Pharmaceutics

11 pages, 2714 KiB

Open AccessEditor’s ChoiceArticle

Novel Fluorescent Strategy for Discriminating T and B Lymphocytes Using Transport System

by Heewon Cho, Na-Kyeong Hong and Young-Tae Chang

Pharmaceutics 2024, 16(3), 424; https://doi.org/10.3390/pharmaceutics16030424 - 19 Mar 2024

Viewed by 1150

Fluorescent bioprobes are invaluable tools for visualizing live cells and deciphering complex biological processes by targeting intracellular biomarkers without disrupting cellular functions. In addition to protein-binding concepts, fluorescent probes utilize various mechanisms, including membrane, metabolism, and gating-oriented strategies. This study introduces a novel [...] Read more.

Fluorescent bioprobes are invaluable tools for visualizing live cells and deciphering complex biological processes by targeting intracellular biomarkers without disrupting cellular functions. In addition to protein-binding concepts, fluorescent probes utilize various mechanisms, including membrane, metabolism, and gating-oriented strategies. This study introduces a novel fluorescent mechanism distinct from existing ways. Here, we developed a B cell selective probe, CDrB, with unique transport mechanisms. Through SLC-CRISPRa screening, we identified two transporters, SLCO1B3 and SLC25A41, by sorting out populations exhibiting higher and lower fluorescence intensities, respectively, demonstrating contrasting activities. We confirmed that SLCO1B3, with comparable expression levels in T and B cells, facilitates the transport of CDrB into cells, while SLC25A41, overexpressed in T lymphocytes, actively exports CDrB. This observation suggests that SLC25A41 plays a crucial role in discriminating between T and B lymphocytes. Furthermore, it reveals the potential for the reversible localization of SLC25A41 to demonstrate its distinct activity. This study is the first report to unveil a novel strategy of SLC by exporting the probe. We anticipate that this research will open up new avenues for developing fluorescent probes. Full article

(This article belongs to the Special Issue Transport and Metabolism of Small-Molecule Drugs, 2nd Edition)

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21 pages, 1305 KiB

Open AccessEditor’s ChoiceReview

Nanomedicine for the Treatment of Viral Diseases: Smaller Solution to Bigger Problems

by Suvankar Ghorai, Harshita Shand, Soumendu Patra, Kingshuk Panda, Maria J. Santiago, Md. Sohanur Rahman, Srinivasan Chinnapaiyan and Hoshang J. Unwalla

Pharmaceutics 2024, 16(3), 407; https://doi.org/10.3390/pharmaceutics16030407 - 16 Mar 2024

Cited by 3 | Viewed by 1796

Abstract

The continuous evolution of new viruses poses a danger to world health. Rampant outbreaks may advance to pandemic level, often straining financial and medical resources to breaking point. While vaccination remains the gold standard to prevent viral illnesses, these are mostly prophylactic and [...] Read more.

The continuous evolution of new viruses poses a danger to world health. Rampant outbreaks may advance to pandemic level, often straining financial and medical resources to breaking point. While vaccination remains the gold standard to prevent viral illnesses, these are mostly prophylactic and offer minimal assistance to those who have already developed viral illnesses. Moreover, the timeline to vaccine development and testing can be extensive, leading to a lapse in controlling the spread of viral infection during pandemics. Antiviral therapeutics can provide a temporary fix to tide over the time lag when vaccines are not available during the commencement of a disease outburst. At times, these medications can have negative side effects that outweigh the benefits, and they are not always effective against newly emerging virus strains. Several limitations with conventional antiviral therapies may be addressed by nanotechnology. By using nano delivery vehicles, for instance, the pharmacokinetic profile of antiviral medications can be significantly improved while decreasing systemic toxicity. The virucidal or virus-neutralizing qualities of other special nanomaterials can be exploited. This review focuses on the recent advancements in nanomedicine against RNA viruses, including nano-vaccines and nano-herbal therapeutics. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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25 pages, 1517 KiB

Open AccessEditor’s ChoiceArticle

Effects of Combined Treatment with Sodium Dichloroacetate and Sodium Valproate on the Genes in Inflammation- and Immune-Related Pathways in T Lymphocytes from Patients with SARS-CoV-2 Infection with Pneumonia: Sex-Related Differences

by Donatas Stakišaitis, Linas Kapočius, Vacis Tatarūnas, Dovydas Gečys, Auksė Mickienė, Tomas Tamošuitis, Rasa Ugenskienė, Arūnas Vaitkevičius, Ingrida Balnytė and Vaiva Lesauskaitė

Pharmaceutics 2024, 16(3), 409; https://doi.org/10.3390/pharmaceutics16030409 - 16 Mar 2024

Cited by 1 | Viewed by 1374

Abstract

The study presents data on the anti-inflammatory effects of a combination of sodium dichloroacetate and sodium valproate (DCA–VPA) on the expression of inflammation- and immune response-related genes in T lymphocytes of SARS-CoV-2 patients. The study aimed to assess the effects of DCA–VPA on [...] Read more.

The study presents data on the anti-inflammatory effects of a combination of sodium dichloroacetate and sodium valproate (DCA–VPA) on the expression of inflammation- and immune response-related genes in T lymphocytes of SARS-CoV-2 patients. The study aimed to assess the effects of DCA–VPA on the genes of cytokine activity, chemokine-mediated signaling, neutrophil chemotaxis, lymphocyte chemotaxis, T-cell chemotaxis, and regulation of T-cell proliferation pathways. The study included 21 patients with SARS-CoV-2 infection and pneumonia: 9 male patients with a mean age of 68.44 ± 15.32 years and 12 female patients with a mean age of 65.42 ± 15.74 years. They were hospitalized between December 2022 and March 2023. At the time of testing, over 90% of sequences analyzed in Lithuania were found to be of the omicron variant of SARS-CoV-2. The T lymphocytes from patients were treated with 5 mmol DCA and 2 mmol VPA for 24 h in vitro. The effect of the DCA–VPA treatment on gene expression in T lymphocytes was analyzed via gene sequencing. The study shows that DCA–VPA has significant anti-inflammatory effects and apparent sex-related differences. The effect is more potent in T cells from male patients with SARS-CoV-2 infection and pneumonia than in females. Full article

(This article belongs to the Special Issue Antiviral and Antibacterial: Focus on Novel Therapeutic Agents and Drug Delivery Systems)

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18 pages, 1449 KiB

Open AccessEditor’s ChoiceReview

Role of Biofunctionalized Nanoparticles in Digestive Cancer Vaccine Development

by Razvan Zdrehus, Cristian Delcea and Lucian Mocan

Pharmaceutics 2024, 16(3), 410; https://doi.org/10.3390/pharmaceutics16030410 - 16 Mar 2024

Viewed by 1513

Abstract

Nanotechnology has provided an opportunity for unparalleled development of the treatment of various severe diseases. The unique properties of nanoparticles offer a promising strategy for enhancing antitumor immunity by enhancing immunogenicity and presentation of tumor autoantigens for cancer immunotherapy. Polymeric, liposomal, carbon or [...] Read more.

Nanotechnology has provided an opportunity for unparalleled development of the treatment of various severe diseases. The unique properties of nanoparticles offer a promising strategy for enhancing antitumor immunity by enhancing immunogenicity and presentation of tumor autoantigens for cancer immunotherapy. Polymeric, liposomal, carbon or silica-based nanoparticles are among those with major immunomodulatory roles in various cancer treatments. Cancer vaccines, in particular digestive cancer vaccines, have been researched and developed on nanotechnological platforms. Due to their safety, controlled release, targeting of dendritic cells (DCs) and improved antigen uptake, as well as enhanced immunogenicity, nanoparticles have been used as carriers, as adjuvants for increased effect at the tumor level, for their immunomodulating effect, or for targeting the tumor microenvironment, thereby increasing tumor immunogenicity and reducing tumor inflammatory response. This review looks at digestive cancer vaccines developed on nanoparticle platforms and the impact nanoparticles have on the effects of these vaccines. Full article

(This article belongs to the Special Issue Functionalized Nanoparticles in Cancer Therapeutics, 2nd Edition)

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15 pages, 3907 KiB

Open AccessEditor’s ChoiceArticle

Designing a Placebo Microneedle Stamp: Modeling and Validation in a Clinical Control Trial

by Seung-Yeon Jeong, Ye-Seul Lee, Ji-Yeun Park, Jung-Hwan Park, Hi-Joon Park and Song-Yi Kim

Pharmaceutics 2024, 16(3), 395; https://doi.org/10.3390/pharmaceutics16030395 - 14 Mar 2024

Viewed by 1099

Abstract

Recently, several clinical studies have been conducted using microneedles (MNs), and various devices have been developed. This study aimed to propose and confirm the feasibility of a placebo control for activating MN clinical research. A 0.5 mm MN stamp with 42 needles was [...] Read more.

Recently, several clinical studies have been conducted using microneedles (MNs), and various devices have been developed. This study aimed to propose and confirm the feasibility of a placebo control for activating MN clinical research. A 0.5 mm MN stamp with 42 needles was used as a treatment intervention, and a placebo stamp with four acupressure-type needles that did not penetrate was proposed and designed as a control for comparison. First, to check whether the placebo stamp did not invade the skin and to set an appropriate level of pressure to be provided during skin stimulation, two participants were stimulated with five different forces on the forearm, and then the skin was dyed. Secondly, to evaluate the validity of the placebo control group, a blinded study between the MN and placebo stamps was performed on 15 participants. We confirmed that the placebo stamp did not penetrate the skin at any intensity or location. Both types of stamps reported relatively low pain levels, but the MN stamp induced higher pain compared to the placebo stamp. Based on the speculation regarding the type of intervention received, the MN stamp was successfully blinded (random guess), whereas the placebo stamp was unblinded. However, according to a subgroup analysis, it was confirmed that the group with low skin sensitivity was completely blind. Blinding the placebo MN stamp had limited success in participants with low skin sensitivity. Future research on suitable placebo controls, considering the variations in MN stamp length and needle count, is warranted. Full article

(This article belongs to the Special Issue Recent Advances in Microneedle-Mediated Drug Delivery, 2nd Edition)

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46 pages, 4899 KiB

Open AccessEditor’s ChoiceReview

Lipid Nanocarriers-Enabled Delivery of Antibiotics and Antimicrobial Adjuvants to Overcome Bacterial Biofilms

by Anam Ahsan, Nicky Thomas, Timothy J. Barnes, Santhni Subramaniam, Thou Chen Loh, Paul Joyce and Clive A. Prestidge

Pharmaceutics 2024, 16(3), 396; https://doi.org/10.3390/pharmaceutics16030396 - 14 Mar 2024

Viewed by 2600

Abstract

The opportunistic bacteria growing in biofilms play a decisive role in the pathogenesis of chronic infectious diseases. Biofilm-dwelling bacteria behave differently than planktonic bacteria and are likely to increase resistance and tolerance to antimicrobial therapeutics. Antimicrobial adjuvants have emerged as a promising strategy [...] Read more.

The opportunistic bacteria growing in biofilms play a decisive role in the pathogenesis of chronic infectious diseases. Biofilm-dwelling bacteria behave differently than planktonic bacteria and are likely to increase resistance and tolerance to antimicrobial therapeutics. Antimicrobial adjuvants have emerged as a promising strategy to combat antimicrobial resistance (AMR) and restore the efficacy of existing antibiotics. A combination of antibiotics and potential antimicrobial adjuvants, (e.g., extracellular polymeric substance (EPS)-degrading enzymes and quorum sensing inhibitors (QSI) can improve the effects of antibiotics and potentially reduce bacterial resistance). In addition, encapsulation of antimicrobials within nanoparticulate systems can improve their stability and their delivery into biofilms. Lipid nanocarriers (LNCs) have been established as having the potential to improve the efficacy of existing antibiotics in combination with antimicrobial adjuvants. Among them, liquid crystal nanoparticles (LCNPs), liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) are promising due to their superior properties compared to traditional formulations, including their greater biocompatibility, higher drug loading capacity, drug protection from chemical or enzymatic degradation, controlled drug release, targeted delivery, ease of preparation, and scale-up feasibility. This article reviews the recent advances in developing various LNCs to co-deliver some well-studied antimicrobial adjuvants combined with antibiotics from different classes. The efficacy of various combination treatments is compared against bacterial biofilms, and synergistic therapeutics that deserve further investigation are also highlighted. This review identifies promising LNCs for the delivery of combination therapies that are in recent development. It discusses how LNC-enabled co-delivery of antibiotics and adjuvants can advance current clinical antimicrobial treatments, leading to innovative products, enabling the reuse of antibiotics, and providing opportunities for saving millions of lives from bacterial infections. Full article

(This article belongs to the Special Issue Photodynamic, Photothermal and Photoimmune Therapy and Other Antimicrobial Nanomedicine-Related Applications)

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23 pages, 8398 KiB

Open AccessEditor’s ChoiceArticle

Cellular Uptake and Transport Mechanism Investigations of PEGylated Niosomes for Improving the Oral Delivery of Thymopentin

by Mengyang Liu, Darren Svirskis, Thomas Proft, Jacelyn Loh, Yuan Huang and Jingyuan Wen

Pharmaceutics 2024, 16(3), 397; https://doi.org/10.3390/pharmaceutics16030397 - 14 Mar 2024

Viewed by 1244

Abstract

Background: Although its immunomodulatory properties make thymopentin (TP5) appealing, its rapid metabolism and inactivation in the digestive system pose significant challenges for global scientists. PEGylated niosomal nanocarriers are hypothesized to improve the physicochemical stability of TP5, and to enhance its intestinal permeability for [...] Read more.

