and [...] Read more.

Determination of the hypericin–photodynamic (HY–PDT) effect on the secretion of cytokines secreted by the skin cells, may be the basis for using the immunomodulatory effect of photodynamic action in the treatment of inflammatory skin diseases. The study aimed to evaluate the cytotoxic and immunomodulatory effects of hypericin (HY) in photodynamic therapy (PDT) performed in vitro on cultures of selected skin cell lines. The study used two human cell lines, primary dermal fibroblast (HDFa) and primary epidermal keratinocytes (HEKa). The MTT test was used to define the metabolic activity of treated cells. Cell supernatants subjected to sublethal PDT were assessed to determine the interleukins: IL-2, IL-8, IL-10, IL-11, IL-19, IL-22, and metalloproteinase 1 (MMP-1). The results confirm the destructive effect of HY–PDT and the immunomodulatory effects of sublethal doses on the selected skin cells, depending on the concentration of HY and the light doses. No statistically significant differences were noted in IL-2 and IL-10 concentration after HY–PDT for HEKa and HDFa lines. After using HY–PDT, the concentration of IL-8, MMP-1, IL-22, and IL-11 significantly decreased in the HEKa line. Moreover, the concentration of IL-19 and MMP-1 significantly decreased in the HDFa line. The concentration of IL-11 in the HDFa line after using only the HY, without the light, increased but decreased after HY–PDT. Our experiment confirmed that HY–PDT has not only a cytotoxic effect but, used in sublethal doses, also presents immunomodulatory properties. These may be an advantage of HY–PDT when used in the treatment of persistent skin inflammation, connected with the release of pro-inflammatory cytokines resistant to conventional treatment methods. Full article

(This article belongs to the Special Issue Natural Products in Photodynamic Therapy)

► Show Figures

Figure 1

23 pages, 1109 KiB

Open AccessEditor’s ChoiceReview

Emerging Trends in Bilosomes as Therapeutic Drug Delivery Systems

by Hemlata Kaurav, Meenakshi Tripathi, Simran Deep Kaur, Amit Bansal, Deepak N. Kapoor and Sandeep Sheth

Pharmaceutics 2024, 16(6), 697; https://doi.org/10.3390/pharmaceutics16060697 - 23 May 2024

Cited by 3 | Viewed by 2014

Abstract

In recent years, there has been a notable surge in the utilization of stabilized bile acid liposomes, chemical conjugates, complexes, mixed micelles, and other drug delivery systems derived from bile acids, often referred to as bilosomes. The molecular structure and interactions of these [...] Read more.

In recent years, there has been a notable surge in the utilization of stabilized bile acid liposomes, chemical conjugates, complexes, mixed micelles, and other drug delivery systems derived from bile acids, often referred to as bilosomes. The molecular structure and interactions of these amphiphilic compounds provide a distinctive and captivating subject for investigation. The enhanced stability of new generation bilosomes inside the gastrointestinal system results in the prevention of drug degradation and an improvement in mucosal penetration. These characteristics render bilosomes to be a prospective nanocarrier for pharmaceutical administration, prompting researchers to investigate their potential in other domains. This review paper discusses bilosomes that have emerged as a viable modality in the realm of drug delivery and have significant promise for use across several domains. Moreover, this underscores the need for additional investigation and advancement in order to comprehensively comprehend the prospective uses of bilosomes and their effectiveness in the field of pharmaceutical administration. This review study explores the current scholarly attention on bilosomes as prospective carriers for drug delivery. Therapeutic areas where bilosomes have shown outstanding performance in terms of drug delivery are outlined in the graphical abstract. Full article

(This article belongs to the Special Issue The 15th Anniversary of Pharmaceutics—Advances and Future Trends in Drug Delivery)

► Show Figures

Graphical abstract

37 pages, 4780 KiB

Open AccessEditor’s ChoiceReview

Unlocking the Potential of Oleanolic Acid: Integrating Pharmacological Insights and Advancements in Delivery Systems

by Muhammad Wasim and Maria Camilla Bergonzi

Pharmaceutics 2024, 16(6), 692; https://doi.org/10.3390/pharmaceutics16060692 - 21 May 2024

Cited by 5 | Viewed by 1524

Abstract

The growing interest in oleanolic acid (OA) as a triterpenoid with remarkable health benefits prompts an emphasis on its efficient use in pharmaceutical research. OA exhibits a range of pharmacological effects, including antidiabetic, anti-inflammatory, immune-enhancing, gastroprotective, hepatoprotective, antitumor, and antiviral properties. While OA [...] Read more.

The growing interest in oleanolic acid (OA) as a triterpenoid with remarkable health benefits prompts an emphasis on its efficient use in pharmaceutical research. OA exhibits a range of pharmacological effects, including antidiabetic, anti-inflammatory, immune-enhancing, gastroprotective, hepatoprotective, antitumor, and antiviral properties. While OA demonstrates diverse pharmacological effects, optimizing its therapeutic potential requires overcoming significant challenges. In the field of pharmaceutical research, the exploration of efficient drug delivery systems is essential to maximizing the therapeutic potential of bioactive compounds. Efficiently delivering OA faces challenges, such as poor aqueous solubility and restricted bioavailability, and to unlock its full therapeutic efficacy, novel formulation strategies are imperative. This discussion thoroughly investigates different approaches and advancements in OA drug delivery systems with the aim of enhancing the biopharmaceutical features and overall efficacy in diverse therapeutic contexts. Full article

(This article belongs to the Special Issue Novel Drug Delivery Systems of Phytomedicines)

► Show Figures

Figure 1

16 pages, 4439 KiB

Open AccessEditor’s ChoiceArticle

Fabrication of Ciprofloxacin-Loaded Sodium Alginate Nanobeads Coated with Thiol-Anchored Chitosan Using B-390 Encapsulator Following Optimization by DoE

by Mahwash Mukhtar, Ildikó Csóka, Josipa Martinović, Gordana Šelo, Ana Bucić-Kojić, László Orosz, Dóra Paróczai, Katalin Burian and Rita Ambrus

Pharmaceutics 2024, 16(6), 691; https://doi.org/10.3390/pharmaceutics16060691 - 21 May 2024

Viewed by 1392

Abstract

Most infectious diseases of the gastrointestinal tract can easily be treated by exploiting the already available antibiotics with the change in administration approach and delivery system. Ciprofloxacin (CIP) is used as a drug of choice for many bacterial infections; however, long-term therapy and [...] Read more.

Most infectious diseases of the gastrointestinal tract can easily be treated by exploiting the already available antibiotics with the change in administration approach and delivery system. Ciprofloxacin (CIP) is used as a drug of choice for many bacterial infections; however, long-term therapy and off-site drug accumulation lead to an increased risk of tendinitis and peripheral neuropathy. To overcome this issue, nanotechnology is being exploited to encapsulate antibiotics within polymeric structures, which not only facilitates dose maintenance at the infection site but also limits off-site side effects. Here, sodium alginate (SA) and thiol-anchored chitosan (TC) were used to encapsulate CIP via a calcium chloride (CaCl₂) cross-linker. For this purpose, the B-390 encapsulator was employed in the preparation of nanobeads using a simple technique. The hydrogel-like sample was then freeze-dried, using trehalose or mannitol as a lyoprotectant, to obtain a fine dry powder. Design of Experiment (DoE) was utilized to optimize the nanobead production, in which the influence of different independent variables was studied for their outcome on the polydispersity index (PDI), particle size, zeta potential, and percentage encapsulation efficiency (% EE). In vitro dissolution studies were performed in simulated saliva fluid, simulated gastric fluid, and simulated intestinal fluid. Antibacterial and anti-inflammatory studies were also performed along with cytotoxicity profiling. By and large, the study presented positive outcomes, proving the advantage of using nanotechnology in fabricating new delivery approaches using already available antibiotics. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Chitosan in Biomedicine: Current Status, Future Perspectives and Challenges)

► Show Figures

Figure 1

22 pages, 5653 KiB

Open AccessEditor’s ChoiceArticle

Effects of Nozzle Retraction Elimination on Spray Distribution in Middle-Posterior Turbinate Regions: A Comparative Study

by Amr Seifelnasr, Xiuhua Si and Jinxiang Xi

Pharmaceutics 2024, 16(5), 683; https://doi.org/10.3390/pharmaceutics16050683 - 19 May 2024

Cited by 1 | Viewed by 994

Abstract

The standard multi-dose nasal spray pump features an integrated actuator and nozzle, which inevitably causes a retraction of the nozzle tip during application. The retraction stroke is around 5.5 mm and drastically reduces the nozzle’s insertion depth, which further affects the initial nasal [...] Read more.

The standard multi-dose nasal spray pump features an integrated actuator and nozzle, which inevitably causes a retraction of the nozzle tip during application. The retraction stroke is around 5.5 mm and drastically reduces the nozzle’s insertion depth, which further affects the initial nasal spray deposition and subsequent translocation, potentially increasing drug wastes and dosimetry variability. To address this issue, we designed a new spray pump that separated the nozzle from the actuator and connected them with a flexible tube, thereby eliminating nozzle retraction during application. The objective of this study is to test the new device’s performance in comparison to the conventional nasal pump in terms of spray generation, plume development, and dosimetry distribution. For both devices, the spray droplet size distribution was measured using a laser diffraction particle analyzer. Plume development was recorded with a high-definition camera. Nasal dosimetry was characterized in two transparent nasal cavity casts (normal and decongested) under two breathing conditions (breath-holding and constant inhalation). The nasal formulation was a 0.25% w/v methyl cellulose aqueous solution with a fluorescent dye. For each test case, the temporospatial spray translocation in the nasal cavity was recorded, and the final delivered doses were quantified in five nasal regions. The results indicate minor differences in droplet size distribution between the two devices. The nasal plume from the new device presents a narrower plume angle. The head orientation, the depth at which the nozzle is inserted into the nostril, and the administration angle play crucial roles in determining the initial deposition of nasal sprays as well as the subsequent translocation of the liquid film/droplets. Quantitative measurements of deposition distributions in the nasal models were augmented with visualization recordings to evaluate the delivery enhancements introduced by the new device. With an extension tube, the modified device produced a lower spray output and delivered lower doses in the front, middle, and back turbinate than the conventional nasal pump. However, sprays from the new device were observed to penetrate deeper into the nasal passages, predominantly through the middle-upper meatus. This resulted in consistently enhanced dosing in the middle-upper turbinate regions while at the cost of higher drug loss to the pharynx. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration, 2nd Edition)

► Show Figures

Figure 1

13 pages, 604 KiB

Open AccessEditor’s ChoicePerspective

Therapeutic Drug Monitoring and Biomarkers; towards Better Dosing of Antimicrobial Therapy

by Eman Wehbe, Asad E. Patanwala, Christine Y. Lu, Hannah Yejin Kim, Sophie L. Stocker and Jan-Willem C. Alffenaar

Pharmaceutics 2024, 16(5), 677; https://doi.org/10.3390/pharmaceutics16050677 - 17 May 2024

Viewed by 1353

Abstract

Due to variability in pharmacokinetics and pharmacodynamics, clinical outcomes of antimicrobial drug therapy vary between patients. As such, personalised medication management, considering both pharmacokinetics and pharmacodynamics, is a growing concept of interest in the field of infectious diseases. Therapeutic drug monitoring is used [...] Read more.

Due to variability in pharmacokinetics and pharmacodynamics, clinical outcomes of antimicrobial drug therapy vary between patients. As such, personalised medication management, considering both pharmacokinetics and pharmacodynamics, is a growing concept of interest in the field of infectious diseases. Therapeutic drug monitoring is used to adjust and individualise drug regimens until predefined pharmacokinetic exposure targets are achieved. Minimum inhibitory concentration (drug susceptibility) is the best available pharmacodynamic parameter but is associated with many limitations. Identification of other pharmacodynamic parameters is necessary. Repurposing diagnostic biomarkers as pharmacodynamic parameters to evaluate treatment response is attractive. When combined with therapeutic drug monitoring, it could facilitate making more informed dosing decisions. We believe the approach has potential and justifies further research. Full article

(This article belongs to the Special Issue Therapeutic Drug Monitoring and Pharmacokinetics-Based Individualization of Drug Therapy, 2nd Edition)

► Show Figures

Figure 1

11 pages, 1641 KiB

Open AccessEditor’s ChoiceArticle

Suitable Promoter for DNA Vaccination Using a pDNA Ternary Complex

by Tomoaki Kurosaki, Hiroki Nakamura, Hitoshi Sasaki and Yukinobu Kodama

Pharmaceutics 2024, 16(5), 679; https://doi.org/10.3390/pharmaceutics16050679 - 17 May 2024

Cited by 1 | Viewed by 1087

Abstract

In this study, we evaluated the effect of several promoters on the transfection activity and immune-induction efficiency of a plasmid DNA (pDNA)/polyethylenimine/γ-polyglutamic acid complex (pDNA ternary complex). Model pDNAs encoding firefly luciferase (Luc) were constructed with several promoters, such as simian virus 40 [...] Read more.