Background: Although its immunomodulatory properties make thymopentin (TP5) appealing, its rapid metabolism and inactivation in the digestive system pose significant challenges for global scientists. PEGylated niosomal nanocarriers are hypothesized to improve the physicochemical stability of TP5, and to enhance its intestinal permeability for oral administration. Methods: TP5-loaded PEGylated niosomes were fabricated using the thin film hydration method. Co-cultured Caco-2 and HT29 cells with different ratios were screened as in vitro intestinal models. The cytotoxicity of TP5 and its formulations were evaluated using an MTT assay. The cellular uptake and transport studies were investigated in the absence or presence of variable inhibitors or enhancers, and their mechanisms were explored. Results and Discussion: All TP5 solutions and their niosomal formulations were nontoxic to Caco-2 and HT-29 cells. The uptake of TP5-PEG-niosomes by cells relied on active endocytosis, exhibiting dependence on time, energy, and concentration, which has the potential to significantly enhance its cellular uptake compared to TP5 in solution. Nevertheless, cellular transport rates were similar between TP5 in solution and its niosomal groups. The cellular transport of TP5 in solution was carried out mainly through MRP5 endocytosis and a passive pathway and effluxed by MRP5 transporters, while that of TP5-niosomes and TP5-PEG-niosomes was carried out through adsorptive- and clathrin-mediated endocytosis requiring energy. The permeability and transport rate was further enhanced when EDTA and sodium taurocholate were used as the penetration enhancers. Conclusions: This research has illustrated that PEG-niosomes were able to enhance the cellular uptake and maintain the cellular transport of TP5. This study also shows this formulation’s potential to serve as an effective carrier for improving the oral delivery of peptides. Full article

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

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21 pages, 9487 KiB

Open AccessEditor’s ChoiceArticle

The Effect of Formulation Variables on the Manufacturability of Clopidogrel Tablets via Fluidized Hot-Melt Granulation—From the Lab Scale to the Pilot Scale

by Béla Kovács, Erzsébet-Orsolya Tőkés, Éva Katalin Kelemen, Katalin Zöldi, Francisc Boda, Edit Suba, Boglárka Kovács-Deák and Tibor Casian

Pharmaceutics 2024, 16(3), 391; https://doi.org/10.3390/pharmaceutics16030391 - 13 Mar 2024

Viewed by 1274

Abstract

Solid pharmaceutical formulations with class II active pharmaceutical ingredients (APIs) face dissolution challenges due to limited solubility, affecting in vivo behavior. Robust computational tools, via data mining, offer valuable insights into product performance, complementing traditional methods and aiding in scale-up decisions. This study [...] Read more.

Solid pharmaceutical formulations with class II active pharmaceutical ingredients (APIs) face dissolution challenges due to limited solubility, affecting in vivo behavior. Robust computational tools, via data mining, offer valuable insights into product performance, complementing traditional methods and aiding in scale-up decisions. This study utilizes the design of experiments (DoE) to understand fluidized hot-melt granulation manufacturing technology. Exploratory data analysis (MVDA) highlights similarities and differences in tablet manufacturability and dissolution profiles at both the lab and pilot scales. The study sought to gain insights into the application of multivariate data analysis by identifying variations among batches produced at different manufacturing scales for this technology. DoE and MVDA findings show that the granulation temperature, time, and Macrogol type significantly impact product performance. These factors, by influencing particle size distribution, become key predictors of product quality attributes such as resistance to crushing, disintegration time, and early-stage API dissolution in the profile. Software-aided data mining, with its multivariate and versatile nature, complements the empirical approach, which is reliant on trial and error during product scale-up. Full article

(This article belongs to the Special Issue Pharmaceutical Solids: Advanced Manufacturing and Characterization)

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13 pages, 3110 KiB

Open AccessEditor’s ChoiceArticle

In Vitro Profile of Hydrocortisone Release from Three-Dimensionally Printed Paediatric Mini-Tablets

by Chrystalla Protopapa, Angeliki Siamidi, Siva Satyanarayana Kolipaka, Laura Andrade Junqueira, Dennis Douroumis and Marilena Vlachou

Pharmaceutics 2024, 16(3), 385; https://doi.org/10.3390/pharmaceutics16030385 - 11 Mar 2024

Cited by 2 | Viewed by 1508

Abstract

Three-dimensional (3D) printing is quickly being adopted in pharmaceutics due to the many advantages it offers, including treatment, adaptability, the reduction in waste and the accelerated development of new formulations. In this study, micro-extrusion printing was implemented for the production of modified-release hydrocortisone [...] Read more.

Three-dimensional (3D) printing is quickly being adopted in pharmaceutics due to the many advantages it offers, including treatment, adaptability, the reduction in waste and the accelerated development of new formulations. In this study, micro-extrusion printing was implemented for the production of modified-release hydrocortisone (HCT) mini-tablets for paediatric patients. For the developed formulations, Gelucire^® 44/14 and Precirol^® ATO 5 were used as the main inks at three different ratios: 70%/30%, 60%/40% and 50%/50%, respectively. The printing parameters (temperature and pressure) were altered accordingly for each ratio to achieve printability. The printed mini-tablets exhibited excellent printing quality, featuring consistent layer thicknesses and smooth surfaces. Dissolution tests were performed, and the results indicated a successful modified release of HCT from the mini-tablets. In summary, micro-extrusion exhibited favourable processing abilities for powder blends, facilitating quick printing and the fabrication of potential personalized dosages. Full article

(This article belongs to the Special Issue 3D-Printed Solid Pharmaceutical Formulations: Physicochemical Properties and Modified Release (Volume II))

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16 pages, 3245 KiB

Open AccessEditor’s ChoiceArticle

Enhanced Skin Permeation of 5-Fluorouracil through Drug-in-Adhesive Topical Patches

by Sangseo Kim, Souha H. Youssef, Kyung Min Kirsten Lee, Yunmei Song, Sachin Vaidya and Sanjay Garg

Pharmaceutics 2024, 16(3), 379; https://doi.org/10.3390/pharmaceutics16030379 - 10 Mar 2024

Cited by 1 | Viewed by 1450

Abstract

5-fluorouracil (5-FU), commercially available as a topical product, is approved for non-melanoma skin cancer (NMSC) treatment with several clinical limitations. This work aimed to develop 5-FU-loaded topical patches as a potential alternative to overcome such drawbacks. The patches offer accurate dosing, controlled drug [...] Read more.

5-fluorouracil (5-FU), commercially available as a topical product, is approved for non-melanoma skin cancer (NMSC) treatment with several clinical limitations. This work aimed to develop 5-FU-loaded topical patches as a potential alternative to overcome such drawbacks. The patches offer accurate dosing, controlled drug release and improved patient compliance. Our study highlights the development of Eudragit^® E (EuE)-based drug-in-adhesive (DIA) patches containing a clinically significant high level of 5-FU (approximately 450 µg/cm²) formulated with various chemical permeation enhancers. The patches containing Transcutol^® (Patch-TRAN) or oleic acid (Patch-OA) demonstrated significantly higher skin penetration ex vivo than their control counterpart, reaching 5-FU concentrations of 76.39 ± 27.7 µg/cm² and 82.56 ± 8.2 µg/cm², respectively. Furthermore, the findings from in vitro permeation studies also validated the superior skin permeation of 5-FU achieved by Patch-OA and Patch-TRAN over 72 h. Moreover, the EuE-based DIA patch platform demonstrated suitable adhesive and mechanical properties with an excellent safety profile evaluated through an inaugural in vivo human study involving 11 healthy volunteers. In conclusion, the DIA patches could be a novel alternative option for NMSC as the patches effectively deliver 5-FU into the dermis layer and receptor compartment ex vivo for an extended period with excellent mechanical and safety profiles. Full article

(This article belongs to the Special Issue Biomedical Applications of Topical Formulations for Skin and Mucosal Disorders)

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29 pages, 4222 KiB

Open AccessEditor’s ChoiceArticle

Continuous Microfluidic Antisolvent Crystallization as a Bottom-Up Solution for the Development of Long-Acting Injectable Formulations

by Snehashis Nandi, Laura Verstrepen, Mariana Hugo Silva, Luis Padrela, Lidia Tajber and Alain Collas

Pharmaceutics 2024, 16(3), 376; https://doi.org/10.3390/pharmaceutics16030376 - 8 Mar 2024

Viewed by 1432

Abstract

A bottom-up approach was investigated to produce long-acting injectable (LAI) suspension-based formulations to overcome specific limitations of top-down manufacturing methods by tailoring drug characteristics while making the methods more sustainable and cost-efficient. A Secoya microfluidic crystallization technology-based continuous liquid antisolvent crystallization (SCT-CLASC) process [...] Read more.

A bottom-up approach was investigated to produce long-acting injectable (LAI) suspension-based formulations to overcome specific limitations of top-down manufacturing methods by tailoring drug characteristics while making the methods more sustainable and cost-efficient. A Secoya microfluidic crystallization technology-based continuous liquid antisolvent crystallization (SCT-CLASC) process was optimized and afterward compared to an earlier developed microchannel reactor-based continuous liquid antisolvent crystallization (MCR-CLASC) setup, using itraconazole (ITZ) as the model drug. After operating parameter optimization and downstream processing (i.e., concentrating the suspensions), stable microsuspensions were generated with a final solid loading of 300 mg ITZ/g suspension. The optimized post-precipitation feed suspension consisted of 40 mg ITZ/g suspension with a drug-to-excipient ratio of 53:1. Compared to the MCR-CLASC setup, where the post-precipitation feed suspensions contained 10 mg ITZ/g suspension and had a drug-to-excipient ratio of 2:1, a higher drug concentration and lower excipient use were successfully achieved to produce LAI microsuspensions using the SCT-CLASC setup. To ensure stability during drug crystallization and storage, the suspensions’ quality was monitored for particle size distribution (PSD), solid-state form, and particle morphology. The PSD of the ITZ crystals in suspension was maintained within the target range of 1–10 µm, while the crystals displayed an elongated plate-shaped morphology and the solid state was confirmed to be form I, which is the most thermodynamically stable form of ITZ. In conclusion, this work lays the foundation for the SCT-CLASC process as an energy-efficient, robust, and reproducible bottom-up approach for the manufacture of LAI microsuspensions using ITZ at an industrial scale. Full article

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

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16 pages, 3283 KiB

Open AccessEditor’s ChoiceArticle

Silver Nanoparticles Selectively Treat Neurofibromatosis Type 1-Associated Plexiform Neurofibroma Cells at Doses That Do Not Affect Patient-Matched Schwann Cells

by Bashnona Attiah, Garrett Alewine, Mary-Kate Easter, Robert A. Coover and Cale D. Fahrenholtz

Pharmaceutics 2024, 16(3), 371; https://doi.org/10.3390/pharmaceutics16030371 - 7 Mar 2024

Viewed by 1271

Abstract

Neurofibromatosis Type 1 (NF1) is a common neurogenic condition characterized by heterozygous loss of function mutations in the neurofibromin gene. NF1 patients are susceptible to the development of neurofibromas, including plexiform neurofibromas (pNFs), which occurs in about half of all cases. Plexiform neurofibroma [...] Read more.

Neurofibromatosis Type 1 (NF1) is a common neurogenic condition characterized by heterozygous loss of function mutations in the neurofibromin gene. NF1 patients are susceptible to the development of neurofibromas, including plexiform neurofibromas (pNFs), which occurs in about half of all cases. Plexiform neurofibroma are benign peripheral nerve sheath tumors originating from Schwann cells after complete loss of neurofibromin; they can be debilitating and also transform into deadly malignant peripheral nerve sheath tumors (MPNSTs). Here, our data indicates that silver nanoparticles (AgNPs) may be useful in the treatment of pNFs. We assessed the cytotoxicity of AgNPs using pNF cells and Schwann cells derived from the same NF1 patient. We found that AgNPs are selectively cytotoxic to pNF cells relative to isogenic Schwann cells. We then examined the role of neurofibromin expression on AgNP-mediated cytotoxicity; restoration of neurofibromin expression in pNF cells decreased sensitivity to AgNP, and knockdown of neurofibromin in isogenic Schwann cells increased sensitivity to AgNP, outlining a correlation between neurofibromin expression and AgNP-mediated cytotoxicity. AgNP was able to selectively remove pNF cells from a co-culture with patient-matched Schwann cells. Therefore, AgNPs represent a new approach for clinical management of NF1-associated pNF to address significant clinical need. Full article

(This article belongs to the Special Issue Metal and Carbon Nanomaterials for Pharmaceutical Applications)

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14 pages, 5171 KiB

Open AccessEditor’s ChoiceArticle

Curcumin/Carrier Coprecipitation by Supercritical Antisolvent Route

by Stefania Mottola and Iolanda De Marco

Pharmaceutics 2024, 16(3), 352; https://doi.org/10.3390/pharmaceutics16030352 - 2 Mar 2024

Viewed by 925

Abstract

In this work, polyvinylpyrrolidone (PVP)- and β-cyclodextrin (β-CD)-based composite powders containing curcumin (CURC) were obtained through the supercritical antisolvent (SAS) technique. Pressure, total concentration of CURC/carrier in dimethylsulfoxide, and CURC/carrier ratio effects on the morphology and size of the precipitated powders were investigated. [...] Read more.

In this work, polyvinylpyrrolidone (PVP)- and β-cyclodextrin (β-CD)-based composite powders containing curcumin (CURC) were obtained through the supercritical antisolvent (SAS) technique. Pressure, total concentration of CURC/carrier in dimethylsulfoxide, and CURC/carrier ratio effects on the morphology and size of the precipitated powders were investigated. Using PVP as the carrier, spherical particles with a mean diameter of 1.72 μm were obtained at 12.0 MPa, 20 mg/mL, and a CURC/PVP molar ratio equal to 1/2 mol/mol; using β-CD as the carrier, the optimal operating conditions were 9.0 MPa and 200 mg/mL; well-defined micrometric particles with mean diameters equal to 2.98 and 3.69 μm were obtained at molar ratios of 1/2 and 1/1 mol/mol, respectively. FT-IR spectra of CURC/ β-CD inclusion complexes and coprecipitated CURC/PVP powders revealed the presence of some peaks of the active compounds. The stoichiometry of the complexes evaluated through the Job method revealed that β-CD formed inclusion complexes with CURC at a molar ratio equal to 1/1. Dissolution profiles revealed that in comparison with the curve of the pure ingredient, the SAS-processed powders obtained using both PVP and β-CD have an improved release rate. Full article

(This article belongs to the Special Issue Supercritical Techniques for Pharmaceutical Applications)

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23 pages, 2664 KiB

Open AccessEditor’s ChoiceReview

Lipidic Nanoparticles, Extracellular Vesicles and Hybrid Platforms as Advanced Medicinal Products: Future Therapeutic Prospects for Neurodegenerative Diseases

by Maria Tsakiri, Ioannis Tsichlis, Cristina Zivko, Costas Demetzos and Vasiliki Mahairaki

Pharmaceutics 2024, 16(3), 350; https://doi.org/10.3390/pharmaceutics16030350 - 1 Mar 2024

Cited by 1 | Viewed by 1854

Abstract

Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, affect a wide variety of the population and pose significant challenges with progressive and irreversible neural cell loss. The limitations of brain-targeting therapies and the unclear molecular mechanisms driving neurodegeneration hamper the possibility of developing successful [...] Read more.

Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, affect a wide variety of the population and pose significant challenges with progressive and irreversible neural cell loss. The limitations of brain-targeting therapies and the unclear molecular mechanisms driving neurodegeneration hamper the possibility of developing successful treatment options. Thus, nanoscale drug delivery platforms offer a promising solution. This paper explores and compares lipidic nanoparticles, extracellular vesicles (EVs), and hybrid liposomal–EV nanoplatforms as advanced approaches for targeted delivery to combat neurodegeneration. Lipidic nanoparticles are well-characterized platforms that allow multi-drug loading and scalable production. Conversely, EVs offer the ability of selectively targeting specific tissues and high biocompatibility. The combination of these two platforms in one could lead to promising results in the treatment of neurodegeneration. However, many issues, such as the regulatory framework, remain to be solved before these novel products are translated into clinical practice. Full article

(This article belongs to the Special Issue Nanoliposomes, Liposomes and Solid Lipid Nanoparticles: Novel Drug Delivery Strategies)

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31 pages, 1516 KiB

Open AccessEditor’s ChoiceReview

State-of-the-Art Review on Inhalable Lipid and Polymer Nanocarriers: Design and Development Perspectives

by Gabriella Costabile, Gemma Conte, Susy Brusco, Pouria Savadi, Agnese Miro, Fabiana Quaglia, Ivana d’Angelo and Francesca Ungaro

Pharmaceutics 2024, 16(3), 347; https://doi.org/10.3390/pharmaceutics16030347 - 1 Mar 2024

Cited by 4 | Viewed by 1673

Abstract

Nowadays, the interest in research towards the local administration of drugs via the inhalation route is growing as it enables the direct targeting of the lung tissue, at the same time reducing systemic side effects. This is of great significance in the era [...] Read more.

Nowadays, the interest in research towards the local administration of drugs via the inhalation route is growing as it enables the direct targeting of the lung tissue, at the same time reducing systemic side effects. This is of great significance in the era of nucleic acid therapeutics and personalized medicine for the local treatment of severe lung diseases. However, the success of any inhalation therapy is driven by a delicate interplay of factors, such as the physiochemical profile of the payload, formulation, inhalation device, aerodynamic properties, and interaction with the lung fluids. The development of drug delivery systems tailored to the needs of this administration route is central to its success and to revolutionize the treatment of respiratory diseases. With this review, we aim to provide an up-to-date overview of advances in the development of nanoparticulate carriers for drug delivery to the lung tissue, with special regard concerning lipid and polymer-based nanocarriers (NCs). Starting from the biological barriers that the anatomical structure of the lung imposes, and that need to be overcome, the current strategies to achieve efficient lung delivery and the best support for the success of NCs for inhalation are highlighted. Full article

(This article belongs to the Special Issue Application of Polymeric Nanoparticles in Pulmonary Drug Delivery)

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11 pages, 2920 KiB

Open AccessEditor’s ChoicePerspective

Preclinical and Early Clinical Development of Tenofovir Alafenamide/Elvitegravir Topical Inserts for Effective On-Demand Vaginal and Rectal HIV Prevention

by M. Melissa Peet, Vivek Agrahari, Meredith R. Clark and Gustavo F. Doncel

Pharmaceutics 2024, 16(3), 348; https://doi.org/10.3390/pharmaceutics16030348 - 1 Mar 2024

Viewed by 1439

Abstract

HIV/AIDS remains a global public health issue, and products available for the prevention of HIV infections are limited, especially those for short-acting, on-demand, user-controlled applications. Topical inserts are products that can be applied vaginally or rectally and have been explored as drug delivery [...] Read more.

HIV/AIDS remains a global public health issue, and products available for the prevention of HIV infections are limited, especially those for short-acting, on-demand, user-controlled applications. Topical inserts are products that can be applied vaginally or rectally and have been explored as drug delivery systems. To fill the gap in the HIV prevention product pipeline, CONRAD has developed a topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG), two potent and synergistic antiretrovirals, as a simple, low-cost, and discreet option that can be self-administered vaginally and/or rectally, before and after coitus. In this review, we have described the development path of the TAF/EVG insert up to its current point in clinical testing, highlighting findings from acceptability, preclinical safety, pharmacokinetics, and efficacy evaluations and early clinical studies. In summary, the TAF/EVG inserts are stable, easy to manufacture, low-cost, acceptable, and show highly promising preclinical and clinical results for on-demand topical pre- or post-exposure HIV prevention. Full article

(This article belongs to the Special Issue HIV/AIDS Prevention Formulation Design and Optimization and Its Pharmacokinetic-Pharmacodynamic Evaluation)

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24 pages, 3843 KiB

Open AccessEditor’s ChoiceReview

Beyond Small Molecules: Antibodies and Peptides for Fibroblast Activation Protein Targeting Radiopharmaceuticals

by Xiaona Sun, Yuxuan Wu, Xingkai Wang, Xin Gao, Siqi Zhang, Zhicheng Sun, Ruping Liu and Kuan Hu

Pharmaceutics 2024, 16(3), 345; https://doi.org/10.3390/pharmaceutics16030345 - 29 Feb 2024

Viewed by 2816

Abstract

Fibroblast activation protein (FAP) is a serine protease characterized by its high expression in cancer-associated fibroblasts (CAFs) and near absence in adult normal tissues and benign lesions. This unique expression pattern positions FAP as a prospective biomarker for targeted tumor radiodiagnosis and therapy. [...] Read more.

Fibroblast activation protein (FAP) is a serine protease characterized by its high expression in cancer-associated fibroblasts (CAFs) and near absence in adult normal tissues and benign lesions. This unique expression pattern positions FAP as a prospective biomarker for targeted tumor radiodiagnosis and therapy. The advent of FAP-based radiotheranostics is anticipated to revolutionize cancer management. Among various types of FAP ligands, peptides and antibodies have shown advantages over small molecules, exemplifying prolonged tumor retention in human volunteers. Within its scope, this review summarizes the recent research progress of the FAP radiopharmaceuticals based on antibodies and peptides in tumor imaging and therapy. Additionally, it incorporates insights from recent studies, providing valuable perspectives on the clinical utility of FAP-targeted radiopharmaceuticals. Full article

(This article belongs to the Special Issue Advances in Radiopharmaceuticals for Disease Diagnoses and Therapy)

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23 pages, 2154 KiB

Open AccessEditor’s ChoiceReview

Functional Chitosan and Its Derivative-Related Drug Delivery Systems for Nano-Therapy: Recent Advances

by Zixu Wang, Fangying Yu and Fuqiang Hu

Pharmaceutics 2024, 16(3), 337; https://doi.org/10.3390/pharmaceutics16030337 - 28 Feb 2024

Cited by 3 | Viewed by 1484

Abstract

In the struggle against diseases, the development of nano-therapy has certainly been a tremendous progression owing to the various superiority, and chitosan is no doubt a kind of prominent biopolymer material with versatility for applications in disease treatments. For the rational construction of [...] Read more.

In the struggle against diseases, the development of nano-therapy has certainly been a tremendous progression owing to the various superiority, and chitosan is no doubt a kind of prominent biopolymer material with versatility for applications in disease treatments. For the rational construction of chitosan-related nano-biodevices, it is necessary to pay full attention to the material itself, where it is the material properties that guide the design criteria. Additionally, the well-matched preparation methods between material carriers and therapeutic agents draw much attention to the final construction since they seem to be more realistic. In detail, we present a comprehensive overview of recent advances in rational construction of chitosan-related nano-therapies with respect to material-property-oriented design criteria and preparation methods in the current review article, based on the foundation of continuous investigations. Based on this review, a portion of the various uses of chitosan-related nano-biodevices for biomedical applications are specifically discussed. Here, the strategies demonstrate the versatility of chitosan well, and the concept of being simple yet effective is well illustrated and vividly communicated. Altogether, a fresh concept concerning multi-functional chitosan and its derivative-related drug delivery systems for nano-therapy is proposed in this review, and this could be applied to other materials, which seems to be a novel angle. Full article

(This article belongs to the Special Issue Chitosan and Its Derivatives Functionalized Drug Delivery Systems for Biomedical Application)

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12 pages, 3676 KiB

Open AccessEditor’s ChoiceArticle

Studying the API Distribution of Controlled Release Formulations Produced via Continuous Twin-Screw Wet Granulation: Influence of Matrix Former, Filler and Process Parameters

by Phaedra Denduyver, Chris Vervaet and Valérie Vanhoorne

Pharmaceutics 2024, 16(3), 341; https://doi.org/10.3390/pharmaceutics16030341 - 28 Feb 2024

Viewed by 1227

Abstract

Hydroxypropyl methylcellulose (HPMC) is a preferred hydrophilic matrix former for controlled release formulations produced through continuous twin-screw wet granulation. However, a non-homogeneous API distribution over sieve fractions with underdosing in the fines fraction (<150 µm) was previously reported. This could result in content [...] Read more.

Hydroxypropyl methylcellulose (HPMC) is a preferred hydrophilic matrix former for controlled release formulations produced through continuous twin-screw wet granulation. However, a non-homogeneous API distribution over sieve fractions with underdosing in the fines fraction (<150 µm) was previously reported. This could result in content uniformity issues during downstream processing. Therefore, the current study investigated the root cause of the non-homogeneous theophylline distribution. The effect of process parameters (L/S-ratio and screw configuration) and formulation parameters (matrix former and filler type) on content uniformity was studied. Next, the influence of the formulation parameters on tableting and dissolution behavior was investigated. Altering the L/S-ratio or using a more aggressive screw configuration did not result in a homogeneous API distribution over the granule sieve fractions. Using microcrystalline cellulose (MCC) as filler improved the API distribution due to its similar behavior as HPMC. As excluding HPMC or including a hydrophobic matrix former (Kollidon SR) yielded granules with a homogeneous API distribution, HPMC was identified as the root cause of the non-homogeneous API distribution. This was linked to its fast hydration and swelling (irrespective of the HPMC grade) upon addition of the granulation liquid. Full article

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20 pages, 1877 KiB

Open AccessEditor’s ChoiceArticle

Conjugated Linoleic Acid–Carboxymethyl Chitosan Polymeric Micelles to Improve the Solubility and Oral Bioavailability of Paclitaxel

by Iqra Mubeen, Ghulam Abbas, Shahid Shah and Abdullah A Assiri

Pharmaceutics 2024, 16(3), 342; https://doi.org/10.3390/pharmaceutics16030342 - 28 Feb 2024

Cited by 1 | Viewed by 1187

Abstract

Oral delivery, the most common method of therapeutic administration, has two significant obstacles: drug solubility and permeability. The challenges of current oral medicine delivery are being tackled through an emerging method that uses structures called polymeric micelles. In the present study, polymeric micelles [...] Read more.