In this study, we evaluated the effect of several promoters on the transfection activity and immune-induction efficiency of a plasmid DNA (pDNA)/polyethylenimine/γ-polyglutamic acid complex (pDNA ternary complex). Model pDNAs encoding firefly luciferase (Luc) were constructed with several promoters, such as simian virus 40 (SV40), eukaryotic elongation factor 1 alpha (EF1), cytomegalovirus (CMV), and chicken beta actin hybrid (CBh) (pSV40-Luc, pEF1-Luc, pCMV-Luc, and pCBh-Luc, respectively). Four types of pDNA ternary complexes, each with approximately 145-nm particle size and −30-mV ζ-potential, were stably constructed. The pDNA ternary complex containing pSV40-Luc showed low gene expression, but the other complexes containing pEF1-Luc, pCMV-Luc, and pCBh-Luc showed high gene expression in DC2.4 cells and spleen after intravenous administration. After immunization using various pDNA encoding ovalbumin (OVA) such as pEF1-OVA, pCMV-OVA, and pCBh-OVA, only the pDNA ternary complex containing pCBh-OVA showed significant anti-OVA immunoglobulin G (IgG) induction. In conclusion, our results showed that the CBh promoter is potentially suitable for use in pDNA ternary complex-based DNA vaccination. Full article

(This article belongs to the Special Issue Plasmid DNA for Gene Therapy and DNA Vaccine Applications, 2nd Edition)

► Show Figures

Figure 1

15 pages, 23424 KiB

Open AccessEditor’s ChoiceArticle

The Proteasome Inhibitor CEP-18770 Induces Cell Death in Medulloblastoma

by Swastina Nath Varma, Shany Ye, Sara Ferlin, Charley Comer, Kian Cotton and Maria Victoria Niklison-Chirou

Pharmaceutics 2024, 16(5), 672; https://doi.org/10.3390/pharmaceutics16050672 - 16 May 2024

Viewed by 1263

Abstract

Medulloblastomas (MBs) represent the most prevalent malignant solid tumors in kids. The conventional treatment regimen for MBs includes surgical removal of the tumor, followed by radiation and chemotherapy. However, this approach is associated with significant morbidity and detrimental side effects. Consequently, there is [...] Read more.

Medulloblastomas (MBs) represent the most prevalent malignant solid tumors in kids. The conventional treatment regimen for MBs includes surgical removal of the tumor, followed by radiation and chemotherapy. However, this approach is associated with significant morbidity and detrimental side effects. Consequently, there is a critical demand for more precise and less harmful treatments to enhance the quality of life for survivors. CEP-18770, a novel proteasome inhibitor that targets the 20S subunit, has emerged as a promising candidate, due to its anticancer activity in metastatic solid tumors and multiple myeloma, coupled with an acceptable safety profile. In this study, we aimed to assess the anticancer efficacy of CEP-18770 by employing a variety of MB patient-derived cells and cell lines. Our preclinical investigations revealed that CEP-18770 effectively inhibits proteasome activity and induces apoptosis in MBs cells. Furthermore, we discovered that CEP-18770 and cisplatin, a current component of MB therapy, exhibit a synergistic apoptotic effect. This paper shows that CEP-18770 holds potential as an adjunctive treatment for MB tumors, thereby paving the way for more targeted and less toxic therapeutic strategies. Full article

(This article belongs to the Special Issue Brain Tumors Treatment: Current and Future Challenges from Drug Formulations to Delivery Methods)

► Show Figures

Figure 1

27 pages, 5074 KiB

Open AccessEditor’s ChoiceReview

Strategies to Improve the Transdermal Delivery of Poorly Water-Soluble Non-Steroidal Anti-Inflammatory Drugs

by Alexandra Balmanno, James R. Falconer, Halley G. Ravuri and Paul C. Mills

Pharmaceutics 2024, 16(5), 675; https://doi.org/10.3390/pharmaceutics16050675 - 16 May 2024

Cited by 1 | Viewed by 1725

Abstract

The transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) has the potential to overcome some of the major disadvantages relating to oral NSAID usage, such as gastrointestinal adverse events and compliance. However, the poor solubility of many of the newer NSAIDs creates challenges in [...] Read more.

The transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) has the potential to overcome some of the major disadvantages relating to oral NSAID usage, such as gastrointestinal adverse events and compliance. However, the poor solubility of many of the newer NSAIDs creates challenges in incorporating the drugs into formulations suitable for application to skin and may limit transdermal permeation, particularly if the goal is therapeutic systemic drug concentrations. This review is an overview of the various strategies used to increase the solubility of poorly soluble NSAIDs and enhance their permeation through skin, such as the modification of the vehicle, the modification of or bypassing the barrier function of the skin, and using advanced nano-sized formulations. Furthermore, the simple yet highly versatile microemulsion system has been found to be a cost-effective and highly successful technology to deliver poorly water-soluble NSAIDs. Full article

(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Improvement of Drug Bioavailability)

► Show Figures

Figure 1

23 pages, 11650 KiB

Open AccessEditor’s ChoiceArticle

Sweeteners Show a Plasticizing Effect on PVP K30—A Solution for the Hot-Melt Extrusion of Fixed-Dose Amorphous Curcumin-Hesperetin Solid Dispersions

by Kamil Wdowiak, Lidia Tajber, Andrzej Miklaszewski and Judyta Cielecka-Piontek

Pharmaceutics 2024, 16(5), 659; https://doi.org/10.3390/pharmaceutics16050659 - 15 May 2024

Cited by 2 | Viewed by 1329

Abstract

The co-administration of curcumin and hesperetin might be beneficial in terms of neuroprotective activity; therefore, in this study, we attempted to develop a fixed-dose formulation comprising these two compounds in an amorphous state. The aim of obtaining an amorphous state was to overcome [...] Read more.

The co-administration of curcumin and hesperetin might be beneficial in terms of neuroprotective activity; therefore, in this study, we attempted to develop a fixed-dose formulation comprising these two compounds in an amorphous state. The aim of obtaining an amorphous state was to overcome the limitations of the low solubility of the active compounds. First, we assessed the possibility of using popular sweeteners (erythritol, xylitol, and sorbitol) as plasticizers to reduce the glass transition temperature of PVP K30 to prepare the polymer–excipient blends, which allowed the preparation of amorphous solid dispersions via hot-melt extrusion at a temperature below the original glass transition of PVP K30. Erythritol proved to be the superior plasticizer. Then, we focused on the development of fixed-dose amorphous solid dispersions of curcumin and hesperetin. Powder X-ray diffraction and thermal analysis confirmed the amorphous character of dispersions, whereas infrared spectroscopy helped to assess the presence of intermolecular interactions. The amorphous state of the produced dispersions was maintained for 6 months, as shown in a stability study. Pharmaceutical parameters such as dissolution rate, solubility, and in vitro permeability through artificial membranes were evaluated. The best improvement in these features was noted for the dispersion, which contained 15% of the total content of the active compounds with erythritol used as the plasticizer. Full article

(This article belongs to the Special Issue Further Research in Polyphenols Formulations)

► Show Figures

Graphical abstract

20 pages, 3609 KiB

Open AccessEditor’s ChoiceArticle

An Investigation into the Effects of Processing Factors on the Properties and Scaling-Up Potential of Propranolol-Loaded Chitosan Nanogels

by Hei Ming Kenneth Ho, Richard M. Day and Duncan Q. M. Craig

Pharmaceutics 2024, 16(5), 662; https://doi.org/10.3390/pharmaceutics16050662 - 15 May 2024

Viewed by 849

Abstract

Chitosan-triphosphate (TPP) nanogels are widely studied drug delivery carrier systems, typically prepared via a simple mixing process. However, the effects of the processing factors on nanogel production have not been extensively explored, despite the importance of understanding and standardising such factors to allow [...] Read more.

Chitosan-triphosphate (TPP) nanogels are widely studied drug delivery carrier systems, typically prepared via a simple mixing process. However, the effects of the processing factors on nanogel production have not been extensively explored, despite the importance of understanding and standardising such factors to allow upscaling and commercial usage. This study aims to systematically evaluate the effects of various fabrication and processing factors on the properties of nanogels using a Design of Experiment approach. Hydrodynamic size, polydispersity index (PDI), zeta potential, and encapsulation efficiency were determined as the dependent factors. The temperature, stirring rate, chitosan grade, crosslinker choice, and the interaction term between temperature and chitosan grade were found to have a significant effect on the particle size, whereas the effect of temperature and the addition rate of crosslinker on the PDI was also noteworthy. Moreover, the addition rate of the crosslinker and the volume of the reaction vessel were found to impact the encapsulation efficiency. The zeta potential of the nanogels was found to be governed by the chitosan grade. The optimal fabrication conditions for the development of medium molecular weight chitosan and TPP nanogels included the following: the addition rate for TPP solution was set at 2 mL/min, while the solution was then stirred at a temperature of 50 °C and a stirring speed of 600 rpm. The volume of the glass vial used was 28 mL, while the stirrer size was 20 mm. The second aim of the study was to evaluate the potential for scaling up the nanogels. Size and PDI were found to increase from 128 nm to 151 nm and from 0.232 to 0.267, respectively, when the volume of the reaction mixture was increased from 4 to 20 mL and other processing factors were kept unchanged. These results indicate that caution is required when scaling up as the nanogel properties may be significantly altered with an increasing production scale. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

► Show Figures

Figure 1

14 pages, 1225 KiB

Open AccessEditor’s ChoiceReview

Beyond Traditional Sunscreens: A Review of Liposomal-Based Systems for Photoprotection

by Júlio Abreu Miranda, Yasmin Ferreira da Cruz, Ícaro Chaves Girão, Fabia Julliana Jorge de Souza, Wógenes Nunes de Oliveira, Éverton do Nascimento Alencar, Lucas Amaral-Machado and Eryvaldo Sócrates Tabosa do Egito

Pharmaceutics 2024, 16(5), 661; https://doi.org/10.3390/pharmaceutics16050661 - 15 May 2024

Cited by 1 | Viewed by 1545

Abstract

Sunscreen products are essential for shielding the skin from ultraviolet (UV) radiation, a leading cause of skin cancer. While existing products serve this purpose, there is a growing need to enhance their efficacy while minimizing potential systemic absorption of UV filters and associated [...] Read more.

Sunscreen products are essential for shielding the skin from ultraviolet (UV) radiation, a leading cause of skin cancer. While existing products serve this purpose, there is a growing need to enhance their efficacy while minimizing potential systemic absorption of UV filters and associated toxicological risks. Liposomal-based formulations have emerged as a promising approach to address these challenges and develop advanced photoprotective products. These vesicular systems offer versatility in carrying both hydrophilic and lipophilic UV filters, enabling the creation of broad-spectrum sunscreens. Moreover, their composition based on phospholipids, resembling that of the stratum corneum, facilitates adherence to the skin’s surface layers, thereby improving photoprotective efficacy. The research discussed in this review underscores the significant advantages of liposomes in photoprotection, including their ability to limit the systemic absorption of UV filters, enhance formulation stability, and augment photoprotective effects. However, despite these benefits, there remains a notable gap between the potential of liposomal systems and their utilization in sunscreen development. Consequently, this review emphasizes the importance of leveraging liposomes and related vesicular systems as innovative tools for crafting novel and more efficient photoprotective formulations. Full article

(This article belongs to the Special Issue Nano-Based Drug Delivery System: Recent Developments and Future Prospects)

► Show Figures

Graphical abstract

23 pages, 4276 KiB

Open AccessEditor’s ChoiceArticle

Drug Integrating Amphiphilic Nano-Assemblies: 2. Spatiotemporal Distribution within Inflammation Sites

by Teresa De Toni, Teodora Dal Buono, Chris M. Li, Grisell C. Gonzalez, Sung-Ting Chuang, Peter Buchwald, Alice A. Tomei and Diana Velluto

Pharmaceutics 2024, 16(5), 652; https://doi.org/10.3390/pharmaceutics16050652 - 13 May 2024

Viewed by 1544

Abstract

The need for chronic systemic immunosuppression, which is associated with unavoidable side-effects, greatly limits the applicability of allogeneic cell transplantation for regenerative medicine applications including pancreatic islet cell transplantation to restore insulin production in type 1 diabetes (T1D). Cell transplantation in confined sites [...] Read more.