Oral delivery, the most common method of therapeutic administration, has two significant obstacles: drug solubility and permeability. The challenges of current oral medicine delivery are being tackled through an emerging method that uses structures called polymeric micelles. In the present study, polymeric micelles were developed using conjugates of linoleic acid–carboxymethyl chitosan (LA-CMCS) for the oral delivery of paclitaxel (PCL). The developed micelles were evaluated by particle size, zeta potential, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). When PCL was contained within micelles, its solubility increased by almost 13.65 times (around 60 µg/mL). The micelles’ zeta potentials were −29 mV, their polydispersity indices were 0.023, and their particle diameters were 93 nm. Micelles showed PCL loading and entrapment efficiencies of 67% and 61%, respectively. The sustained release qualities of the PCL release data from micelles were good. In comparison to the pure PCL suspension, the permeability of the PCL from micelles was 2.2 times higher. The pharmacokinetic data revealed that PCL with LA-CMCS micelles had a relative bioavailability of 239.17%, which was much greater than the PCL in the suspension. The oral bioavailability of PCL was effectively increased by LA-CMCS micelles according to an in vivo study on animals. The polymer choice, maybe through improved permeability, plays an essential role when assessing oral bioavailability enhancement and solubility improvement (13.65 times). The outcomes demonstrated that PCL’s solubility and pharmacokinetics were improved in the micelles of the LA-CMCS conjugate. Full article

(This article belongs to the Special Issue Biofunctional Pharmaceutical Additives for Targeted, Improved Bioavailability and Safety of Medicine)

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22 pages, 32030 KiB

Open AccessEditor’s ChoiceArticle

Design of Etched- and Functionalized-Halloysite/Meloxicam Hybrids: A Tool for Enhancing Drug Solubility and Dissolution Rate

by Valeria Friuli, Claudia Urru, Chiara Ferrara, Debora Maria Conti, Giovanna Bruni, Lauretta Maggi and Doretta Capsoni

Pharmaceutics 2024, 16(3), 338; https://doi.org/10.3390/pharmaceutics16030338 - 28 Feb 2024

Cited by 1 | Viewed by 991

Abstract

The study focuses on the synthesis and characterization of Meloxicam–halloysite nanotube (HNT) composites as a viable approach to enhance the solubility and dissolution rate of meloxicam, a poorly water-soluble drug (BCS class II). Meloxicam is loaded on commercial and modified halloysite (acidic and [...] Read more.

The study focuses on the synthesis and characterization of Meloxicam–halloysite nanotube (HNT) composites as a viable approach to enhance the solubility and dissolution rate of meloxicam, a poorly water-soluble drug (BCS class II). Meloxicam is loaded on commercial and modified halloysite (acidic and alkaline etching, or APTES and chitosan functionalization) via a solution method. Several techniques (XRPD, FT-IR, ¹³C solid-state NMR, SEM, EDS, TEM, DSC, TGA) are applied to characterize both HNTs and meloxicam–HNT systems. In all the investigated drug–clay hybrids, a high meloxicam loading of about 40 wt% is detected. The halloysite modification processes and the drug loading do not alter the structure and morphology of both meloxicam and halloysite nanotubes, which are in intimate contact in the composites. Weak drug–clay and drug-functionalizing agent interactions occur, involving the meloxicam amidic functional group. All the meloxicam–halloysite composites exhibit enhanced dissolution rates, as compared to meloxicam. The meloxicam–halloysite composite, functionalized with chitosan, showed the best performance both in water and in buffer at pH 7.5. The drug is completely released in 4–5 h in water and in less than 1 h in phosphate buffer. Notably, an equilibrium solubility of 13.7 ± 4.2 mg/L in distilled water at 21 °C is detected, and wettability dramatically increases, compared to the raw meloxicam. These promising results can be explained by the chitosan grafting on the outer surface of halloysite nanotubes, which provides increased specific surface area (100 m²/g) disposable for drug adsorption/desorption. Full article

(This article belongs to the Special Issue Innovative Formulations of Poorly Soluble Drugs)

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19 pages, 2894 KiB

Open AccessEditor’s ChoiceReview

Structure–Activity Relationship of PAD4 Inhibitors and Their Role in Tumor Immunotherapy

by Yijiang Jia, Renbo Jia, Ayijiang Taledaohan, Yanming Wang and Yuji Wang

Pharmaceutics 2024, 16(3), 335; https://doi.org/10.3390/pharmaceutics16030335 - 28 Feb 2024

Viewed by 2227

Abstract

Protein arginine deiminase 4 (PAD4) plays an important role in cancer progression by participating in gene regulation, protein modification, and neutrophil extracellular trap (NET) formation. Many reversible and irreversible PAD4 inhibitors have been reported recently. In this review, we summarize the structure–activity relationships [...] Read more.

Protein arginine deiminase 4 (PAD4) plays an important role in cancer progression by participating in gene regulation, protein modification, and neutrophil extracellular trap (NET) formation. Many reversible and irreversible PAD4 inhibitors have been reported recently. In this review, we summarize the structure–activity relationships of newly investigated PAD4 inhibitors to bring researchers up to speed by guiding and describing new scaffolds as optimization and development leads for new effective, safe, and selective cancer treatments. In addition, some recent reports have shown evidence that PAD4 inhibitors are expected to trigger antitumor immune responses, regulate immune cells and related immune factors, enhance the effects of immune checkpoint inhibitors, and enhance their antitumor efficacy. Therefore, PAD4 inhibitors may potentially change tumor immunotherapy and provide an excellent direction for the development and clinical application of immunotherapy strategies for related diseases. Full article

(This article belongs to the Topic The Tumor Microenvironment, Immuno-Oncology, and Immune Checkpoint: Implications for Current and Emergent Immunotherapies, 2nd Edition)

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15 pages, 2571 KiB

Open AccessEditor’s ChoiceArticle

Pharmacokinetic Modeling of Bepotastine for Determination of Optimal Dosage Regimen in Pediatric Patients with Allergic Rhinitis or Urticaria

by Sukyong Yoon, Byung Hak Jin, Choon Ok Kim, Kyungsoo Park, Min Soo Park and Dongwoo Chae

Pharmaceutics 2024, 16(3), 334; https://doi.org/10.3390/pharmaceutics16030334 - 27 Feb 2024

Cited by 1 | Viewed by 1255

Abstract

Bepotastine, a second-generation antihistamine for allergic rhinitis and urticaria, is widely used in all age groups but lacks appropriate dosing guidelines for pediatric patients, leading to off-label prescriptions. We conducted this study to propose an optimal dosing regimen for pediatric patients based on [...] Read more.

Bepotastine, a second-generation antihistamine for allergic rhinitis and urticaria, is widely used in all age groups but lacks appropriate dosing guidelines for pediatric patients, leading to off-label prescriptions. We conducted this study to propose an optimal dosing regimen for pediatric patients based on population pharmacokinetic (popPK) and physiologically based pharmacokinetic (PBPK) models using data from two previous trials. A popPK model was built using NONMEM software. A one-compartment model with first-order absorption and absorption lag time described our data well, with body weight incorporated as the only covariate. A PBPK model was developed using PK-Sim software version 10, and the model well predicted the drug concentrations obtained from pediatric patients. Furthermore, the final PBPK model showed good concordance with the known properties of bepotastine. Appropriate pediatric doses for different weight and age groups were proposed based on the simulations. Discrepancies in recommended doses from the two models were likely due to the incorporation of age-dependent physiological factors in the PBPK model. In conclusion, our study is the first to suggest an optimal oral dosing regimen of bepotastine in pediatric patients using both approaches. This is expected to foster safer and more productive use of the drug. Full article

(This article belongs to the Special Issue Model-Informed Drug Discovery and Development, 2nd Edition)

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18 pages, 4626 KiB

Open AccessEditor’s ChoiceArticle

Ivermectin-Loaded Mesoporous Silica and Polymeric Nanocapsules: Impact on Drug Loading, In Vitro Solubility Enhancement, and Release Performance

by Maiara Callegaro Velho, Nadine Lysyk Funk, Monique Deon, Edilson Valmir Benvenutti, Silvio Buchner, Ruth Hinrichs, Diogo André Pilger and Ruy Carlos Ruver Beck

Pharmaceutics 2024, 16(3), 325; https://doi.org/10.3390/pharmaceutics16030325 - 26 Feb 2024

Cited by 1 | Viewed by 1615

Abstract

Ivermectin (IVM), a widely used drug for parasitic infections, faces formulation and application challenges due to its poor water solubility and limited bioavailability. Pondering the impact of IVM’s high partition coefficient value (log P) on its drug release performance, it is relevant to [...] Read more.

Ivermectin (IVM), a widely used drug for parasitic infections, faces formulation and application challenges due to its poor water solubility and limited bioavailability. Pondering the impact of IVM’s high partition coefficient value (log P) on its drug release performance, it is relevant to explore whether IVM nanoencapsulation in organic or inorganic nanoparticles would afford comparable enhanced aqueous solubility. To date, the use of inorganic nanoparticles remains an unexplored approach for delivering IVM. Therefore, here we loaded IVM in mesoporous silica particles (IVM-MCM), as inorganic nanomaterial, and in well-known poly(ε-caprolactone) nanocapsules (IVM-NC). IVM-MCM had a well-organized hexagonal mesoporous structure, reduced surface area, and high drug loading of 10% w/w. IVM-NC had a nanometric mean size (196 nm), high encapsulation efficiency (100%), physicochemical stability as an aqueous dispersion, and drug loading of 0.1% w/w. Despite differing characteristics, both nanoencapsulated forms enhance IVM’s aqueous intrinsic solubility compared to a crystalline IVM: after 72 h, IVM-MCM and IVM-NC achieve 72% and 78% releases through a dialysis bag, whereas crystalline IVM dispersion achieves only 40% drug diffusion. These results show distinct controlled release profiles, where IVM-NC provides a deeper sustained controlled release over the whole experiment compared to the inorganic nanomaterial (IVM-MCM). Discussing differences, including drug loading and release kinetics, is crucial for optimizing IVM’s therapeutic performance. The study design, combined with administration route plans and safety considerations for humans and animals, may expedite the rational optimization of IVM nanoformulations for swift clinical translation. Full article

(This article belongs to the Special Issue Drug Nanocarriers for Pharmaceutical Applications)

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22 pages, 8097 KiB

Open AccessEditor’s ChoiceArticle

Formulation Development of Solid Self-Nanoemulsifying Drug Delivery Systems of Quetiapine Fumarate via Hot-Melt Extrusion Technology: Optimization Using Central Composite Design

by Prateek Uttreja, Ahmed Adel Ali Youssef, Indrajeet Karnik, Kavish Sanil, Nagarjuna Narala, Honghe Wang, Rasha M. Elkanayati, Sateesh Kumar Vemula and Michael A. Repka

Pharmaceutics 2024, 16(3), 324; https://doi.org/10.3390/pharmaceutics16030324 - 26 Feb 2024

Cited by 3 | Viewed by 1856

Abstract

Quetiapine fumarate (QTF) was approved for the treatment of schizophrenia and acute manic episodes. QTF can also be used as an adjunctive treatment for major depressive disorders. QTF oral bioavailability is limited due to its poor aqueous solubility and pre-systemic metabolism. The objective [...] Read more.

Quetiapine fumarate (QTF) was approved for the treatment of schizophrenia and acute manic episodes. QTF can also be used as an adjunctive treatment for major depressive disorders. QTF oral bioavailability is limited due to its poor aqueous solubility and pre-systemic metabolism. The objective of the current investigation was the formulation development and manufacturing of solid self-nanoemulsifying drug delivery system (S-SNEDDS) formulation through a single-step continuous hot-melt extrusion (HME) process to address these drawbacks. In this study, Capmul^® MCM, Gelucire^® 48/16, and propylene glycol were selected as oil, surfactant, and co-surfactant, respectively, for the preparation of S-SNEDDS. Soluplus^® and Klucel™ EF (1:1) were selected as the solid carrier. Response surface methodology in the form of central composite design (CCD) was utilized in the current experimental design to develop the S-SNEDDS formulations via a continuous HME technology. The developed formulations were evaluated for self-emulsifying properties, particle size distribution, thermal behavior, crystallinity, morphology, physicochemical incompatibility, accelerated stability, and in vitro drug release studies. The globule size and emulsification time of the optimized SNEDDS formulation was 92.27 ± 3.4 nm and 3.4 ± 3.38 min. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies revealed the amorphous nature of the drug within the formulation. There were no drug-excipient incompatibilities observed following the Fourier transform infrared (FTIR) spectroscopy. The optimized formulation showed an extended-release profile for 24 h. The optimized formulation was stable for three months (last time-point tested) at 40 °C/75% RH. Therefore, the developed S-SNEDDS formulation could be an effective oral delivery platform for QTF and could lead to better therapeutic outcomes. Full article

(This article belongs to the Special Issue Formulation Optimization and Delivery Strategies for Self-Nanoemulsions)

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19 pages, 1501 KiB

Open AccessEditor’s ChoiceReview

Research Progress of Extracellular Vesicles-Loaded Microneedle Technology

by Xue Wang, Wei Cheng and Jiandong Su

Pharmaceutics 2024, 16(3), 326; https://doi.org/10.3390/pharmaceutics16030326 - 26 Feb 2024

Viewed by 1832

Abstract

Microneedles (MNs), renowned for their painless and minimally invasive qualities, exhibit significant potential for facilitating effective drug delivery, vaccination, and targeted sample extraction. Extracellular vesicles (EVs), serving as cargo for MNs, are naturally occurring nanovesicles secreted by cells and characterized by novel biomarkers, [...] Read more.

Microneedles (MNs), renowned for their painless and minimally invasive qualities, exhibit significant potential for facilitating effective drug delivery, vaccination, and targeted sample extraction. Extracellular vesicles (EVs), serving as cargo for MNs, are naturally occurring nanovesicles secreted by cells and characterized by novel biomarkers, low immunogenicity, and cell-source-specific traits. MNs prove instrumental in extracting EVs from the sample fluid, thereby facilitating a promising diagnostic and prognostic tool. To harness the therapeutic potential of EVs in tissue repair, MNs with sustained delivery of EVs leverage micron-sized channels to enhance targeted site concentration, demonstrating efficacy in treating various diseases, such as Achillea tendinopathy, hair loss, spinal cord injury, and diabetic ulcers. EV-loaded MNs emerge as a promising platform for repair applications of skin, cardiac, tendon, hair, and spinal cord tissues. This review commences with an overview of MNs, subsequently delving into the role of EVs as cargo for MNs. The paper then synthesizes the latest advancements in the use of EV-loaded MNs for tissue regenerative repair, extending to research progress in extracting EVs from MNs for disease diagnosis and prognostic evaluations. It aims to offer valuable insights and forecast future research trajectories with the hope of inspiring innovative ideas among researchers in this field. Full article

(This article belongs to the Special Issue Novel Technologies for Buccal and Transdermal Drug Delivery)

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17 pages, 3147 KiB

Open AccessEditor’s ChoiceArticle

Design Space and Control Strategy for the Manufacturing of Wet Media Milled Drug Nanocrystal Suspensions by Adopting Mechanistic Process Modeling

by André Bitterlich, Andrej Mihorko and Michael Juhnke

Pharmaceutics 2024, 16(3), 328; https://doi.org/10.3390/pharmaceutics16030328 - 26 Feb 2024

Cited by 1 | Viewed by 1383

Abstract

Wet media milling is a fully industrialized technology for the manufacturing of drug nanocrystal suspensions. This work describes the development of an advanced control strategy and an associated design space for a manufacturing process at a commercial scale. Full-scale experiments and mechanistic process [...] Read more.

Wet media milling is a fully industrialized technology for the manufacturing of drug nanocrystal suspensions. This work describes the development of an advanced control strategy and an associated design space for a manufacturing process at a commercial scale. Full-scale experiments and mechanistic process modeling have been used to establish a physically reasonable control strategy of factors relevant to the quality attributes of the nanocrystal suspension. The design space has been developed based on a mature mechanistic process model of the wet media milling procedure. It presents the process–product attribute relationship between a multidimensional range of measured process parameters and a range of the product-quality attribute mean particle sizes. The control strategy allows for simple, robust, and sound scientific process control as well as the operational flexibility of the suspension batch size. This is an industrial case study of control strategy and design-space definition with the crucial contribution of mechanistic process modeling for an intended commercial manufacturing process. Full article

(This article belongs to the Special Issue 15th Anniversary of Pharmaceutics—Advances in Process and Formulation Modeling)

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18 pages, 8366 KiB

Open AccessEditor’s ChoiceArticle

The Development and Characterization of Novel Ionic Liquids Based on Mono- and Dicarboxylates with Meglumine for Drug Solubilizers and Skin Permeation Enhancers

by Takayuki Furuishi, Sara Taguchi, Siran Wang, Kaori Fukuzawa and Etsuo Yonemochi

Pharmaceutics 2024, 16(3), 322; https://doi.org/10.3390/pharmaceutics16030322 - 26 Feb 2024

Cited by 1 | Viewed by 1212

Abstract

In this study, we synthesized a family of novel ionic liquids (ILs) with meglumine (MGM) as cations and tartaric acid (TA), azelaic acid (AA), geranic acid (GA), and capric acid (CPA) as anions, using pharmaceutical additives via simple acid–base neutralization reactions. The successful [...] Read more.

In this study, we synthesized a family of novel ionic liquids (ILs) with meglumine (MGM) as cations and tartaric acid (TA), azelaic acid (AA), geranic acid (GA), and capric acid (CPA) as anions, using pharmaceutical additives via simple acid–base neutralization reactions. The successful synthesis was validated by attenuated total reflection–Fourier transform infrared (ATR-FTIR) and powder X-ray diffraction (PXRD). Thermal analysis using differential scanning calorimetry confirmed the glass transition temperature of MGM-ILs to be within the range of −43.4 °C–−13.8 °C. We investigated the solubilization of 15 drugs with varying pKa and partition coefficient (log P) values using these ILs and performed a comparative analysis. Furthermore, we present MGM-IL as a new skin permeation enhancer for the drug model flurbiprofen (FRP). We confirmed that AA/MGM-IL improves the skin permeation of FRP through hairless mouse skin. Moreover, AA/MGM-IL enhanced drug skin permeability by affecting keratin rather than stratum corneum lipids, as confirmed by ATR-FTIR. To conclude, MGM-ILs exhibited potential as drug solubilizer and skin permeation enhancers of drugs. Full article

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

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18 pages, 6808 KiB

Open AccessEditor’s ChoiceArticle

Liposomes Coated with Novel Synthetic Bifunctional Chitosan Derivatives as Potential Carriers of Anticancer Drugs

by Elisabetta Mazzotta, Antonia Marazioti, Spyridon Mourtas, Rita Muzzalupo and Sophia G. Antimisiaris

Pharmaceutics 2024, 16(3), 319; https://doi.org/10.3390/pharmaceutics16030319 - 24 Feb 2024

Cited by 3 | Viewed by 1295

Abstract

In this study, liposomes coated with novel multifunctional polymers were proposed as an innovative platform for tumor targeted drug delivery. Novel Folic acid–Cysteine-Thiolated chitosan (FTC) derivatives possessing active targeting ability and redox responsivity were synthesized, characterized, and employed to develop FTC-coated liposomes. Liposomes [...] Read more.

In this study, liposomes coated with novel multifunctional polymers were proposed as an innovative platform for tumor targeted drug delivery. Novel Folic acid–Cysteine-Thiolated chitosan (FTC) derivatives possessing active targeting ability and redox responsivity were synthesized, characterized, and employed to develop FTC-coated liposomes. Liposomes were characterized for size, surface charge and drug encapsulation efficiency before and after coating. The formation of a coating layer on liposomal surface was confirmed by the slight increase in particle size and by zeta-potential changes. FTC-coated liposomes showed a redox-dependent drug release profile: good stability at physiological conditions and rapid release of liposome-entrapped calcein in presence of glutathione. Moreover, the uptake and cytotoxic activity of doxorubicin-loaded FTC-coated liposomes was evaluated on murine B16-F10 and human SKMEL2 melanoma cancer cells. Results demonstrated enhanced uptake and antitumor efficacy of FTC-coated liposomes compared to control chitosan-coated liposomes in both cancer lines, which is attributed to higher cellular uptake via folate receptor-mediated endocytosis and to triggered drug release by the reductive microenvironment of tumor cells. The proposed novel liposomes show great potential as nanocarriers for targeted therapy of cancer. Full article

(This article belongs to the Special Issue Recent Trends in Nano-Based Drug Delivery Systems)

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15 pages, 884 KiB

Open AccessEditor’s ChoiceArticle

An Analytical Target Profile for the Development of an In Vitro Release Test Method and Apparatus Selection in the Case of Semisolid Topical Formulations

by Réka Szoleczky, Anita Kovács, Szilvia Berkó and Mária Budai-Szűcs

Pharmaceutics 2024, 16(3), 313; https://doi.org/10.3390/pharmaceutics16030313 - 23 Feb 2024

Viewed by 1139

Abstract

This study focuses on how to define an Analytical Target Profile (ATP) which is intended for use in practice and on facilitating the selection of in vitro release test (IVRT) technology for diclofenac sodium topical hydrogel and cream. The implementation involves incorporating the [...] Read more.

This study focuses on how to define an Analytical Target Profile (ATP) which is intended for use in practice and on facilitating the selection of in vitro release test (IVRT) technology for diclofenac sodium topical hydrogel and cream. The implementation involves incorporating the new draft guidelines of the International Council for Harmonisation (ICH Q14) and USP (United States Pharmacopeia) Chapter 1220. Four IVRT apparatuses were compared (USP Apparatus II with immersion cell, USP Apparatus IV with semisolid adapter, static vertical diffusion cell, and a new, in-house-developed flow-through diffusion cell) with the help of the ATP. Performance characteristics such as accuracy, precision, cumulative amount released at the end of the IVRT experiment, and robustness were investigated. We found that the best apparatus for developing IVRT quality control (QC) tests in both cases was USP II with an immersion cell. All four different IVRT apparatuses were compared with each other and with the data found in the literature. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Current Status and Perspectives)

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13 pages, 914 KiB

Open AccessEditor’s ChoiceReview

Ranibizumab Port Delivery System in Neovascular Age-Related Macular Degeneration: Where Do We Stand? Overview of Pharmacokinetics, Clinical Results, and Future Directions

by Matteo Mario Carlà, Maria Cristina Savastano, Francesco Boselli, Federico Giannuzzi and Stanislao Rizzo

Pharmaceutics 2024, 16(3), 314; https://doi.org/10.3390/pharmaceutics16030314 - 23 Feb 2024

Viewed by 1357

Abstract

The ranibizumab (RBZ) port delivery system (PDS) is a device designed to continuously deliver RBZ in the vitreous chamber for the treatment of neovascular age-related macular degeneration (nAMD). It is implanted during a surgical procedure and can provide sustained release of the medication [...] Read more.

The ranibizumab (RBZ) port delivery system (PDS) is a device designed to continuously deliver RBZ in the vitreous chamber for the treatment of neovascular age-related macular degeneration (nAMD). It is implanted during a surgical procedure and can provide sustained release of the medication for several months. This review, updated to January 2024, focuses on past clinical studies as well as current and forthcoming trials looking into a PDS with RBZ. In the phase 2 LADDER trial, the mean time to first refill of a PDS with RBZ 100 mg/mL was 15.8 months, with the pharmacokinetic (PK) profile showing a sustained concentration of RBZ in the blood and aqueous humor. More recently, a PDS with RBZ (100 mg/mL) refilled every 24 weeks was shown to be non-inferior to a monthly intravitreal injection (IVI) with RBZ (0.5 mg) over 40 and 92 weeks in the phase 3 ARCHWAY trial. The refill every 24 weeks allowed for a RBZ vitreous exposure within the concentration range of monthly intravitreal injections (IVIs), and the expected half-life (106 days) was comparable with the in vitro results. Nonetheless, vitreous hemorrhage and endophthalmitis were more common side effects in PDS patients. In conclusion, a PDS continuously delivering RBZ has a clinical effectiveness level comparable with IVI treatment. However, a greater frequency of unfavorable occurrences highlights the need for procedure optimization for a wider adoption. Ongoing trials and possible future approaches need to be addressed. Full article

(This article belongs to the Special Issue Controlled-Release Systems for Ophthalmic Applications)

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26 pages, 1660 KiB

Open AccessEditor’s ChoiceReview

Extracellular Vesicles in Therapeutics: A Comprehensive Review on Applications, Challenges, and Clinical Progress

by Jiyoung Goo, Yeji Lee, Jeongmin Lee, In-San Kim and Cherlhyun Jeong

Pharmaceutics 2024, 16(3), 311; https://doi.org/10.3390/pharmaceutics16030311 - 22 Feb 2024

Cited by 5 | Viewed by 1700

Abstract

Small Extracellular Vesicles (sEVs) are typically 30–150 nm in diameter, produced inside cells, and released into the extracellular space. These vesicles carry RNA, DNA, proteins, and lipids that reflect the characteristics of their parent cells, enabling communication between cells and the alteration of [...] Read more.