The need for chronic systemic immunosuppression, which is associated with unavoidable side-effects, greatly limits the applicability of allogeneic cell transplantation for regenerative medicine applications including pancreatic islet cell transplantation to restore insulin production in type 1 diabetes (T1D). Cell transplantation in confined sites enables the localized delivery of anti-inflammatory and immunomodulatory drugs to prevent graft loss by innate and adaptive immunity, providing an opportunity to achieve local effects while minimizing unwanted systemic side effects. Nanoparticles can provide the means to achieve the needed localized and sustained drug delivery either by graft targeting or co-implantation. Here, we evaluated the potential of our versatile platform of drug-integrating amphiphilic nanomaterial assemblies (DIANAs) for targeted drug delivery to an inflamed site model relevant for islet transplantation. We tested either passive targeting of intravenous administered spherical nanomicelles (nMIC; 20–25 nm diameter) or co-implantation of elongated nanofibrils (nFIB; 5 nm diameter and >1 μm length). To assess the ability of nMIC and nFIB to target an inflamed graft site, we used a lipophilic fluorescent cargo (DiD and DiR) and evaluated the in vivo biodistribution and cellular uptake in the graft site and other organs, including draining and non-draining lymph nodes, after systemic administration (nMIC) and/or graft co-transplantation (nFIB) in mice. Localized inflammation was generated either by using an LPS injection or by using biomaterial-coated islet-like bead implantation in the subcutaneous site. A cell transplant inflammation model was used as well to test nMIC- and nFIB-targeted biodistribution. We found that nMIC can reach the inflamed site after systemic administration, while nFIB remains localized for several days after co-implantation. We confirmed that DIANAs are taken up by different immune cell populations responsible for graft inflammation. Therefore, DIANA is a useful approach for targeted and/or localized delivery of immunomodulatory drugs to decrease innate and adaptive immune responses that cause graft loss after transplantation of therapeutic cells. Full article

(This article belongs to the Special Issue Self-Assembled Amphiphilic Copolymers in Drug Delivery, 2nd Edition)

► Show Figures

Graphical abstract

24 pages, 5816 KiB

Open AccessEditor’s ChoiceReview

Functionalized Calcium Carbonate-Based Microparticles as a Versatile Tool for Targeted Drug Delivery and Cancer Treatment

by Lara Biny, Evgeniia Gerasimovich, Alexander Karaulov, Alyona Sukhanova and Igor Nabiev

Pharmaceutics 2024, 16(5), 653; https://doi.org/10.3390/pharmaceutics16050653 - 13 May 2024

Viewed by 2037

Abstract

Nano- and microparticles are increasingly widely used in biomedical research and applications, particularly as specific labels and targeted delivery vehicles. Silica has long been considered the best material for such vehicles, but it has some disadvantages limiting its potential, such as the proneness [...] Read more.

Nano- and microparticles are increasingly widely used in biomedical research and applications, particularly as specific labels and targeted delivery vehicles. Silica has long been considered the best material for such vehicles, but it has some disadvantages limiting its potential, such as the proneness of silica-based carriers to spontaneous drug release. Calcium carbonate (CaCO₃) is an emerging alternative, being an easily available, cost-effective, and biocompatible material with high porosity and surface reactivity, which makes it an attractive choice for targeted drug delivery. CaCO₃ particles are used in this field in the form of either bare CaCO₃ microbeads or core/shell microparticles representing polymer-coated CaCO₃ cores. In addition, they serve as removable templates for obtaining hollow polymer microcapsules. Each of these types of particles has its specific advantages in terms of biomedical applications. CaCO₃ microbeads are primarily used due to their capacity for carrying pharmaceutics, whereas core/shell systems ensure better protection of the drug-loaded core from the environment. Hollow polymer capsules are particularly attractive because they can encapsulate large amounts of pharmaceutical agents and can be so designed as to release their contents in the target site in response to specific stimuli. This review focuses first on the chemistry of the CaCO₃ cores, core/shell microbeads, and polymer microcapsules. Then, systems using these structures for the delivery of therapeutic agents, including drugs, proteins, and DNA, are outlined. The results of the systematic analysis of available data are presented. They show that the encapsulation of various therapeutic agents in CaCO₃-based microbeads or polymer microcapsules is a promising technique of drug delivery, especially in cancer therapy, enhancing drug bioavailability and specific targeting of cancer cells while reducing side effects. To date, research in CaCO₃-based microparticles and polymer microcapsules assembled on CaCO₃ templates has mainly dealt with their properties in vitro, whereas their in vivo behavior still remains poorly studied. However, the enormous potential of these highly biocompatible carriers for in vivo applications is undoubted. This last issue is addressed in depth in the Conclusions and Outlook sections of the review. Full article

(This article belongs to the Topic Recent Advances in Anticancer Strategies)

► Show Figures

Figure 1

30 pages, 3155 KiB

Open AccessEditor’s ChoiceReview

Ciprofloxacin-Loaded Inhalable Formulations against Lower Respiratory Tract Infections: Challenges, Recent Advances, and Future Perspectives

by Vijay Kumar Panthi, Kathryn E. Fairfull-Smith and Nazrul Islam

Pharmaceutics 2024, 16(5), 648; https://doi.org/10.3390/pharmaceutics16050648 - 11 May 2024

Cited by 1 | Viewed by 2891

Abstract

Inhaled ciprofloxacin (CFX) has been investigated as a treatment for lower respiratory tract infections (LRTIs) associated with cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and bronchiectasis. The challenges in CFX effectiveness for LRTI treatment include poor aqueous solubility and therapy resistance. CFX [...] Read more.

Inhaled ciprofloxacin (CFX) has been investigated as a treatment for lower respiratory tract infections (LRTIs) associated with cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and bronchiectasis. The challenges in CFX effectiveness for LRTI treatment include poor aqueous solubility and therapy resistance. CFX dry powder for inhalation (DPI) formulations were well-tolerated, showing a remarkable decline in overall bacterial burden compared to a placebo in bronchiectasis patients. Recent research using an inhalable powder combining Pseudomonas phage PEV20 with CFX exhibited a substantial reduction in bacterial density in mouse lungs infected with clinical P. aeruginosa strains and reduced inflammation. Currently, studies suggest that elevated biosynthesis of fatty acids could serve as a potential biomarker for detecting CFX resistance in LRTIs. Furthermore, inhaled CFX has successfully addressed various challenges associated with traditional CFX, including the incapacity to eliminate the pathogen, the recurrence of colonization, and the development of resistance. However, further exploration is needed to address three key unresolved issues: identifying the right patient group, determining the optimal treatment duration, and accurately assessing the risk of antibiotic resistance, with additional multicenter randomized controlled trials suggested to tackle these challenges. Importantly, future investigations will focus on the effectiveness of CFX DPI in bronchiectasis and COPD, aiming to differentiate prognoses between these two conditions. This review underscores the importance of CFX inhalable formulations against LRTIs in preclinical and clinical sectors, their challenges, recent advancements, and future perspectives. Full article

(This article belongs to the Special Issue Recent Advances in Pulmonary Drug Delivery Systems)

► Show Figures

Graphical abstract

37 pages, 10656 KiB

Open AccessEditor’s ChoiceArticle

Synthesis, Characterisation, and In Vitro Evaluation of Biocompatibility, Antibacterial and Antitumor Activity of Imidazolium Ionic Liquids

by Elisabetta Novello, Giuseppina Scalzo, Giovanni D’Agata, Maria G. Raucci, Luigi Ambrosio, Alessandra Soriente, Barbara Tomasello, Cristina Restuccia, Lucia Parafati, Grazia M. L. Consoli, Loredana Ferreri, Antonio Rescifina, Chiara Zagni and Daniela C. Zampino

Pharmaceutics 2024, 16(5), 642; https://doi.org/10.3390/pharmaceutics16050642 - 10 May 2024

Viewed by 1640

Abstract

In recent decades, ionic liquids (ILs) have garnered research interest for their noteworthy properties, such as thermal stability, low or no flammability, and negligible vapour pressure. Moreover, their tunability offers limitless opportunities to design ILs with properties suitable for applications in many industrial [...] Read more.

In recent decades, ionic liquids (ILs) have garnered research interest for their noteworthy properties, such as thermal stability, low or no flammability, and negligible vapour pressure. Moreover, their tunability offers limitless opportunities to design ILs with properties suitable for applications in many industrial fields. This study aims to synthetise two series of methylimidazolium ILs bearing long alkyl chain in their cations (C9, C10, C12, C14, C16, C18, C20) and with tetrafluoroborate (BF₄) and the 1,3-dimethyl-5-sulfoisophthalate (DMSIP) as counter ions. The ILs were characterised using ¹H-NMR and MALDI-TOF, and their thermal behaviour was investigated through DSC and TGA. Additionally, the antimicrobial, anticancer, and cytotoxic activities of the ILs were analysed. Moreover, the most promising ILs were incorporated at different concentrations (0.5, 1, 5 wt%) into polyvinyl chloride (PVC) by solvent casting to obtain antimicrobial blend films. The thermal properties and stability of the resulting PVC/IL films, along with their hydrophobicity/hydrophilicity, IL surface distribution, and release, were studied using DSC and TGA, contact angle (CA), SEM, and UV–vis spectrometry, respectively. Furthermore, the antimicrobial and cytotoxic properties of blends were analysed. The in vitro results demonstrated that the antimicrobial and antitumor activities of pure ILs against t Listeria monocytogenes, Escherichia coli, Pseudomonas fluorescens strains, and the breast cancer cell line (MCF7), respectively, were mainly dependent on their structure. These activities were higher in the series containing the BF₄ anion and increased with the increase in the methylimidazolium cation alkyl chain length. However, the elongation of the alkyl chain beyond C16 induced a decrease in antimicrobial activity, indicating a cut-off effect. A similar trend was also observed in terms of in vitro biocompatibility. The loading of both the series of ILs into the PVC matrix did not affect the thermal stability of PVC blend films. However, their T_onset decreased with increased IL concentration and alkyl chain length. Similarly, both the series of PVC/IL films became more hydrophilic with increasing IL concentration and alkyl chain. The loading of ILs at 5% concentration led to considerable IL accumulation on the blend film surfaces (as observed in SEM images) and, subsequently, their higher release. The biocompatibility assessment with healthy human dermal fibroblast (HDF) cells and the investigation of antitumoral properties unveiled promising pharmacological characteristics. These findings provide strong support for the potential utilisation of ILs in biomedical applications, especially in the context of cancer therapy and as antibacterial agents to address the challenge of antibiotic resistance. Furthermore, the unique properties of the PVC/IL films make them versatile materials for advancing healthcare technologies, from drug delivery to tissue engineering and antimicrobial coatings to diagnostic devices. Full article

(This article belongs to the Special Issue Ionic Liquids in Pharmaceutical and Biomedical Applications, 2nd Edition)

► Show Figures

Figure 1

22 pages, 5833 KiB

Open AccessEditor’s ChoiceArticle

A Novel Approach for Dermal Application of Pranoprofen-Loaded Lipid Nanoparticles for the Treatment of Post-Tattoo Inflammatory Reactions

by Guillermo De Grau-Bassal, Mireia Mallandrich, Lilian Sosa, Lupe Espinoza, Ana Cristina Calpena, Núria Bozal-de Febrer, María J. Rodríguez-Lagunas, María L. Garduño-Ramírez and María Rincón

Pharmaceutics 2024, 16(5), 643; https://doi.org/10.3390/pharmaceutics16050643 - 10 May 2024

Cited by 1 | Viewed by 1934

Abstract

Recently, the number of people acquiring tattoos has increased, with tattoos gaining significant popularity in people between 20 and 40 years old. Inflammation is a common reaction associated with tattooing. The purpose of this study was to evaluate a nanostructured lipid carrier loading [...] Read more.

Recently, the number of people acquiring tattoos has increased, with tattoos gaining significant popularity in people between 20 and 40 years old. Inflammation is a common reaction associated with tattooing. The purpose of this study was to evaluate a nanostructured lipid carrier loading pranoprofen (PRA-NLC) as a tattoo aftercare formulation to reduce the inflammation associated with tattooing. In this context, the in vitro drug release and the ex vivo permeation-through-human-skin tests using Franz cells were appraised. The tolerance of our formulation on the skin was evaluated by studying the skin’s biomechanical properties. In addition, an in vivo anti-inflammatory study was conducted on mice skin to evaluate the efficacy of the formulation applied topically after tattooing the animals. PRA-NLC showed a sustained release up to 72 h, and the amount of pranoprofen retained in the skin was found to be 33.48 µg/g/cm². The formulation proved to be well tolerated; it increased stratum corneum hydration, and no signs of skin irritation were observed. Furthermore, it was demonstrated to be non-cytotoxic since the cell viability was greater than 80%. Based on these results, we concluded that PRA-NLC represents a suitable drug delivery carrier for the transdermal delivery of pranoprofen to alleviate the local skin inflammation associated with tattooing. Full article

► Show Figures

Graphical abstract

13 pages, 1303 KiB

Open AccessEditor’s ChoiceArticle

Effect of Antioxidants in Medicinal Products on Intestinal Drug Transporters

by Chetan P. Kulkarni, Jia Yang, Megan L. Koleske, Giovanni Lara, Khondoker Alam, Andre Raw, Bhagwant Rege, Liang Zhao, Dongmei Lu, Lei Zhang, Lawrence X. Yu, Robert A. Lionberger, Kathleen M. Giacomini, Deanna L. Kroetz and Sook Wah Yee

Pharmaceutics 2024, 16(5), 647; https://doi.org/10.3390/pharmaceutics16050647 - 10 May 2024

Cited by 1 | Viewed by 2039

Abstract

The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants [...] Read more.

The presence of mutagenic and carcinogenic N-nitrosamine impurities in medicinal products poses a safety risk. While incorporating antioxidants in formulations is a potential mitigation strategy, concerns arise regarding their interference with drug absorption by inhibiting intestinal drug transporters. Our study screened thirty antioxidants for inhibitory effects on key intestinal transporters—OATP2B1, P-gp, and BCRP in HEK-293 cells (OATP2B1) or membrane vesicles (P-gp, BCRP) using ³H-estrone sulfate, ³H-N-methyl quinidine, and ³H-CCK8 as substrates, respectively. The screen identified that butylated hydroxyanisole (BHA) and carnosic acid inhibited all three transporters (OATP2B1, P-gp, and BCRP), while ascorbyl palmitate (AP) inhibited OATP2B1 by more than 50%. BHA had IC₅₀ values of 71 ± 20 µM, 206 ± 14 µM, and 182 ± 49 µM for OATP2B1, BCRP, and P-gp, respectively. AP exhibited IC₅₀ values of 23 ± 10 µM for OATP2B1. The potency of AP and BHA was tested with valsartan, an OATP2B1 substrate, and revealed IC₅₀ values of 26 ± 17 µM and 19 ± 11 µM, respectively, in HEK-293-OATP2B1 cells. Comparing IC₅₀ values of AP and BHA with estimated intestinal concentrations suggests an unlikely inhibition of intestinal transporters at clinical concentrations of drugs formulated with antioxidants. Full article

(This article belongs to the Special Issue New Insights into Transporters in Drug Development)

► Show Figures

Graphical abstract

31 pages, 1659 KiB

Open AccessEditor’s ChoiceReview

Lipid Nanoparticles in Lung Cancer Therapy

by Hossein Omidian, Erma J. Gill and Luigi X. Cubeddu

Pharmaceutics 2024, 16(5), 644; https://doi.org/10.3390/pharmaceutics16050644 - 10 May 2024

Cited by 5 | Viewed by 2012

Abstract

This manuscript explores the use of lipid nanoparticles (LNPs) in addressing the pivotal challenges of lung cancer treatment, including drug delivery inefficacy and multi-drug resistance. LNPs have significantly advanced targeted therapy by improving the precision and reducing the systemic toxicity of chemotherapeutics such [...] Read more.

This manuscript explores the use of lipid nanoparticles (LNPs) in addressing the pivotal challenges of lung cancer treatment, including drug delivery inefficacy and multi-drug resistance. LNPs have significantly advanced targeted therapy by improving the precision and reducing the systemic toxicity of chemotherapeutics such as doxorubicin and paclitaxel. This manuscript details the design and benefits of various LNP systems, including solid lipid–polymer hybrids, which offer controlled release and enhanced drug encapsulation. Despite achievements in reducing tumor size and enhancing survival, challenges such as manufacturing complexity, biocompatibility, and variable clinical outcomes persist. Future directions are aimed at refining targeting capabilities, expanding combinatorial therapies, and integrating advanced manufacturing techniques to tailor treatments to individual patient profiles, thus promising to transform lung cancer therapy through interdisciplinary collaboration and regulatory innovation. Full article

(This article belongs to the Special Issue Lipid Nanostructures as Drug Carriers for Cancer Therapy)

► Show Figures

Figure 1

18 pages, 1370 KiB

Open AccessEditor’s ChoiceReview

An Overview of Hydrothermally Synthesized Titanate Nanotubes: The Factors Affecting Preparation and Their Promising Pharmaceutical Applications

by Ranim Saker, Hadi Shammout, Géza Regdon, Jr. and Tamás Sovány

Pharmaceutics 2024, 16(5), 635; https://doi.org/10.3390/pharmaceutics16050635 - 9 May 2024

Cited by 2 | Viewed by 1185

Abstract

Recently, titanate nanotubes (TNTs) have been receiving more attention and becoming an attractive candidate for use in several disciplines. With their promising results and outstanding performance, they bring added value to any field using them, such as green chemistry, engineering, and medicine. Their [...] Read more.

Recently, titanate nanotubes (TNTs) have been receiving more attention and becoming an attractive candidate for use in several disciplines. With their promising results and outstanding performance, they bring added value to any field using them, such as green chemistry, engineering, and medicine. Their good biocompatibility, high resistance, and special physicochemical properties also provide a wide spectrum of advantages that could be of crucial importance for investment in different platforms, especially medical and pharmaceutical ones. Hydrothermal treatment is one of the most popular methods for TNT preparation because it is a simple, cost-effective, and environmentally friendly water-based procedure. It is also considered as a strong candidate for large-scale production intended for biomedical application because of its high yield and the special properties of the resulting nanotubes, especially their small diameters, which are more appropriate for drug delivery and long circulation. TNTs’ properties highly differ according to the preparation conditions, which would later affect their subsequent application field. The aim of this review is to discuss the factors that could possibly affect their synthesis and determine the transformations that could happen according to the variation of factors. To fulfil this aim, relevant scientific databases (Web of Science, Scopus, PubMed, etc.) were searched using the keywords titanate nanotubes, hydrothermal treatment, synthesis, temperature, time, alkaline medium, post treatment, acid washing, calcination, pharmaceutical applications, drug delivery, etc. The articles discussing TNTs preparation by hydrothermal synthesis were selected, and papers discussing other preparation methods were excluded; then, the results were evaluated based on a careful reading of the selected articles. This investigation and comprehensive review of different parameters could be the answer to several problems concerning establishing a producible method of TNTs production, and it might also help to optimize their characteristics and then extend their application limits to further domains that are not yet totally revealed, especially the pharmaceutical industry and drug delivery. Full article

(This article belongs to the Special Issue Advanced Pharmaceutical Excipients Used in Solid Dosage Forms)

► Show Figures

Figure 1

22 pages, 1808 KiB

Open AccessEditor’s ChoiceReview

Innovative Delivery Systems for Curcumin: Exploring Nanosized and Conventional Formulations

by Jibira Yakubu and Amit V. Pandey

Pharmaceutics 2024, 16(5), 637; https://doi.org/10.3390/pharmaceutics16050637 - 9 May 2024

Cited by 2 | Viewed by 3638

Abstract

Curcumin, a polyphenol with a rich history spanning two centuries, has emerged as a promising therapeutic agent targeting multiple signaling pathways and exhibiting cellular-level activities that contribute to its diverse health benefits. Extensive preclinical and clinical studies have demonstrated its ability to enhance [...] Read more.

Curcumin, a polyphenol with a rich history spanning two centuries, has emerged as a promising therapeutic agent targeting multiple signaling pathways and exhibiting cellular-level activities that contribute to its diverse health benefits. Extensive preclinical and clinical studies have demonstrated its ability to enhance the therapeutic potential of various bioactive compounds. While its reported therapeutic advantages are manifold, predominantly attributed to its antioxidant and anti-inflammatory properties, its efficacy is hindered by poor bioavailability stemming from inadequate absorption, rapid metabolism, and elimination. To address this challenge, nanodelivery systems have emerged as a promising approach, offering enhanced solubility, biocompatibility, and therapeutic effects for curcumin. We have analyzed the knowledge on curcumin nanoencapsulation and its synergistic effects with other compounds, extracted from electronic databases. We discuss the pharmacokinetic profile of curcumin, current advancements in nanoencapsulation techniques, and the combined effects of curcumin with other agents across various disorders. By unifying existing knowledge, this analysis intends to provide insights into the potential of nanoencapsulation technologies to overcome constraints associated with curcumin treatments, emphasizing the importance of combinatorial approaches in improving therapeutic efficacy. Finally, this compilation of study data aims to inform and inspire future research into encapsulating drugs with poor pharmacokinetic characteristics and investigating innovative drug combinations to improve bioavailability and therapeutic outcomes. Full article

(This article belongs to the Special Issue Curcumin in Biomedical Applications, 2nd Edition)

► Show Figures

Figure 1

19 pages, 2319 KiB

Open AccessEditor’s ChoiceReview

The Potential of Selenium-Based Therapies for Ocular Oxidative Stress

by Lulwah Al-Bassam, Gemma C. Shearman, Steve Brocchini, Raid G. Alany and Gareth R. Williams

Pharmaceutics 2024, 16(5), 631; https://doi.org/10.3390/pharmaceutics16050631 - 8 May 2024

Cited by 2 | Viewed by 1738

Abstract

Oxidative stress plays a critical role in the development of chronic ocular conditions including cataracts, age-related macular degeneration, and diabetic retinopathy. There is a need to explore the potential of topical antioxidants to slow the progression of those conditions by mediating oxidative stress [...] Read more.

Oxidative stress plays a critical role in the development of chronic ocular conditions including cataracts, age-related macular degeneration, and diabetic retinopathy. There is a need to explore the potential of topical antioxidants to slow the progression of those conditions by mediating oxidative stress and maintaining ocular health. Selenium has attracted considerable attention because it is a component of selenoproteins and antioxidant enzymes. The application of selenium to a patient can increase selenoprotein expression, counteracting the effect of reactive oxygen species by increasing the presence of antioxidant enzymes, and thus slowing the progression of chronic ocular disorders. Oxidative stress effects at the biomolecular level for prevalent ocular conditions are described in this review along with some of the known defensive mechanisms, with a focus on selenoproteins. The importance of selenium in the eye is described, along with a discussion of selenium studies and uses. Selenium’s antioxidant and anti-inflammatory qualities may prevent or delay eye diseases. Recent breakthroughs in drug delivery methods and nanotechnology for selenium-based ocular medication delivery are enumerated. Different types of selenium may be employed in formulations aimed at managing ocular oxidative stress conditions. Full article

(This article belongs to the Special Issue Oxidative Stress and Inflammation: Novel Drug Formulation and Delivery Systems)

► Show Figures

Figure 1

17 pages, 17237 KiB

Open AccessEditor’s ChoiceArticle

Using Polymers as Crystal Inhibitors to Prevent the Crystallization of the Rotigotine Patch

by Qiantong Liu, Xing Li, Bo Liu, Jiahao Kong, Qing Wang and Zhigang Gao

Pharmaceutics 2024, 16(5), 630; https://doi.org/10.3390/pharmaceutics16050630 - 8 May 2024

Cited by 1 | Viewed by 1117

Abstract

This study aimed to enhance the stability of the Rotigotine (ROT) patch using polymers as crystal inhibitors. Three polymers (Poloxamer 188, Soluplus, TPGS) were selected as crystal inhibitors to formulate ROT patches with varying drug loadings (20%, 40%, 60%, and 80%, w/ [...] Read more.