Small Extracellular Vesicles (sEVs) are typically 30–150 nm in diameter, produced inside cells, and released into the extracellular space. These vesicles carry RNA, DNA, proteins, and lipids that reflect the characteristics of their parent cells, enabling communication between cells and the alteration of functions or differentiation of target cells. Owing to these properties, sEVs have recently gained attention as potential carriers for functional molecules and drug delivery tools. However, their use as a therapeutic platform faces limitations, such as challenges in mass production, purity issues, and the absence of established protocols and characterization methods. To overcome these, researchers are exploring the characterization and engineering of sEVs for various applications. This review discusses the origins of sEVs and their engineering for therapeutic effects, proposing areas needing intensive study. It covers the use of cell-derived sEVs in their natural state and in engineered forms for specific purposes. Additionally, the review details the sources of sEVs and their subsequent purification methods. It also outlines the potential of therapeutic sEVs and the requirements for successful clinical trials, including methods for large-scale production and purification. Finally, we discuss the progress of ongoing clinical trials and the implications for future healthcare, offering a comprehensive overview of the latest research in sEV applications. Full article

(This article belongs to the Special Issue Exosome-Based Drug Delivery: Translation from Bench to Clinic)

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15 pages, 2644 KiB

Open AccessEditor’s ChoiceArticle

Electrospun Polyvinylpyrrolidone-Based Dressings Containing GO/ZnO Nanocomposites: A Novel Frontier in Antibacterial Wound Care

by Cristina Martín, Adalyz Ferreiro Fernández, Julia C. Salazar Romero, Juan P. Fernández-Blázquez, Jabier Mendizabal, Koldo Artola, José L. Jorcano and M. Eugenia Rabanal

Pharmaceutics 2024, 16(3), 305; https://doi.org/10.3390/pharmaceutics16030305 - 22 Feb 2024

Viewed by 1428

Abstract

In recent years, the rapid emergence of antibiotic-resistant bacteria has become a significant concern in the healthcare field, and although bactericidal dressings loaded with various classes of antibiotics have been used in clinics, in addition to other anti-infective strategies, this alarming issue necessitates [...] Read more.

In recent years, the rapid emergence of antibiotic-resistant bacteria has become a significant concern in the healthcare field, and although bactericidal dressings loaded with various classes of antibiotics have been used in clinics, in addition to other anti-infective strategies, this alarming issue necessitates the development of innovative strategies to combat bacterial infections and promote wound healing. Electrospinning technology has gained significant attention as a versatile method for fabricating advanced wound dressings with enhanced functionalities. This work is based on the generation of polyvinylpyrrolidone (PVP)-based dressings through electrospinning, using a DomoBIO4A bioprinter, and incorporating graphene oxide (GO)/zinc oxide (ZnO) nanocomposites as a potent antibacterial agent. GO and ZnO nanoparticles offer unique properties, including broad-spectrum antibacterial activity for improved wound healing capabilities. The synthesis process was performed in an inexpensive one-pot reaction, and the nanocomposites were thoroughly characterized using XRD, TEM, EDX, SEM, EDS, and TGA. The antibacterial activity of the dispersions was demonstrated against E. coli and B. subtilis, Gram-negative and Gram-positive bacteria, respectively, using the well diffusion method and the spread plate method. Bactericidal mats were synthesized in a rapid and cost-effective manner, and the fiber-based structure of the electrospun dressings was studied by SEM. Evaluations of their antibacterial efficacy against E. coli and B. subtilis were explored by the disk-diffusion method, revealing an outstanding antibacterial capacity, especially against the Gram-positive strain. Overall, the findings of this research contribute to the development of next-generation wound dressings that effectively combat bacterial infections and pave the way for advanced therapeutic interventions in the field of wound care. Full article

(This article belongs to the Special Issue Metal and Carbon Nanomaterials for Pharmaceutical Applications)

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14 pages, 7476 KiB

Open AccessEditor’s ChoiceArticle

Solid Dispersions of Genistein via Solvent Rotary Evaporation for Improving Solubility, Bioavailability, and Amelioration Effect in HFD-Induced Obesity Mice

by Chenxu Qiu, Yancui Zhang, Yingsai Fan, Shupeng Li, Jianting Gao, Xin He and Xinghua Zhao

Pharmaceutics 2024, 16(3), 306; https://doi.org/10.3390/pharmaceutics16030306 - 22 Feb 2024

Viewed by 1159

Abstract

Genistein (GEN) is an active pharmaceutical ingredient that presents the challenges of poor water solubility and low oral bioavailability. To tackle these challenges, a GEN solid dispersion was prepared by solvent rotary evaporation using polyvinylpyrrolidone K30 (PVP K30) as a carrier. The optimal [...] Read more.

Genistein (GEN) is an active pharmaceutical ingredient that presents the challenges of poor water solubility and low oral bioavailability. To tackle these challenges, a GEN solid dispersion was prepared by solvent rotary evaporation using polyvinylpyrrolidone K30 (PVP K30) as a carrier. The optimal formulation was determined by drug loading efficiency and in vitro release. The physical state of the solid dispersion was characterized by DSC, XRD, SEM and FT-IR. And the results of the in vitro release study indicate that the drug release of SD (1:7) increased 482-fold that of pure GEN at 60 min. Following oral administration to rats, the C_max and AUC_0–24 of SD (1:7) was increased 6.86- and 2.06-fold to that of pure GEN. The adipose fat index and body weight of the SD (1:7) group were significantly lower than those of the GEN group (p < 0.05). Meanwhile, the levels of TC and TG in the serum were significantly decreased in the SD (1:7) group compared with the GEN group (p < 0.05). All experiments revealed that solid dispersion could be a promising formulation approach to improve the dissolution rate, oral bioavailability, and effect on the reduction of lipid accumulation in high-fat diet-induced obesity mice. Full article

(This article belongs to the Section Physical Pharmacy and Formulation)

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17 pages, 1331 KiB

Open AccessEditor’s ChoiceSystematic Review

Influence of Photosensitizer on Photodynamic Therapy for Peri-Implantitis: A Systematic Review

by Thaís B. M. O. Schweigert, João P. R. Afonso, Renata K. da Palma, Iransé Oliveira-Silva, Carlos H. M. Silva, Elias Ilias Jirjos, Wilson Rodrigues Freitas Júnior, Giuseppe Insalaco, Orlando A. Guedes and Luís V. F. Oliveira

Pharmaceutics 2024, 16(3), 307; https://doi.org/10.3390/pharmaceutics16030307 - 22 Feb 2024

Cited by 1 | Viewed by 1300

Abstract

The treatment of peri-implantitis is challenging in the clinical practice of implant dentistry. With limited therapeutic options and drug resistance, there is a need for alternative methods, such as photodynamic therapy (PDT), which is a minimally invasive procedure used to treat peri-implantitis. This [...] Read more.

The treatment of peri-implantitis is challenging in the clinical practice of implant dentistry. With limited therapeutic options and drug resistance, there is a need for alternative methods, such as photodynamic therapy (PDT), which is a minimally invasive procedure used to treat peri-implantitis. This study evaluated whether the type of photosensitizer used influences the results of inflammatory control, reduction in peri-implant pocket depth, bleeding during probing, and reduction in bone loss in the dental implant region. We registered the study in the PROSPERO (International Prospective Register of Systematic Review) database. We searched three main databases and gray literature in English without date restrictions. In vivo randomized clinical studies involving individuals with peri-implantitis, smokers, patients with diabetes, and healthy controls were included. PDT was used as the primary intervention. Comparators considered mechanical debridement with a reduction in pocket depth as the primary outcome and clinical attachment level, bleeding on probing, gingival index, plaque index, and microbiological analysis as secondary outcomes. After reviewing the eligibility criteria, we included seven articles out of 266. A great variety of photosensitizers were observed, and it was concluded that the selection of the most appropriate type of photosensitizer must consider the patient’s characteristics and peri-implantitis conditions. The effectiveness of PDT, its effects on the oral microbiome, and the clinical patterns of peri-implantitis may vary depending on the photosensitizer chosen, which is a crucial factor in personalizing peri-implantitis treatment. Full article

(This article belongs to the Special Issue Photodynamic Therapy: Rising Star in Pharmaceutical Applications)

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25 pages, 12971 KiB

Open AccessEditor’s ChoiceArticle

Microneedle-Assisted Transdermal Delivery of Lurasidone Nanoparticles

by Ariana Radmard and Ajay K. Banga

Pharmaceutics 2024, 16(3), 308; https://doi.org/10.3390/pharmaceutics16030308 - 22 Feb 2024

Cited by 3 | Viewed by 1661

Abstract

Lurasidone, an antipsychotic medication for schizophrenia, is administered daily via oral intake. Adherence is a critical challenge, given that many schizophrenia patients deny their condition, thus making alternative delivery methods desirable. This study aimed to deliver lurasidone by the transdermal route and provide [...] Read more.

Lurasidone, an antipsychotic medication for schizophrenia, is administered daily via oral intake. Adherence is a critical challenge, given that many schizophrenia patients deny their condition, thus making alternative delivery methods desirable. This study aimed to deliver lurasidone by the transdermal route and provide therapeutic effects for three days. Passive diffusion was found to be insufficient for lurasidone delivery. The addition of chemical enhancers increased permeation, but it was still insufficient to reach the designed target dose from a patch, so a microneedle patch array was fabricated by using biodegradable polymers. For prolonged and effective delivery, the drug was encapsulated in Poly (lactic-co-glycolic acid) (PLGA) nanoparticles which were made using the solvent evaporation method and incorporated in microneedles. Effervescent technology was also employed in the preparation of the microneedle patch to facilitate the separation of the needle tip from the patch. Once separated, only the needle tip remains embedded in the skin, thus preventing premature removal by the patient. The microneedles demonstrated robust preformation in a characterization test evaluating their insertion capacity, mechanical strength, and the uniformity of microneedle arrays, and were able to deliver a dose equivalent to 20 mg oral administration. Therefore, the potential of a transdermal delivery system for lurasidone using microneedles with nanoparticles was demonstrated. Full article

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11 pages, 239 KiB

Open AccessEditor’s ChoiceArticle

Drug–Drug Interactions in Patients with Acute Respiratory Distress Syndrome

by Thorsten Bischof, Christoph Schaller, Nina Buchtele, Thomas Staudinger, Roman Ullrich, Felix Kraft, Marine L. Andersson, Bernd Jilma and Christian Schoergenhofer

Pharmaceutics 2024, 16(3), 303; https://doi.org/10.3390/pharmaceutics16030303 - 21 Feb 2024

Viewed by 1129

Abstract

Acute respiratory distress syndrome (ARDS) is a potential life-threatening, heterogenous, inflammatory lung disease. There are no data available on potential drug–drug interactions (pDDIs) in critically ill patients with ARDS. This study analyzed pDDIs in this specific cohort and aimed to investigate possible associations [...] Read more.

Acute respiratory distress syndrome (ARDS) is a potential life-threatening, heterogenous, inflammatory lung disease. There are no data available on potential drug–drug interactions (pDDIs) in critically ill patients with ARDS. This study analyzed pDDIs in this specific cohort and aimed to investigate possible associations of coronavirus disease 2019 (COVID-19) as an underlying cause of ARDS and treatment with extracorporeal membrane oxygenation (ECMO) with the occurrence of pDDIs. This retrospective study included patients ≥18 years of age diagnosed with ARDS between January 2010 and September 2021. The Janusmed database was used for the identification of pDDIs. A total of 2694 pDDIs were identified in 189 patients with a median treatment duration of 22 days. These included 323 (12%) clinically relevant drug combinations that are best avoided, corresponding to a median rate of 0.05 per day. There was no difference in the number of pDDIs between COVID-19- and non-COVID-19-associated ARDS. In patients treated with ECMO, the rate of the most severely graded pDDIs per day was significantly higher compared with those who did not require ECMO. PDDIs occur frequently in patients with ARDS. On average, each patient may encounter at least one clinically relevant drug combination that should be avoided during their intensive care unit stay. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions, 2nd Edition)

22 pages, 9747 KiB

Open AccessEditor’s ChoiceArticle

Exploring the Effects of Process Parameters during W/O/W Emulsion Preparation and Supercritical Fluid Extraction on the Protein Encapsulation and Release Properties of PLGA Microspheres

by Heejun Park

Pharmaceutics 2024, 16(3), 302; https://doi.org/10.3390/pharmaceutics16030302 - 21 Feb 2024

Cited by 1 | Viewed by 1417

Abstract

In this study, protein-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared via supercritical fluid extraction of emulsion (SFEE) technology. To understand the correlation between process parameters and the main quality characteristics of PLGA microspheres, a comprehensive prior study on the influence of process variables [...] Read more.

In this study, protein-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared via supercritical fluid extraction of emulsion (SFEE) technology. To understand the correlation between process parameters and the main quality characteristics of PLGA microspheres, a comprehensive prior study on the influence of process variables on encapsulation efficiency (EE), initial drug burst release (IBR), morphology, surface property, and particle size distribution (PSD) was conducted within a wide process condition range of each unit process step, from the double-emulsion preparation step to the extraction step. Bovine serum albumin (BSA), a high-molecular weight-protein that is difficult to control the IBR and EE of PLGA microspheres with, was used as a model material. As double-emulsion manufacturing process parameters, the primary (W/O) and secondary emulsion (W/O/W) homogenization speed and secondary emulsification time were evaluated. In addition, the effect of the SFEE process parameters, including the pressure (70–160 bar), temperature (35–65 °C), stirring rate (50–1000 rpm), and flow rate of supercritical carbon dioxide, SC-CO₂ (1–40 mL/min), on PLGA microsphere quality properties were also evaluated. An increase in the homogenization speed of the primary emulsion resulted in an increase in EE and a decrease in IBR. In contrast, increasing the secondary emulsification speed resulted in a decrease in EE and an increase in IBR along with a decrease in microsphere size. The insufficient secondary emulsification time resulted in excessive increases in particle size, and excessive durations resulted in decreased EE and increased IBR. Increasing the temperature and pressure of SFEE resulted in an overall increase in particle size, a decrease in EE, and an increase in IBR. It was observed that, at low stirring rates or SC-CO₂ flow rates, there was an increase in particle size and SPAN value, while the EE decreased. Overall, when the EE of the prepared microspheres is low, a higher proportion of drugs is distributed on the external surface of the microspheres, resulting in a larger IBR. In conclusion, this study contributes to the scientific understanding of the influence of SFEE process variables on PLGA microspheres. Full article

(This article belongs to the Special Issue Supercritical Techniques for Pharmaceutical Applications)

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19 pages, 1856 KiB

Open AccessEditor’s ChoiceReview

Precise Therapy Using the Selective Endogenous Encapsidation for Cellular Delivery Vector System

by Vacis Tatarūnas, Ieva Čiapienė and Agnė Giedraitienė

Pharmaceutics 2024, 16(2), 292; https://doi.org/10.3390/pharmaceutics16020292 - 19 Feb 2024

Cited by 2 | Viewed by 2014

Abstract

Interindividual variability in drug response is a major problem in the prescription of pharmacological treatments. The therapeutic effect of drugs can be influenced by human genes. Pharmacogenomic guidelines for individualization of treatment have been validated and used for conventional dosage forms. However, drugs [...] Read more.

Interindividual variability in drug response is a major problem in the prescription of pharmacological treatments. The therapeutic effect of drugs can be influenced by human genes. Pharmacogenomic guidelines for individualization of treatment have been validated and used for conventional dosage forms. However, drugs can often target non-specific areas and produce both desired and undesired pharmacological effects. The use of nanoparticles, liposomes, or other available forms for drug formulation could help to overcome the latter problem. Virus-like particles based on retroviruses could be a potential envelope for safe and efficient drug formulations. Human endogenous retroviruses would make it possible to overcome the host immune response and deliver drugs to the desired target. PEG10 is a promising candidate that can bind to mRNA because it is secreted like an enveloped virus-like extracellular vesicle. PEG10 is a retrotransposon-derived gene that has been domesticated. Therefore, formulations with PEG10 may have a lower immunogenicity. The use of existing knowledge can lead to the development of suitable drug formulations for the precise treatment of individual diseases. Full article

(This article belongs to the Special Issue New Pharmaceutical Formulations for Personalized Therapies)

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20 pages, 1059 KiB

Open AccessEditor’s ChoiceSystematic Review

Biological Properties and Medical Applications of Carbonate Apatite: A Systematic Review

by Ralitsa Yotsova and Stefan Peev

Pharmaceutics 2024, 16(2), 291; https://doi.org/10.3390/pharmaceutics16020291 - 18 Feb 2024

Cited by 2 | Viewed by 2011

Abstract

Bone defects represent an everyday challenge for clinicians who work in the fields of orthopedic surgery, maxillofacial and oral surgery, otorhinolaryngology, and dental implantology. Various bone substitutes have been developed and utilized, according to the needs of bone reconstructive surgery. Carbonate apatite has [...] Read more.

Bone defects represent an everyday challenge for clinicians who work in the fields of orthopedic surgery, maxillofacial and oral surgery, otorhinolaryngology, and dental implantology. Various bone substitutes have been developed and utilized, according to the needs of bone reconstructive surgery. Carbonate apatite has gained popularity in recent years, due to its excellent tissue behavior and osteoconductive potential. This systematic review aims to evaluate the role of carbonate apatite in bone reconstructive surgery and tissue engineering, analyze its advantages and limitations, and suggest further directions for research and development. The Web of Science, PubMed, and Scopus electronic databases were searched for relevant review articles, published from January 2014 to 21 July 2023. The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eighteen studies were included in the present review. The biological properties and medical applications of carbonate apatite (CO₃Ap) are discussed and evaluated. The majority of articles demonstrated that CO₃Ap has excellent biocompatibility, resorbability, and osteoconductivity. Furthermore, it resembles bone tissue and causes minimal immunological reactions. Therefore, it may be successfully utilized in various medical applications, such as bone substitution, scaffolding, implant coating, drug delivery, and tissue engineering. Full article

(This article belongs to the Special Issue Biomedical Applications: Advances in Bioengineering and Drug Delivery)

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19 pages, 2945 KiB

Open AccessEditor’s ChoiceArticle

Intranasal Delivery of Anti-Apoptotic siRNA Complexed with Fas-Signaling Blocking Peptides Attenuates Cellular Apoptosis in Brain Ischemia

by Kunho Chung, Irfan Ullah, Yujong Yi, Eunhwa Kang, Gyeongju Yun, Seoyoun Heo, Minkyung Kim, Seong-Eun Chung, Seongjun Park, Jaeyeoung Lim, Minhyung Lee, Taiyoun Rhim and Sang-Kyung Lee

Pharmaceutics 2024, 16(2), 290; https://doi.org/10.3390/pharmaceutics16020290 - 18 Feb 2024

Cited by 1 | Viewed by 1378

Abstract

Ischemic stroke-induced neuronal cell death leads to the permanent impairment of brain function. The Fas-mediating extrinsic apoptosis pathway and the cytochrome c-mediating intrinsic apoptosis pathway are two major molecular mechanisms contributing to neuronal injury in ischemic stroke. In this study, we employed a [...] Read more.

Ischemic stroke-induced neuronal cell death leads to the permanent impairment of brain function. The Fas-mediating extrinsic apoptosis pathway and the cytochrome c-mediating intrinsic apoptosis pathway are two major molecular mechanisms contributing to neuronal injury in ischemic stroke. In this study, we employed a Fas-blocking peptide (FBP) coupled with a positively charged nona-arginine peptide (9R) to form a complex with negatively charged siRNA targeting Bax (FBP9R/siBax). This complex is specifically designed to deliver siRNA to Fas-expressing ischemic brain cells. This complex enables the targeted inhibition of Fas-mediating extrinsic apoptosis pathways and cytochrome c-mediating intrinsic apoptosis pathways. Specifically, the FBP targets the Fas/Fas ligand signaling, while siBax targets Bax involved in mitochondria disruption in the intrinsic pathway. The FBP9R carrier system enables the delivery of functional siRNA to hypoxic cells expressing the Fas receptor on their surface—a finding validated through qPCR and confocal microscopy analyses. Through intranasal (IN) administration of FBP9R/siCy5 to middle cerebral artery occlusion (MCAO) ischemic rat models, brain imaging revealed the complex specifically localized to the Fas-expressing infarcted region but did not localize in the non-infarcted region of the brain. A single IN administration of FBP9R/siBax demonstrated a significant reduction in neuronal cell death by effectively inhibiting Fas signaling and preventing the release of cytochrome c. The targeted delivery of FBP9R/siBax represents a promising alternative strategy for the treatment of brain ischemia. Full article

(This article belongs to the Special Issue Nasal Drug Delivery: Challenges and Future Opportunities)

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46 pages, 9227 KiB

Open AccessEditor’s ChoiceReview

Carbon-Based Nanostructures as Emerging Materials for Gene Delivery Applications

by Sara Yazdani, Mehrdad Mozaffarian, Gholamreza Pazuki, Naghmeh Hadidi, Ilia Villate-Beitia, Jon Zárate, Gustavo Puras and Jose Luis Pedraz

Pharmaceutics 2024, 16(2), 288; https://doi.org/10.3390/pharmaceutics16020288 - 18 Feb 2024

Cited by 7 | Viewed by 2544

Abstract

Gene therapeutics are promising for treating diseases at the genetic level, with some already validated for clinical use. Recently, nanostructures have emerged for the targeted delivery of genetic material. Nanomaterials, exhibiting advantageous properties such as a high surface-to-volume ratio, biocompatibility, facile functionalization, substantial [...] Read more.

Gene therapeutics are promising for treating diseases at the genetic level, with some already validated for clinical use. Recently, nanostructures have emerged for the targeted delivery of genetic material. Nanomaterials, exhibiting advantageous properties such as a high surface-to-volume ratio, biocompatibility, facile functionalization, substantial loading capacity, and tunable physicochemical characteristics, are recognized as non-viral vectors in gene therapy applications. Despite progress, current non-viral vectors exhibit notably low gene delivery efficiency. Progress in nanotechnology is essential to overcome extracellular and intracellular barriers in gene delivery. Specific nanostructures such as carbon nanotubes (CNTs), carbon quantum dots (CQDs), nanodiamonds (NDs), and similar carbon-based structures can accommodate diverse genetic materials such as plasmid DNA (pDNA), messenger RNA (mRNA), small interference RNA (siRNA), micro RNA (miRNA), and antisense oligonucleotides (AONs). To address challenges such as high toxicity and low transfection efficiency, advancements in the features of carbon-based nanostructures (CBNs) are imperative. This overview delves into three types of CBNs employed as vectors in drug/gene delivery systems, encompassing their synthesis methods, properties, and biomedical applications. Ultimately, we present insights into the opportunities and challenges within the captivating realm of gene delivery using CBNs. Full article

(This article belongs to the Special Issue Metal and Carbon Nanomaterials for Pharmaceutical Applications)

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19 pages, 1883 KiB

Open AccessEditor’s ChoiceReview

The Necessity to Investigate In Vivo Fate of Nanoparticle-Loaded Dissolving Microneedles

by Ziyao Chang, Yuhuan Wu, Ping Hu, Junhuang Jiang, Guilan Quan, Chuanbin Wu, Xin Pan and Zhengwei Huang

Pharmaceutics 2024, 16(2), 286; https://doi.org/10.3390/pharmaceutics16020286 - 17 Feb 2024

Cited by 1 | Viewed by 1721

Abstract

Transdermal drug delivery systems are rapidly gaining prominence and have found widespread application in the treatment of numerous diseases. However, they encounter the challenge of a low transdermal absorption rate. Microneedles can overcome the stratum corneum barrier to enhance the transdermal absorption rate. [...] Read more.

Transdermal drug delivery systems are rapidly gaining prominence and have found widespread application in the treatment of numerous diseases. However, they encounter the challenge of a low transdermal absorption rate. Microneedles can overcome the stratum corneum barrier to enhance the transdermal absorption rate. Among various types of microneedles, nanoparticle-loaded dissolving microneedles (DMNs) present a unique combination of advantages, leveraging the strengths of DMNs (high payload, good mechanical properties, and easy fabrication) and nanocarriers (satisfactory solubilization capacity and a controlled release profile). Consequently, they hold considerable clinical application potential in the precision medicine era. Despite this promise, no nanoparticle-loaded DMN products have been approved thus far. The lack of understanding regarding their in vivo fate represents a critical bottleneck impeding the clinical translation of relevant products. This review aims to elucidate the current research status of the in vivo fate of nanoparticle-loaded DMNs and elaborate the necessity to investigate the in vivo fate of nanoparticle-loaded DMNs from diverse aspects. Furthermore, it offers insights into potential entry points for research into the in vivo fate of nanoparticle-loaded DMNs, aiming to foster further advancements in this field. Full article

(This article belongs to the Special Issue Recent Advances in Microneedle-Mediated Drug Delivery, 2nd Edition)

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20 pages, 3000 KiB

Open AccessEditor’s ChoiceArticle

New Multitarget Rivastigmine–Indole Hybrids as Potential Drug Candidates for Alzheimer’s Disease

by Leo Bon, Angelika Banaś, Inês Dias, Inês Melo-Marques, Sandra M. Cardoso, Sílvia Chaves and M. Amélia Santos

Pharmaceutics 2024, 16(2), 281; https://doi.org/10.3390/pharmaceutics16020281 - 16 Feb 2024

Viewed by 1434

Abstract

Alzheimer’s disease (AD) is the most common form of dementia with no cure so far, probably due to the complexity of this multifactorial disease with diverse processes associated with its origin and progress. Several neuropathological hallmarks have been identified that encourage the search [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia with no cure so far, probably due to the complexity of this multifactorial disease with diverse processes associated with its origin and progress. Several neuropathological hallmarks have been identified that encourage the search for new multitarget drugs. Therefore, following a multitarget approach, nine rivastigmine–indole (RIV-IND) hybrids (5a1-3, 5b1-3, 5c1-3) were designed, synthesized and evaluated for their multiple biological properties and free radical scavenging activity, as potential multitarget anti-AD drugs. The molecular docking studies of these hybrids on the active center of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) suggest their capacity to act as dual enzyme inhibitors with probable greater disease-modifying impact relative to AChE-selective FDA-approved drugs. Compounds 5a3 (IC₅₀ = 10.9 µM) and 5c3 (IC₅₀ = 26.8 µM) revealed higher AChE inhibition than the parent RIV drug. Radical scavenging assays demonstrated that all the hybrids containing a hydroxyl substituent in the IND moiety (5a2-3, 5b2-3, 5c2-3) have good antioxidant activity (EC₅₀ 7.8–20.7 µM). The most effective inhibitors of Aβ₄₂ self-aggregation are 5a3, 5b3 and 5c3 (47.8–55.5%), and compounds 5b2 and 5c2 can prevent the toxicity induced by Aβ_1-42 to cells. The in silico evaluation of the drug-likeness of the hybrids also showed that all the compounds seem to have potential oral availability. Overall, within this class of RIV-IND hybrids, 5a3 and 5c3 appear as lead compounds for anti-AD drug candidates, deserving further investigation. Full article

(This article belongs to the Special Issue The Therapy of Alzheimer’s Disease: Towards a New Generation of Drugs)

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20 pages, 4286 KiB

Open AccessEditor’s ChoiceArticle

Chitosan and Anionic Solubility Enhancer Sulfobutylether-β-Cyclodextrin-Based Nanoparticles as Dexamethasone Ophthalmic Delivery System for Anti-Inflammatory Therapy

by Giuseppe Francesco Racaniello, Gennaro Balenzano, Ilaria Arduino, Rosa Maria Iacobazzi, Antonio Lopalco, Angela Assunta Lopedota, Hakon Hrafn Sigurdsson and Nunzio Denora

Pharmaceutics 2024, 16(2), 277; https://doi.org/10.3390/pharmaceutics16020277 - 16 Feb 2024

Cited by 1 | Viewed by 1638

Abstract

Cataract surgery interventions are constantly increasing, particularly among adult and elderly patients. This type of surgery can lead to inflammatory states of the ocular anterior segment (AS), usually healed via postoperative treatment with dexamethasone (DEX)-containing eye drops. The application of eye drops is [...] Read more.