This study aimed to enhance the stability of the Rotigotine (ROT) patch using polymers as crystal inhibitors. Three polymers (Poloxamer 188, Soluplus, TPGS) were selected as crystal inhibitors to formulate ROT patches with varying drug loadings (20%, 40%, 60%, and 80%, w/w). SEM and XRD analysis revealed that the Soluplus and Soluplus-TPGS groups with a high concentration (80%, w/w) of ROT could be stored at room temperature for at least 90 days without crystallization. Moreover, the crystallization nucleation time and growth rate were utilized to assess the ability of Poloxamer 188, Soluplus, and TPGS to hinder the formation of ROT crystals and slow down its crystallization rate. Molecular docking results elucidated the intermolecular forces between ROT and different polymers, revealing their mechanisms for crystal inhibition. The ROT-Soluplus-TPGS combination exhibited the lowest binding free energy (−5.3 kcal/mol), indicating the highest binding stability, thereby effectively reducing crystal precipitation. In vitro skin permeation studies demonstrated that ROT patches containing crystal inhibitors exhibited promising transdermal effects. With increasing ROT concentration, the cumulative drug permeation substantially increased, while the lag time was notably reduced. This study offers novel insights for the development of ROT patches. Full article

(This article belongs to the Special Issue Formulation of Poorly Water-Soluble Drugs)

► Show Figures

Figure 1

17 pages, 3262 KiB

Open AccessEditor’s ChoiceArticle

Five Novel Polymorphs of Cardarine/GW501516 and Their Characterization by X-ray Diffraction, Computational Methods, Thermal Analysis and a Pharmaceutical Perspective

by Alexandru Turza, Petru Pascuta, Marieta Muresan-Pop, Liviu Mare, Gheorghe Borodi and Violeta Popescu

Pharmaceutics 2024, 16(5), 623; https://doi.org/10.3390/pharmaceutics16050623 - 7 May 2024

Cited by 1 | Viewed by 2247

Abstract

GW501516, also known by the name of cardarine, is a synthetic peroxisome-proliferator-activated receptor delta (PPR-δ) agonist agent developed for applications in the treatment of metabolic disorders and cardiovascular diseases. A broad polymorph screening in various solvents and mixtures was completed in order to [...] Read more.

GW501516, also known by the name of cardarine, is a synthetic peroxisome-proliferator-activated receptor delta (PPR-δ) agonist agent developed for applications in the treatment of metabolic disorders and cardiovascular diseases. A broad polymorph screening in various solvents and mixtures was completed in order to explore its capabilities to grow polymorphs. The crystal structures of four polymorphs were elucidated using single-crystal X-ray diffraction, while one structure was solved via a powder X-ray diffraction method. The solid state features (nature of intermolecular interactions) were investigated by computational methods. The polymorphs were further investigated by thermal DSC analysis and X-ray diffraction on powders. From a pharmaceutical perspective, the stability and solubility of the polymorphs were analyzed as well. Full article

(This article belongs to the Special Issue Pharmaceutical Polymorphs and Cocrystals and Their In Vitro and In Vivo Evaluation)

► Show Figures

Graphical abstract

24 pages, 3539 KiB

Open AccessEditor’s ChoiceReview

Challenges in Optimizing Nanoplatforms Used for Local and Systemic Delivery in the Oral Cavity

by Dorin Ioan Cocoș, Olimpia Dumitriu Buzia, Alin Laurențiu Tatu, Monica Dinu, Lawrence Chukwudi Nwabudike, Claudia Simona Stefan, Kamel Earar and Carmen Galea

Pharmaceutics 2024, 16(5), 626; https://doi.org/10.3390/pharmaceutics16050626 - 7 May 2024

Viewed by 1731

Abstract

In this study, we focused on innovative approaches to improve drug administration in oral pathology, especially by transmucosal and transdermal pathways. These improvements refer to the type of microneedles used (proposing needles in the saw), to the use of certain enhancers such as [...] Read more.

In this study, we focused on innovative approaches to improve drug administration in oral pathology, especially by transmucosal and transdermal pathways. These improvements refer to the type of microneedles used (proposing needles in the saw), to the use of certain enhancers such as essential oils (which, besides the amplifier action, also have intrinsic actions on oral health), to associations of active substances with synergistic action, as well as the use of copolymeric membranes, cemented directly on the tooth. We also propose a review of the principles of release at the level of the oral mucosa and of the main release systems used in oral pathology. Controlled failure systems applicable in oral pathology include the following: fast dissolving films, mucoadhesive tablets, hydrogels, intraoral mucoadhesive films, composite wafers, and smart drugs. The novelty elements brought by this paper refer to the possibilities of optimizing the localized drug delivery system in osteoarthritis of the temporomandibular joint, neuropathic pain, oral cancer, periodontitis, and pericoronitis, as well as in maintaining oral health. We would like to mention the possibility of incorporating natural products into the controlled failure systems used in oral pathology, paying special attention to essential oils. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

► Show Figures

Figure 1

14 pages, 1529 KiB

Open AccessEditor’s ChoiceArticle

Enhancing Cellular Uptake of Native Proteins through Bio-Orthogonal Conjugation with Chemically Synthesized Cell-Penetrating Peptides

by Jekaterina Nebogatova, Ly Porosk, Heleri Heike Härk and Kaido Kurrikoff

Pharmaceutics 2024, 16(5), 617; https://doi.org/10.3390/pharmaceutics16050617 - 3 May 2024

Cited by 1 | Viewed by 1413

Abstract

The potential for native proteins to serve as a platform for biocompatible, targeted, and personalized therapeutics in the context of genetic and metabolic disorders is vast. Nevertheless, their clinical application encounters challenges, particularly in overcoming biological barriers and addressing the complexities involved in [...] Read more.

The potential for native proteins to serve as a platform for biocompatible, targeted, and personalized therapeutics in the context of genetic and metabolic disorders is vast. Nevertheless, their clinical application encounters challenges, particularly in overcoming biological barriers and addressing the complexities involved in engineering transmembrane permeability. This study is dedicated to the development of a multifunctional nanoentity in which a model therapeutic protein is covalently linked to a cell-penetrating peptide, NickFect 55, with the objective of enhancing its intracellular delivery. Successful binding of the nanoentity fragments was achieved through the utilization of an intein-mediated protein-trans splicing reaction. Our research demonstrates that the fully assembled nanoentity-containing protein was effectively internalized by the cells, underscoring the potential of this approach in overcoming barriers associated with protein-based therapeutics for the treatment of genetic disorders. Full article

(This article belongs to the Special Issue Delivery System for Biomacromolecule Drugs: Design and Application)

► Show Figures

Figure 1

20 pages, 2199 KiB

Open AccessEditor’s ChoiceArticle

Organ-on-a-Chip: Ubi sumus? Fundamentals and Design Aspects

by Ana Sofia Morais, Maria Mendes, Marta Agostinho Cordeiro, João J. Sousa, Alberto Canelas Pais, Silvia M. Mihăilă and Carla Vitorino

Pharmaceutics 2024, 16(5), 615; https://doi.org/10.3390/pharmaceutics16050615 - 2 May 2024

Cited by 1 | Viewed by 1846

Abstract

This review outlines the evolutionary journey from traditional two-dimensional (2D) cell culture to the revolutionary field of organ-on-a-chip technology. Organ-on-a-chip technology integrates microfluidic systems to mimic the complex physiological environments of human organs, surpassing the limitations of conventional 2D cultures. This evolution has [...] Read more.

This review outlines the evolutionary journey from traditional two-dimensional (2D) cell culture to the revolutionary field of organ-on-a-chip technology. Organ-on-a-chip technology integrates microfluidic systems to mimic the complex physiological environments of human organs, surpassing the limitations of conventional 2D cultures. This evolution has opened new possibilities for understanding cell–cell interactions, cellular responses, drug screening, and disease modeling. However, the design and manufacture of microchips significantly influence their functionality, reliability, and applicability to different biomedical applications. Therefore, it is important to carefully consider design parameters, including the number of channels (single, double, or multi-channels), the channel shape, and the biological context. Simultaneously, the selection of appropriate materials compatible with the cells and fabrication methods optimize the chips’ capabilities for specific applications, mitigating some disadvantages associated with these systems. Furthermore, the success of organ-on-a-chip platforms greatly depends on the careful selection and utilization of cell resources. Advances in stem cell technology and tissue engineering have contributed to the availability of diverse cell sources, facilitating the development of more accurate and reliable organ-on-a-chip models. In conclusion, a holistic perspective of in vitro cellular modeling is provided, highlighting the integration of microfluidic technology and meticulous chip design, which play a pivotal role in replicating organ-specific microenvironments. At the same time, the sensible use of cell resources ensures the fidelity and applicability of these innovative platforms in several biomedical applications. Full article

(This article belongs to the Section Pharmaceutical Technology, Manufacturing and Devices)

► Show Figures

Figure 1

13 pages, 1154 KiB

Open AccessEditor’s ChoiceArticle

The Role of a Cholecystokinin Receptor Antagonist in the Management of Chronic Pancreatitis: A Phase 1 Trial

by Victor Ciofoaia, Wenqiang Chen, Bakain W. Tarek, Martha Gay, Narayan Shivapurkar and Jill P. Smith

Pharmaceutics 2024, 16(5), 611; https://doi.org/10.3390/pharmaceutics16050611 - 30 Apr 2024

Cited by 2 | Viewed by 1717

Abstract

Chronic pancreatitis (CP) is a rare but debilitating condition with an 8-fold increased risk of developing pancreatic cancer. In addition to the symptoms that come from the loss of endocrine and exocrine function in CP, the management of chronic pain is problematic. We [...] Read more.

Chronic pancreatitis (CP) is a rare but debilitating condition with an 8-fold increased risk of developing pancreatic cancer. In addition to the symptoms that come from the loss of endocrine and exocrine function in CP, the management of chronic pain is problematic. We previously showed that the CCK-receptor antagonist called proglumide could decrease inflammation, acinar-ductal metaplasia, and fibrosis in murine models of CP. We hypothesized that proglumide would be safe and diminish pain caused by CP. A Phase 1 open-labeled safety study was performed in subjects with clinical and radiographic evidence of CP with moderate to severe pain. After a 4-week observation period, the subjects were treated with proglumide in 400 mg capsules three times daily (1200 mg per day) by mouth for 12 weeks, and then subjects returned for a safety visit 4 weeks after the discontinuation of the study medication. The results of three pain surveys (Numeric Rating Scale, COMPAT-SF, and NIH PROMIS) showed that the patients had significantly less pain after 12 weeks of proglumide compared to the pre-treatment observation phase. Of the eight subjects in this study, two experienced nausea and diarrhea with proglumide. These side effects resolved in one subject with doses reduced to 800 mg per day. No abnormalities were noted in the blood chemistries. A blood microRNA blood biomarker panel that corresponded to pancreatic inflammation and fibrosis showed significant improvement. We conclude that proglumide is safe and well tolerated in most subjects with CP at a dose of 1200 mg per day. Furthermore, proglumide therapy may have a beneficial effect by decreasing pain associated with CP. Full article

(This article belongs to the Special Issue New Pharmaceutical Targets to Counteract Chronic Inflammation)

► Show Figures

Figure 1

15 pages, 2699 KiB

Open AccessEditor’s ChoiceArticle

Enhanced In Vitro Antiviral Activity of Ivermectin-Loaded Nanostructured Lipid Carriers against Porcine Epidemic Diarrhea Virus via Improved Intracellular Delivery

by Xiaolin Xu, Shasha Gao, Qindan Zuo, Jiahao Gong, Xinhao Song, Yongshi Liu, Jing Xiao, Xiaofeng Zhai, Haifeng Sun, Mingzhi Zhang, Xiuge Gao and Dawei Guo

Pharmaceutics 2024, 16(5), 601; https://doi.org/10.3390/pharmaceutics16050601 - 29 Apr 2024

Cited by 1 | Viewed by 1273

Abstract

Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the [...] Read more.

Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of −31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake. Full article

(This article belongs to the Special Issue Lipid/Polymer-Based Drug Delivery Systems)

► Show Figures

Figure 1

18 pages, 10346 KiB

Open AccessEditor’s ChoiceArticle

Development of 5-Fluorouracil/pH-Responsive Adjuvant-Embedded Extracellular Vesicles for Targeting α_vβ₃ Integrin Receptors in Tumors

by Jiseung Kim, Eunsol Lee and Eun Seong Lee

Pharmaceutics 2024, 16(5), 599; https://doi.org/10.3390/pharmaceutics16050599 - 29 Apr 2024

Cited by 1 | Viewed by 1315

Abstract

To selectively target and treat murine melanoma B16BL6 tumors expressing α_vβ₃ integrin receptors, we engineered tumor-specific functional extracellular vesicles (EVs) tailored for the targeted delivery of antitumor drugs. This objective was achieved through the incorporation of a pH-responsive adjuvant, cyclic [...] Read more.

To selectively target and treat murine melanoma B16BL6 tumors expressing α_vβ₃ integrin receptors, we engineered tumor-specific functional extracellular vesicles (EVs) tailored for the targeted delivery of antitumor drugs. This objective was achieved through the incorporation of a pH-responsive adjuvant, cyclic arginine-glycine-aspartic acid peptide (cRGD, serving as a tumor-targeting ligand), and 5-fluorouracil (5-FU, employed as a model antitumor drug). The pH-responsive adjuvant, essential for modulating drug release, was synthesized by chemically conjugating 3-(diethylamino)propylamine (DEAP) to deoxycholic acid (DOCA, a lipophilic substance capable of integrating into EVs’ membranes), denoted as DEAP-DOCA. The DOCA, preactivated using N-(2-aminoethyl)maleimide (AEM), was chemically coupled with the thiol group of the cRGD-DOCA through the thiol–maleimide click reaction, resulting in the formation of cRGD-DOCA. Subsequently, DEAP-DOCA, cRGD-DOCA, and 5-FU were efficiently incorporated into EVs using a sonication method. The resulting tumor-targeting EVs, expressing cRGD ligands, demonstrated enhanced in vitro/in vivo cellular uptake specifically for B16BL6 tumors expressing α_vβ₃ integrin receptors. The ionization characteristics of the DEAP in DEAP-DOCA induced destabilization of the EVs membrane at pH 6.5 through protonation of the DEAP substance, thereby expediting 5-FU release. Consequently, an improvement in the in vivo antitumor efficacy was observed for B16BL6 tumors. Based on these comprehensive in vitro/in vivo findings, we anticipate that this EV system holds substantial promise as an exceptionally effective platform for antitumor therapeutic delivery. Full article

(This article belongs to the Special Issue Extracellular Vesicle-Based Drug Delivery Systems)

► Show Figures

Figure 1

24 pages, 3776 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Surfactant Spheroidal Micelle Structure for Pharmaceutical Applications: A Novel Analytical Framework

by Liberato De Caro, Thibaud Stoll, Arnaud Grandeury, Fabia Gozzo and Cinzia Giannini

Pharmaceutics 2024, 16(5), 604; https://doi.org/10.3390/pharmaceutics16050604 - 29 Apr 2024

Viewed by 1131

Abstract

We introduce an innovative theoretical framework tailored for the analysis of Pair Distribution Function (PDF) data derived from Small-Angle X-ray Scattering (SAXS) measurements of core-shell micelles. The new approach involves the exploitation of the first derivative of the PDF and the derivation of [...] Read more.

We introduce an innovative theoretical framework tailored for the analysis of Pair Distribution Function (PDF) data derived from Small-Angle X-ray Scattering (SAXS) measurements of core-shell micelles. The new approach involves the exploitation of the first derivative of the PDF and the derivation of analytical equations to solve the core-shell micelle structure under the hypothesis of a spheroidal shape. These analytical equations enable us to determine the micelle’s aggregation number, degree of ellipticity, and contrast in electron density between the core-shell and shell-buffer regions after having determined the whole micelle size and its shell size from the analysis of the first derivative of the PDF. We have formulated an overdetermined system of analytical equations based on the unknowns that characterize the micelle structure. This allows us to establish a Figure of Merit, which is utilized to identify the most reliable solution within the system of equations. Full article

► Show Figures

Figure 1

16 pages, 6430 KiB

Open AccessEditor’s ChoiceArticle

Linseed Oil-Based Oleogel Vehicles for Hydrophobic Drug Delivery—Physicochemical and Applicative Properties

by Sonia Kudłacik-Kramarczyk, Anna Drabczyk, Alicja Przybyłowicz and Marcel Krzan

Pharmaceutics 2024, 16(5), 600; https://doi.org/10.3390/pharmaceutics16050600 - 29 Apr 2024

Cited by 1 | Viewed by 1158

Abstract

In this study, a methodology for synthesizing oleogels based on linseed oil and emulsifiers, such as beeswax and Tween 20 and Tween 80, was developed. Linseed oil served as the main oil phase, while beeswax acted as a gelling and emulsifying agent. Tween [...] Read more.

In this study, a methodology for synthesizing oleogels based on linseed oil and emulsifiers, such as beeswax and Tween 20 and Tween 80, was developed. Linseed oil served as the main oil phase, while beeswax acted as a gelling and emulsifying agent. Tween compounds are non-ionic surfactants composed of hydrophobic and hydrophilic parts, allowing for the formation of a stable system with promising properties. Surface wetting analysis of the obtained oleogels, FT-IR spectroscopy, and determination of relative and absolute humidity over time, as well as optical microscope analysis and rheological analysis of the obtained oleogels, were conducted as part of the research. The results indicate that increasing the amount of Tween 20 decreases the hydrophilicity of the oleogel, while Tween 80 exhibits the opposite effect. Surface energy analysis suggests that a higher content of Tween 20 may lead to a reduction in the surface energy of the oleogels, which may indicate greater material stability. Changes in relative humidity and FT-IR spectral analysis confirm the influence of emulsifiers on the presence of characteristic functional groups in the structure of the oleogels. Additionally, microscopic analysis suggests that an emulsifier with a longer hydrophobic tail leads to a denser material structure. Full article

(This article belongs to the Special Issue Functional Biomaterials in Biomedical Applications)

► Show Figures

Figure 1

19 pages, 5058 KiB

Open AccessEditor’s ChoiceArticle

Development and Efficacy Evaluation of Innovative Cosmetic Formulations with Caryocar brasiliense Fruit Pulp Oil Encapsulated in Freeze-Dried Liposomes

by Letícia Kakuda, Patrícia M. B. G. Maia Campos and Wanderley P. Oliveira

Pharmaceutics 2024, 16(5), 595; https://doi.org/10.3390/pharmaceutics16050595 - 27 Apr 2024

Cited by 1 | Viewed by 1630

Abstract

Encapsulation and drying technologies allow the engineering of innovative raw materials from plant biodiversity, with potential applications in pharmaceutical and cosmetic fields. Lipid-based nanoencapsulation stands out for its efficiency, ease of production, and versatility in encapsulating substances, whether hydrophilic or lipophilic. This work [...] Read more.

Encapsulation and drying technologies allow the engineering of innovative raw materials from plant biodiversity, with potential applications in pharmaceutical and cosmetic fields. Lipid-based nanoencapsulation stands out for its efficiency, ease of production, and versatility in encapsulating substances, whether hydrophilic or lipophilic. This work aimed at encapsulating pequi oil in liposomes and freeze-dried liposomes to enhance its stability and functional benefits, such as skin hydration and anti-aging effects, for use in innovative cosmetic formulations. Pequi oil—extracted from the Caryocar brasiliense fruit pulp, a plant species from Brazilian plant biodiversity—is rich in secondary metabolites and fatty acids. Liposomes and dried liposomes offer controlled production processes and seamless integration into cosmetic formulations. The physicochemical analysis of the developed liposomes confirmed that the formulations are homogeneous and electrokinetically stable, as evidenced by consistent particle size distribution and zeta potential values, respectively. The gel-type formulations loaded with the dried liposomes exhibit enhanced skin hydration, improved barrier function, and refined microrelief, indicating improvements in skin conditions. These results highlight the potential of dried liposomes containing pequi oil for the development of innovative cosmeceutical products. This research contributes to the valorization of Brazilian biodiversity by presenting an innovative approach to leveraging the dermatological benefits of pequi oil in cosmetic applications. Full article

(This article belongs to the Special Issue Spray Drying and Encapsulation of Pharmaceuticals and Phytopharmaceuticals)

► Show Figures

Graphical abstract

15 pages, 3790 KiB

Open AccessEditor’s ChoiceArticle

Targeted Thrombolysis with Magnetic Nanotherapeutics: A Translational Assessment

by Ming-Lu Lin, Siao-Yun Wu, Jyh-Ping Chen, Yi-Ching Lu, Shih-Ming Jung, Shiaw-Pyng Wey, Tony Wu and Yunn-Hwa Ma

Pharmaceutics 2024, 16(5), 596; https://doi.org/10.3390/pharmaceutics16050596 - 27 Apr 2024

Viewed by 1154

Abstract

Plasminogen activators, such as recombinant tissue-type plasminogen activators (rtPAs), while effective in treating thromboembolic diseases, often induce hemorrhagic complications due to non-specific enzyme activities in the systemic circulation. This study evaluated the targeting efficiency, efficacy, biodistribution, and potential toxicity of a rtPA covalently [...] Read more.

Plasminogen activators, such as recombinant tissue-type plasminogen activators (rtPAs), while effective in treating thromboembolic diseases, often induce hemorrhagic complications due to non-specific enzyme activities in the systemic circulation. This study evaluated the targeting efficiency, efficacy, biodistribution, and potential toxicity of a rtPA covalently attached to chitosan-coated magnetic nanoparticles (chitosan-MNP-rtPA). The thrombolytic activity of a chitosan-MNP-rtPA was preserved by protection from an endogenous plasminogen activator inhibitor-1 (PAI-1) in whole blood and after circulation in vivo, as examined by thromboelastometry. Single-photon emission computed tomography (SPECT) demonstrated real-time retention of a ^99mTc-MNP-rtPA induced by magnet application in a rat embolic model; an 80% reduction in rtPA dosage for a chitosan-MNP-rtPA with magnetic guidance was shown to restore blood flow. After treatment, iron deposition was observed in the reticuloendothelial systems, with portal edema and neutrophil infiltration in the liver at a ten-fold higher dose but not the regular dose. Nevertheless, no liver or renal toxicity was observed at this higher dose. In conclusion, the liver may still be the major deposit site of rtPA nanocomposites after targeted delivery; chitosan-coated MNPs are potentially amenable to target therapeutics with parenteral administration. Full article

(This article belongs to the Special Issue Recent Advances in Biomedical Applications of Magnetic Nanomaterials)

► Show Figures

Graphical abstract

18 pages, 7262 KiB

Open AccessEditor’s ChoiceArticle

QbD Approach-Based Preparation and Optimization of Hydrophobic Ion-Pairing Complex of Lysozyme with Sodium Dodecyl Sulphate to Enhance Stability in Lipid-Based Carriers

by Alharith A. A. Hassan, Tamás Sovány, Krisztián Pamlényi, Martin Deák, Viktória Hornok, Edit Csapó, Géza Regdon, Jr., Ildikó Csóka and Katalin Kristó

Pharmaceutics 2024, 16(5), 589; https://doi.org/10.3390/pharmaceutics16050589 - 26 Apr 2024

Cited by 1 | Viewed by 1384

Abstract

Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the [...] Read more.