Cataract surgery interventions are constantly increasing, particularly among adult and elderly patients. This type of surgery can lead to inflammatory states of the ocular anterior segment (AS), usually healed via postoperative treatment with dexamethasone (DEX)-containing eye drops. The application of eye drops is challenging due to the high number of daily administrations. In this study, mucoadhesive nanoparticles (NPs) were formulated to improve the residence time of DEX on the corneal mucosa, enhancing the drug’s solubility and bioavailability. The NPs were generated using an ionotropic gelation technique, exploiting the interaction between the cationic group of chitosan (CS) and the anionic group of sulfobutylether-β-cyclodextrin (SBE-β-CD). The formation of the inclusion complex and its stoichiometry were studied through phase solubility studies, Job’s plot method, and Bi-directional transport studies on MDCKII-MDR1. The obtained NPs showed good chemical and physical characteristics suitable for drug loading and subsequent testing on animal mucosa. The DEX-loaded CS/SBE-β-CD NPs exhibited a prolonged residence time on animal mucosa and demonstrated enhanced drug permeability through the corneal membrane, showing a sustained release profile. The developed NPs posed no irritation or toxicity concerns upon local administration, making them an optimal and innovative drug delivery system for inflammatory AS diseases treatment. Full article

(This article belongs to the Special Issue Development of Chitosan/Cyclodextrins in Drug Delivery Field)

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21 pages, 9678 KiB

Open AccessEditor’s ChoiceArticle

Triphenylphosphonium-Functionalized Gold Nanorod/Zinc Oxide Core–Shell Nanocomposites for Mitochondrial-Targeted Phototherapy

by Ara Joe, Hyo-Won Han, Yu-Ra Lim, Panchanathan Manivasagan and Eue-Soon Jang

Pharmaceutics 2024, 16(2), 284; https://doi.org/10.3390/pharmaceutics16020284 - 16 Feb 2024

Cited by 2 | Viewed by 1272

Abstract

Phototherapies, such as photothermal therapy (PTT) and photodynamic therapy (PDT), combined with novel all-in-one light-responsive nanocomposites have recently emerged as new therapeutic modalities for the treatment of cancer. Herein, we developed novel all-in-one triphenylphosphonium-functionalized gold nanorod/zinc oxide core–shell nanocomposites (CTPP-GNR@ZnO) for mitochondrial-targeted PTT/PDT [...] Read more.

Phototherapies, such as photothermal therapy (PTT) and photodynamic therapy (PDT), combined with novel all-in-one light-responsive nanocomposites have recently emerged as new therapeutic modalities for the treatment of cancer. Herein, we developed novel all-in-one triphenylphosphonium-functionalized gold nanorod/zinc oxide core–shell nanocomposites (CTPP-GNR@ZnO) for mitochondrial-targeted PTT/PDT owing to their good biocompatibility, tunable and high optical absorption, photothermal conversion efficiency, highest reactive oxygen species (ROS) generation, and high mitochondrial-targeting capability. Under laser irradiation of 780 nm, the CTPP-GNR@ZnO core–shell nanocomposites effectively produced heat in addition to generating ROS to induce cell death, implying a synergistic effect of mild PTT and PDT in combating cancer. Notably, the in vitro PTT/PDT effect of CTPP-GNR@ZnO core–shell nanocomposites exhibited effective cell ablation (95%) and induced significant intracellular ROS after the 780 nm laser irradiation for 50 min, indicating that CTPP in CTPP-GNR@ZnO core–shell nanocomposites can specifically target the mitochondria of CT-26 cells, as well as generate heat and ROS to completely kill cancer cells. Overall, this light-responsive nanocomposite-based phototherapy provides a new approach for cancer synergistic therapy. Full article

(This article belongs to the Special Issue Metal Nanoparticles for Cancer Therapy, 2nd Edition)

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42 pages, 2857 KiB

Open AccessEditor’s ChoiceReview

Chemical Insights into Topical Agents in Intraocular Pressure Management: From Glaucoma Etiopathology to Therapeutic Approaches

by Geewoo Nam Patton and Hyuck Jin Lee

Pharmaceutics 2024, 16(2), 274; https://doi.org/10.3390/pharmaceutics16020274 - 15 Feb 2024

Cited by 1 | Viewed by 1538

Abstract

Glaucoma encompasses a group of optic neuropathies characterized by complex and often elusive etiopathology, involvihttng neurodegeneration of the optic nerve in conjunction with abnormal intraocular pressure (IOP). Currently, there is no cure for glaucoma, and treatment strategies primarily aim to halt disease progression [...] Read more.

Glaucoma encompasses a group of optic neuropathies characterized by complex and often elusive etiopathology, involvihttng neurodegeneration of the optic nerve in conjunction with abnormal intraocular pressure (IOP). Currently, there is no cure for glaucoma, and treatment strategies primarily aim to halt disease progression by managing IOP. This review delves into the etiopathology, diagnostic methods, and treatment approaches for glaucoma, with a special focus on IOP management. We discuss a range of active pharmaceutical ingredients used in glaucoma therapy, emphasizing their chemical structure, pharmacological action, therapeutic effectiveness, and safety/tolerability profiles. Notably, most of these therapeutic agents are administered as topical formulations, a critical aspect considering patient compliance and drug delivery efficiency. The classes of glaucoma therapeutics covered in this review include prostaglandin analogs, beta blockers, alpha agonists, carbonic anhydrase inhibitors, Rho kinase inhibitors, and miotic (cholinergic) agents. This comprehensive overview highlights the importance of topical administration in glaucoma treatment, offering insights into the current state and future directions of pharmacological management in glaucoma. Full article

(This article belongs to the Special Issue Topical Drug Delivery: Current Status and Perspectives)

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38 pages, 8570 KiB

Open AccessEditor’s ChoiceArticle

Development and Characterization of New Miconazole-Based Microemulsions for Buccal Delivery by Implementing a Full Factorial Design Modeling

by Marina-Theodora Talianu, Cristina-Elena Dinu-Pîrvu, Mihaela Violeta Ghica, Valentina Anuţa, Răzvan Mihai Prisada and Lăcrămioara Popa

Pharmaceutics 2024, 16(2), 271; https://doi.org/10.3390/pharmaceutics16020271 - 14 Feb 2024

Cited by 3 | Viewed by 1711

Abstract

This research aimed to develop miconazole-based microemulsions using oleic acid as a natural lipophilic phase and a stabilizer mixture comprising Tween 20 and PEG 400 to solubilize miconazole as an antifungal agent known for its activity in oral candidiasis and to improve its [...] Read more.

This research aimed to develop miconazole-based microemulsions using oleic acid as a natural lipophilic phase and a stabilizer mixture comprising Tween 20 and PEG 400 to solubilize miconazole as an antifungal agent known for its activity in oral candidiasis and to improve its bioavailability. The formulation and preparation process was combined with a mathematical approach using a 2³-full factorial plan. Fluid and gel-like microemulsions were obtained and analyzed considering pH, conductivity, and refractive index, followed by extensive analyses focused on droplet size, zeta potential, rheological behavior, and goniometry. In vitro release tests were performed to assess their biopharmaceutical characteristics. Independent variables coded X₁-Oleic acid (%, w/w), X₂-Tween 20 (%, w/w), and X₃-PEG 400 (%, w/w) were analyzed in relationship with three main outputs like mean droplet size, work of adhesion, and diffusion coefficient by combining statistical tools with response surface methodology. The microemulsion containing miconazole base–2%, oleic acid–5%, Tween 20–40%, PEG 400–20%, and water–33% exhibited a mean droplet size of 119.6 nm, a work of adhesion of 71.98 mN/m, a diffusion coefficient of 2.11·10⁻⁵ cm²/s, and together with remarked attributes of two gel-like systems formulated with higher oil concentrations, modeled the final optimization step of microemulsions as potential systems for buccal delivery. Full article

(This article belongs to the Special Issue Advanced Strategies for Sublingual and Buccal Drug Delivery)

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22 pages, 2892 KiB

Open AccessEditor’s ChoiceReview

The Evolution of Emerging Nanovesicle Technologies for Enhanced Delivery of Molecules into and across the Skin

by Elka Touitou and Hiba Natsheh

Pharmaceutics 2024, 16(2), 267; https://doi.org/10.3390/pharmaceutics16020267 - 13 Feb 2024

Cited by 3 | Viewed by 1720

Abstract

This review focuses on nanovesicular carriers for enhanced delivery of molecules into and across the skin, from their design to recent emerging technologies. During the last four decades, several approaches have been used aiming to design new nanovesicles, some of them by altering [...] Read more.

This review focuses on nanovesicular carriers for enhanced delivery of molecules into and across the skin, from their design to recent emerging technologies. During the last four decades, several approaches have been used aiming to design new nanovesicles, some of them by altering the properties of the classic phospholipid vesicle, the liposome. Phospholipid nanovesicular systems, including the phospholipid soft vesicles as well as the non-phospholipid vesicular carries, are reviewed. The altered nanovesicles have served in the manufacture of various cosmetic products and have been investigated and used for the treatment of a wide variety of skin conditions. The evolution and recent advances of these nanovesicular technologies are highlighted in this review. Full article

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

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17 pages, 2401 KiB

Open AccessEditor’s ChoiceArticle

Sample Size Requirements of a Pharmaceutical Material Library: A Case in Predicting Direct Compression Tablet Tensile Strength by Latent Variable Modeling

by Junjie Cao, Haoran Shen, Shuying Zhao, Xiao Ma, Liping Chen, Shengyun Dai, Bing Xu and Yanjiang Qiao

Pharmaceutics 2024, 16(2), 242; https://doi.org/10.3390/pharmaceutics16020242 - 7 Feb 2024

Viewed by 1343

Abstract

The material library is an emerging, new data-driven approach for developing pharmaceutical process models. How many materials or samples should be involved in a particular application scenario is unclear, and the impact of sample size on process modeling is worth discussing. In this [...] Read more.

The material library is an emerging, new data-driven approach for developing pharmaceutical process models. How many materials or samples should be involved in a particular application scenario is unclear, and the impact of sample size on process modeling is worth discussing. In this work, the direct compression process was taken as the research object, and the effects of different sample sizes of material libraries on partial least squares (PLS) modeling in the prediction of tablet tensile strength were investigated. A primary material library comprising 45 materials was built. Then, material subsets containing 5 × i (i = 1, 2, 3, …, 8) materials were sampled from the primary material library. Each subset underwent sampling 1000 times to analyze variations in model fitting performance. Both hierarchical sampling and random sampling were employed and compared, with hierarchical sampling implemented with the help of the tabletability classification index d. For each subset, modeling data were organized, incorporating 18 physical properties and tableting pressure as the independent variables and tablet tensile strength as the dependent variable. A series of chemometric indicators was used to assess model performance and find important materials for model training. It was found that the minimum R² and RMSE values reached their maximum, and the corresponding values were kept almost unchanged when the sample sizes varied from 20 to 45. When the sample size was smaller than 15, the hierarchical sampling method was more reliable in avoiding low-quality few-shot PLS models than the random sampling method. Two important materials were identified as useful for building an initial material library. Overall, this work demonstrated that as the number of materials increased, the model’s reliability improved. It also highlighted the potential for effective few-shot modeling on a small material library by controlling its information richness. Full article

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