Hydrophobic ion pairing (HIP) complexation was found to be an efficient approach in modulating the release and enhancing the stability and encapsulation of hydrophilic macromolecules such as proteins in hydrophobic nano/microcarriers. The present work strives to develop and optimize the preparation of the HIP complex of the antimicrobial enzyme lysozyme (LYZ) with the ion-pairing agent (IPA) sodium dodecyl sulphate (SDS) relying on the quality-by-design (QbD) approach. The quality target product profile (QTPP) includes the achievement of maximal lipophilicity in a reversible manner to enable the maintenance of biological activity. The related critical quality attributes (CQAs) were defined as complexation efficacy, complex stability, enzyme recovery and activity. Three risk assessment (RA) tools were used to identify and rank the critical process parameters (CPPs) and critical material attributes (CMAs). From this assessment, the pH of the medium, LYZ:SDS molar ratio and drying conditions were determined as high-risk factors that need to be investigated. To the best of our knowledge, for the first time, electrostatic titration was used as a smart approach to determine the optimum molar ratio at different pH values. Based on the predefined CQAs, pH 8 with an LYZ/SDS molar ratio of 1:8 was found to be the optimal condition for complexation efficiency and recovery (%) of a biologically active enzyme. A cost-effective drying process based on a ventilated oven was developed, which resulted in complex qualities comparable to those obtained by the commonly used freeze-drying method. In a nutshell, the optimum conditions for the preparation of the LYZ/SDS HIP complex were efficiently facilitated by the rational application of QbD principles and the utilization of efficient electrostatic titration and ventilated oven-drying methods. Full article

(This article belongs to the Special Issue Advances in Delivering Protein and Peptide Therapeutics, 2nd Edition)

► Show Figures

Figure 1

17 pages, 13528 KiB

Open AccessEditor’s ChoiceArticle

Taste-Masked Pellets of Warfarin Sodium: Formulation towards the Dose Personalisation

by Lakija Kovalenko, Kirils Kukuls, Marta Berga and Valentyn Mohylyuk

Pharmaceutics 2024, 16(5), 586; https://doi.org/10.3390/pharmaceutics16050586 - 26 Apr 2024

Viewed by 1647

Abstract

The bitter drug, warfarin, has a narrow therapeutic index (NTI) and is used in paediatrics and geriatrics. The aim of this feasibility study was to formulate the taste-masked warfarin-containing pellets to be applicable for dose personalisation and to improve patient compliance, as well [...] Read more.

The bitter drug, warfarin, has a narrow therapeutic index (NTI) and is used in paediatrics and geriatrics. The aim of this feasibility study was to formulate the taste-masked warfarin-containing pellets to be applicable for dose personalisation and to improve patient compliance, as well as to investigate the effect of the core type (PharSQ^® Spheres M, CELPHERE™ CP-507, and NaCl) on the warfarin release from the Kollicoat^® Smartseal taste-masking-coated pellets. The cores were successfully drug-loaded and coated in a fluid-bed coater with a Wurster insert. An increase in particle size and particle size distribution was observed by optical microscopy. In saliva-simulated pH, at the Kollicoat^® Smartseal level of 2 mg/cm², none of the pellets demonstrated drug release, confirming their efficient taste-masking. However, in a stomach-simulated pH, a faster drug release was observed from PharSQ^® Spheres M- and CELPHERE™ CP-507-coated pellets in comparison with NaCl cores. Additional experiments allowed us to explain the slower drug release from NaCl-containing pellets because of the salting-out effect. Despite the successful taste masking, the drug release from pellets was relatively slow (not more than 91% per 60 min), allowing for further formulation improvements. Full article

(This article belongs to the Special Issue Dosage Form Design for Oral Administration)

► Show Figures

Graphical abstract

18 pages, 2582 KiB

Open AccessEditor’s ChoiceReview

Plant-Derived Vesicle-like Nanoparticles: The Next-Generation Drug Delivery Nanoplatforms

by Xiaoxia Wang, Congling Xin, Yu Zhou and Tao Sun

Pharmaceutics 2024, 16(5), 588; https://doi.org/10.3390/pharmaceutics16050588 - 26 Apr 2024

Viewed by 1828

Abstract

A wide variety of natural bioactive compounds derived from plants have demonstrated significant clinical relevance in the treatment of various diseases such as cancer, chronic disease, and inflammation. An increasing number of studies have surfaced that give credence to the potential of plant-derived [...] Read more.

A wide variety of natural bioactive compounds derived from plants have demonstrated significant clinical relevance in the treatment of various diseases such as cancer, chronic disease, and inflammation. An increasing number of studies have surfaced that give credence to the potential of plant-derived vesicle-like nanoparticles (PDVLNs) as compelling candidates for a drug delivery system (DDS). PDVLNs are cost-effective production, non-toxicity and non-immunogenicity and fascinating bi-ocompatibility. In this review, we attempt to comprehensively review and consolidate the position of PDVLNs as next-generation drug delivery nanoplatforms. We aim to give a quick glance to readers of the current developments of PDVLNs, including their biogenesis, characteristic features, composition, administration routes, advantages, and application. Further, we discuss the advantages and limitations of PDVLNs. We expect that the role of PDVLNs in drug delivery will be significantly enhanced, thus positioning them as the next generation of therapeutic modalities in the foreseeable future. Full article

(This article belongs to the Section Drug Delivery and Controlled Release)

► Show Figures

Figure 1

20 pages, 2459 KiB

Open AccessEditor’s ChoiceArticle

Co-Delivery of an Innovative Organoselenium Compound and Paclitaxel by pH-Responsive PCL Nanoparticles to Synergistically Overcome Multidrug Resistance in Cancer

by Daniela Mathes, Letícia Bueno Macedo, Taís Baldissera Pieta, Bianca Costa Maia, Oscar Endrigo Dorneles Rodrigues, Julliano Guerin Leal, Marcelo Wendt, Clarice Madalena Bueno Rolim, Montserrat Mitjans and Daniele Rubert Nogueira-Librelotto

Pharmaceutics 2024, 16(5), 590; https://doi.org/10.3390/pharmaceutics16050590 - 26 Apr 2024

Viewed by 1382

Abstract

In this study, we designed the association of the organoselenium compound 5′-Seleno-(phenyl)-3′-(ferulic-amido)-thymidine (AFAT-Se), a promising innovative nucleoside analogue, with the antitumor drug paclitaxel, in poly(ε-caprolactone) (PCL)-based nanoparticles (NPs). The nanoprecipitation method was used, adding the lysine-based surfactant, 77KS, as a pH-responsive adjuvant. The [...] Read more.

In this study, we designed the association of the organoselenium compound 5′-Seleno-(phenyl)-3′-(ferulic-amido)-thymidine (AFAT-Se), a promising innovative nucleoside analogue, with the antitumor drug paclitaxel, in poly(ε-caprolactone) (PCL)-based nanoparticles (NPs). The nanoprecipitation method was used, adding the lysine-based surfactant, 77KS, as a pH-responsive adjuvant. The physicochemical properties presented by the proposed NPs were consistent with expectations. The co-nanoencapsulation of the bioactive compounds maintained the antioxidant activity of the association and evidenced greater antiproliferative activity in the resistant/MDR tumor cell line NCI/ADR-RES, both in the monolayer/two-dimensional (2D) and in the spheroid/three-dimensional (3D) assays. Hemocompatibility studies indicated the safety of the nanoformulation, corroborating the ability to spare non-tumor 3T3 cells and human mononuclear cells of peripheral blood (PBMCs) from cytotoxic effects, indicating its selectivity for the cancerous cells. Furthermore, the synergistic antiproliferative effect was found for both the association of free compounds and the co-encapsulated formulation. These findings highlight the antitumor potential of combining these bioactives, and the proposed nanoformulation as a potentially safe and effective strategy to overcome multidrug resistance in cancer therapy. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

► Show Figures

Graphical abstract

17 pages, 8529 KiB

Open AccessEditor’s ChoiceArticle

Mass Production of Rg1-Loaded Small Extracellular Vesicles Using a 3D Bioreactor System for Enhanced Cardioprotective Efficacy of Doxorubicin-Induced Cardiotoxicity

by Yunfeng Di, Shuang Zhao, Huilan Fan, Wei Li, Guangjian Jiang, Yong Wang, Chun Li, Wei Wang and Jingyu Wang

Pharmaceutics 2024, 16(5), 593; https://doi.org/10.3390/pharmaceutics16050593 - 26 Apr 2024

Cited by 1 | Viewed by 1394

Abstract

Background: Small extracellular vesicles (sEVs) obtained from human umbilical cord mesenchymal stromal cells (MSCs) have shown cardioprotective efficacy in doxorubicin-induced cardiotoxicity (DIC). However, their clinical application is limited due to the low yield and high consumption. This study aims to achieve large-scale production [...] Read more.

Background: Small extracellular vesicles (sEVs) obtained from human umbilical cord mesenchymal stromal cells (MSCs) have shown cardioprotective efficacy in doxorubicin-induced cardiotoxicity (DIC). However, their clinical application is limited due to the low yield and high consumption. This study aims to achieve large-scale production of sEVs using a three-dimensional (3D) bioreactor system. In addition, sEVs were developed to deliver Ginsenoside Rg1 (Rg1), a compound derived from traditional Chinese medicine, Ginseng, that has cardioprotective properties but limited bioavailability, to enhance the treatment of DIC. Methods: The 3D bioreactor system with spinner flasks was used to expand human umbilical cord MSCs and collect MSC-conditioned medium. Subsequently, sEVs were isolated from the conditioned medium using differential ultra-centrifugation (dUC). The sEVs were loaded with Ginsenoside Rg1 by electroporation and evaluated for cardioprotective efficacy using Cell Counting Kit-8 (CCK-8) analysis, Annexin V/PI staining and live cell count of H9c2 cells under DIC. Results: Using the 3D bioreactor system with spinner flasks, the expansion of MSCs reached ~600 million, and the production of sEVs was up to 2.2 × 10¹² particles in five days with significantly reduced bench work compared to traditional 2D flasks. With the optimized protocol, the Ginsenoside Rg1 loading efficiency of sEVs by electroporation was ~21%, higher than sonication or co-incubation. Moreover, Rg1-loaded sEVs had attenuated DOX-induced cardiotoxicity with reduced apoptosis compared to free Ginsenoside Rg1 or sEVs. Conclusions: The 3D culture system scaled up the production of sEVs, which facilitated the Rg1 delivery and attenuated cardiomyocyte apoptosis, suggesting a potential treatment of DOX-induced cardiotoxicity. Full article

(This article belongs to the Special Issue Advances in Exosomes in Drug Delivery Systems)

► Show Figures

Graphical abstract

23 pages, 6324 KiB

Open AccessEditor’s ChoiceArticle

Investigating the Influence of Processing Conditions on Dissolution and Physical Stability of Solid Dispersions with Fenofibrate and Mesoporous Silica

by Ana Baumgartner, Nina Dobaj and Odon Planinšek

Pharmaceutics 2024, 16(5), 575; https://doi.org/10.3390/pharmaceutics16050575 - 24 Apr 2024

Cited by 3 | Viewed by 1040

Abstract

The study aimed to enhance the solubility of the poorly water-soluble drug, fenofibrate, by loading it onto mesoporous silica, forming amorphous solid dispersions. Solid dispersions with 30% fenofibrate were prepared using the solvent evaporation method with three solvents (ethyl acetate, acetone, and isopropanol) [...] Read more.

The study aimed to enhance the solubility of the poorly water-soluble drug, fenofibrate, by loading it onto mesoporous silica, forming amorphous solid dispersions. Solid dispersions with 30% fenofibrate were prepared using the solvent evaporation method with three solvents (ethyl acetate, acetone, and isopropanol) at different temperatures (40 °C, boiling point temperature). Various characteristics, including solid-state properties, particle morphology, and drug release, were evaluated by different methods and compared to a pure drug and a physical mixture of fenofibrate and silica. Results revealed that higher solvent temperatures facilitated complete amorphization and rapid drug release, with solvent choice having a lesser impact. The optimal conditions for preparation were identified as ethyl acetate at boiling point temperature. Solid dispersions with different fenofibrate amounts (20%, 25%, 35%) were prepared under these conditions. All formulations were fully amorphous, and their dissolution profiles were comparable to the formulation with 30% fenofibrate. Stability assessments after 8 weeks at 40 °C and 75% relative humidity indicated that formulations prepared with ethyl acetate and at 40 °C were physically stable. Interestingly, some formulations showed improved dissolution profiles compared to initial tests. In conclusion, mesoporous silica-based solid dispersions effectively improved fenofibrate dissolution and demonstrated good physical stability if prepared under appropriate conditions. Full article

(This article belongs to the Special Issue Mesoporous Silica-Based Materials in Drug Delivery and Controlled Release)

► Show Figures

Figure 1

13 pages, 1331 KiB

Open AccessEditor’s ChoiceArticle

Pharmaceutical Compounding in Veterinary Medicine: Suspension of Itraconazole

by Gema J. Cabañero-Resta, Bárbara Sánchez-Dengra, Alejandro Ruiz-Picazo, Marival Bermejo, Virginia Merino, Isabel Gonzalez-Alvarez and Marta Gonzalez-Alvarez

Pharmaceutics 2024, 16(5), 576; https://doi.org/10.3390/pharmaceutics16050576 - 24 Apr 2024

Viewed by 1420

Abstract

Itraconazole is a drug used in veterinary medicine for the treatment of different varieties of dermatophytosis at doses between 3–5 mg/kg/day in cats. Nevertheless, in Spain, it is only available in the market as a 52 mL suspension at 10 mg/mL. The lack [...] Read more.

Itraconazole is a drug used in veterinary medicine for the treatment of different varieties of dermatophytosis at doses between 3–5 mg/kg/day in cats. Nevertheless, in Spain, it is only available in the market as a 52 mL suspension at 10 mg/mL. The lack of alternative formulations, which provide sufficient formulation to cover the treatment of large animals or allow the treatment of a group of them, can be overcome with compounding. For this purpose, it has to be considered that itraconazole is a weak base, class II compound, according to the Biopharmaceutics Classification System, that can precipitate when reaching the duodenum. The aim of this work is to develop alternative oral formulations of itraconazole for the treatment of dermatophytosis. Several oral compounds of itraconazole were prepared and compared, in terms of dissolution rate, permeability, and stability, in order to provide alternatives to the medicine commercialized. The most promising formulation contained hydroxypropyl methylcellulose and β-cyclodextrin. This combination of excipients was capable of dissolving the same concentration as the reference product and delaying the precipitation of itraconazole upon leaving the stomach. Moreover, the intestinal permeability of itraconazole was increased more than two-fold. Full article

(This article belongs to the Special Issue Dose Optimization of Traditional and New Drug Formulations in Veterinary and Human Medicine)

► Show Figures

Figure 1

25 pages, 2031 KiB

Open AccessEditor’s ChoiceReview

Attempts to Improve Lipophilic Drugs’ Solubility and Bioavailability: A Focus on Fenretinide

by Silvana Alfei and Guendalina Zuccari

Pharmaceutics 2024, 16(5), 579; https://doi.org/10.3390/pharmaceutics16050579 - 24 Apr 2024

Cited by 1 | Viewed by 1424

Abstract

The development of numerous drugs is often arrested at clinical testing stages, due to their unfavorable biopharmaceutical characteristics. It is the case of fenretinide (4-HPR), a second-generation retinoid, that demonstrated promising in vitro cytotoxic activity against several cancer cell lines. Unfortunately, response rates [...] Read more.

The development of numerous drugs is often arrested at clinical testing stages, due to their unfavorable biopharmaceutical characteristics. It is the case of fenretinide (4-HPR), a second-generation retinoid, that demonstrated promising in vitro cytotoxic activity against several cancer cell lines. Unfortunately, response rates in early clinical trials with 4-HPR did not confirm the in vitro findings, mainly due to the low bioavailability of the oral capsular formulation that was initially developed. Capsular 4-HPR provided variable and insufficient drug plasma levels attributable to the high hepatic first-pass effect and poor drug water solubility. To improve 4-HPR bioavailability, several approaches have been put forward and tested in preclinical and early-phase clinical trials, demonstrating generally improved plasma levels and minimal systemic toxicities, but also modest antitumor efficacy. The challenge is thus currently still far from being met. To redirect the diminished interest of pharmaceutical companies toward 4-HPR and promote its further clinical development, this manuscript reviewed the attempts made so far by researchers to enhance 4-HPR bioavailability. A comparison of the available data was performed, and future directions were proposed. Full article

(This article belongs to the Special Issue Pharmaceutics and Drug Delivery in Italy, 2nd Edition)

► Show Figures

Graphical abstract

16 pages, 1639 KiB

Open AccessEditor’s ChoiceReview

Plant Protease Inhibitors as Emerging Antimicrobial Peptide Agents: A Comprehensive Review

by Mónica G. Parisi, Brenda Ozón, Sofía M. Vera González, Javier García-Pardo and Walter David Obregón

Pharmaceutics 2024, 16(5), 582; https://doi.org/10.3390/pharmaceutics16050582 - 24 Apr 2024

Cited by 1 | Viewed by 1415

Abstract

Antimicrobial peptides (AMPs) are important mediator molecules of the innate defense mechanisms in a wide range of living organisms, including bacteria, mammals, and plants. Among them, peptide protease inhibitors (PPIs) from plants play a central role in their defense mechanisms by directly attacking [...] Read more.

Antimicrobial peptides (AMPs) are important mediator molecules of the innate defense mechanisms in a wide range of living organisms, including bacteria, mammals, and plants. Among them, peptide protease inhibitors (PPIs) from plants play a central role in their defense mechanisms by directly attacking pathogens or by modulating the plant’s defense response. The growing prevalence of microbial resistance to currently available antibiotics has intensified the interest concerning these molecules as novel antimicrobial agents. In this scenario, PPIs isolated from a variety of plants have shown potential in inhibiting the growth of pathogenic bacteria, protozoans, and fungal strains, either by interfering with essential biochemical or physiological processes or by altering the permeability of biological membranes of invading organisms. Moreover, these molecules are active inhibitors of a range of proteases, including aspartic, serine, and cysteine types, with some showing particular efficacy as trypsin and chymotrypsin inhibitors. In this review, we provide a comprehensive analysis of the potential of plant-derived PPIs as novel antimicrobial molecules, highlighting their broad-spectrum antimicrobial efficacy, specificity, and minimal toxicity. These natural compounds exhibit diverse mechanisms of action and often multifunctionality, positioning them as promising molecular scaffolds for developing new therapeutic antibacterial agents. Full article

(This article belongs to the Special Issue Bioactive Molecules from Plants: Discovery and Pharmaceutical Applications, 3rd Edition)

► Show Figures

Figure 1

15 pages, 1963 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of the Transport and Binding of Dopamine-Loaded PLGA Nanoparticles for the Treatment of Parkinson’s Disease Using In Vitro Model Systems

by Karin Danz, Jana Fleddermann, Marcus Koch, Elena Fecioru, Lorenz Maahs, Nicole Kinsinger, Johannes Krämer, Annette Kraegeloh and Sylvia Wagner

Pharmaceutics 2024, 16(5), 571; https://doi.org/10.3390/pharmaceutics16050571 - 23 Apr 2024

Viewed by 1113

Abstract

The treatment of Parkinson’s disease has been moving into the focus of pharmaceutical development. Yet, the necessity for reliable model systems in the development phase has made research challenging and in vivo models necessary. We have established reliable, reproducible in vitro model systems [...] Read more.

The treatment of Parkinson’s disease has been moving into the focus of pharmaceutical development. Yet, the necessity for reliable model systems in the development phase has made research challenging and in vivo models necessary. We have established reliable, reproducible in vitro model systems to evaluate the binding and transport of dopamine-loaded PLGA nanoparticles for the treatment of Parkinson’s disease and put the results in context with comparable in vivo results. The in vitro models have provided similar results concerning the usability of the investigated nanoparticles as the previously used in vivo models and thus provide a good alternative in line with the 3R principles in pharmaceutical research. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

► Show Figures

Figure 1

14 pages, 2158 KiB

Open AccessEditor’s ChoiceArticle

Evaluation of Drug Blood-Brain-Barrier Permeability Using a Microfluidic Chip

by Jung Yoon Yang, Dae-Seop Shin, Moonkyu Jeong, Seong Soon Kim, Ha Neul Jeong, Byung Hoi Lee, Kyu-Seok Hwang, Yuji Son, Hyeon-Cheol Jeong, Chi-Hoon Choi, Kyeong-Ryoon Lee and Myung Ae Bae

Pharmaceutics 2024, 16(5), 574; https://doi.org/10.3390/pharmaceutics16050574 - 23 Apr 2024

Cited by 2 | Viewed by 2444

Abstract

The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage of some compounds. A predictive model of BBB permeability is important in the early stages of drug development. The predicted BBB permeabilities of drugs have been confirmed using a [...] Read more.

The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage of some compounds. A predictive model of BBB permeability is important in the early stages of drug development. The predicted BBB permeabilities of drugs have been confirmed using a variety of in vitro methods to reduce the quantities of drug candidates needed in preclinical and clinical trials. Most prior studies have relied on animal or cell-culture models, which do not fully recapitulate the human BBB. The development of microfluidic models of human-derived BBB cells could address this issue. We analyzed a model for predicting BBB permeability using the Emulate BBB-on-a-chip machine. Ten compounds were evaluated, and their permeabilities were estimated. Our study demonstrated that the permeability trends of ten compounds in our microfluidic-based system resembled those observed in previous animal and cell-based experiments. Furthermore, we established a general correlation between the partition coefficient (

K_{p}

) and the apparent permeability (

P_{a p p}

). In conclusion, we introduced a new paradigm for predicting BBB permeability using microfluidic-based systems. Full article

(This article belongs to the Collection Feature Papers in Pharmaceutical Technology)

► Show Figures

Graphical abstract

19 pages, 8253 KiB

Open AccessEditor’s ChoiceArticle

Nucleolin-Targeting AS1411 Aptamer-Conjugated Nanospheres for Targeted Treatment of Glioblastoma

by Kyeongjin Seo, Kihwan Hwang, Kyung Mi Nam, Min Ju Kim, Yoon-Kyu Song and Chae-Yong Kim

Pharmaceutics 2024, 16(4), 566; https://doi.org/10.3390/pharmaceutics16040566 - 21 Apr 2024

Cited by 2 | Viewed by 2336

Abstract

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), for which nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in [...] Read more.

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), for which nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres (100–300 nm in size) loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than non-specific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study reveals the potential for anti-cancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labeling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier allowing for the precise targeting of tumors. This combination has the potential to produce anti-tumor effects in the active targeted therapy of GBM. Full article

(This article belongs to the Special Issue Anti-Cancer Drug Delivery Systems)

► Show Figures

Graphical abstract

14 pages, 4213 KiB

Open AccessEditor’s ChoiceArticle

Modulating the Nature of Ionizable Lipids and Number of Layers in Hyaluronan-Decorated Lipid Nanoparticles for In Vitro Delivery of RNAi

by Victor Passos Gibson, Houda Tahiri, Claudia Gilbert, Chun Yang, Quoc Thang Phan, Xavier Banquy and Pierre Hardy

Pharmaceutics 2024, 16(4), 563; https://doi.org/10.3390/pharmaceutics16040563 - 20 Apr 2024

Cited by 1 | Viewed by 1614

Abstract

Lipid nanoparticles (LNPs) have established their position as nonviral vectors for gene therapy. Tremendous efforts have been made to modulate the properties of LNPs to unleash their full clinical potential. Among the strategies being pursued, the layer-by-layer (LbL) technique has gained considerable attention [...] Read more.

Lipid nanoparticles (LNPs) have established their position as nonviral vectors for gene therapy. Tremendous efforts have been made to modulate the properties of LNPs to unleash their full clinical potential. Among the strategies being pursued, the layer-by-layer (LbL) technique has gained considerable attention in the biomedical field. Illuminated by our previous work, here we investigate if the LbL approach could be used to modify the LNP cores formulated with three different ionizable lipids: DODMA, MC3, and DODAP. Additionally, we wondered if more than three layers could be loaded onto LNPs without disrupting their gene transfection ability. Taking advantage of physicochemical analysis, as well as uptake and gene silencing studies, we demonstrate the feasibility of modifying the surface of LNPs with the LbL assembly. Precisely, we successfully modified three different LNPs using the layer-by-layer strategy which abrogated luciferase activity in vitro. Additionally, we constructed a 5×-layered HA-LNP containing the MC3 ionizable lipid which outperformed the 3×-layered counterpart in transfecting miRNA-181-5p to the pediatric GBM cell line, as a proof-of-concept in vitro experiment. The method used herein has been proven reproducible, of easy modification to adapt to different ionizable lipid-containing LNPs, and holds great potential for the translation of RNA-based therapeutic strategies. Full article

(This article belongs to the Special Issue New Nano-Systems for Imaging, Diagnostics, and Drug Delivery)

► Show Figures

Figure 1

21 pages, 3239 KiB

Open AccessEditor’s ChoiceArticle

Darunavir Nanoformulation Suppresses HIV Pathogenesis in Macrophages and Improves Drug Delivery to the Brain in Mice

by Lina Zhou, Sandip Godse, Namita Sinha, Sunitha Kodidela, Udai Singh and Santosh Kumar

Pharmaceutics 2024, 16(4), 555; https://doi.org/10.3390/pharmaceutics16040555 - 19 Apr 2024

Viewed by 1596

Abstract

Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using [...] Read more.

Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood–brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders. Full article

(This article belongs to the Special Issue Next Generation of PLGA-Based Nanoparticles as Drug Delivery Systems for Biomedical Applications)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI