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Pharmaceutics
Volume 17
Issue 9
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Pharmaceutics, Volume 17, Issue 9 (September 2025) – 107 articles

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33 pages, 7255 KB  
Article
Anti-Psoriatic Pharmacodynamic Material Basis of Dictamni Cortex Based on Transdermal Constituents Group
by Zhaoyu Wang, Mengting Pi, Ziang Gao, Maobo Du, Liwei Gu, Shuzhi Liu and Shuo Shen
Pharmaceutics 2025, 17(9), 1195; https://doi.org/10.3390/pharmaceutics17091195 (registering DOI) - 14 Sep 2025
Abstract
Background: Psoriasis is a chronic inflammatory skin disorder for which topical medications are the preferred treatment option. However, current therapies are limited by adverse reactions, drug resistance, and economic burdens. Dictamni Cortex (DC; the root bark of Dictamnus dasycarpus Turcz.) has a long [...] Read more.
Background: Psoriasis is a chronic inflammatory skin disorder for which topical medications are the preferred treatment option. However, current therapies are limited by adverse reactions, drug resistance, and economic burdens. Dictamni Cortex (DC; the root bark of Dictamnus dasycarpus Turcz.) has a long history in the treatment of psoriasis, with its transdermal bioactive constituents serving as the pharmacodynamic foundation for topical anti-psoriatic therapy. Methods: Building on the separation of DC’s chemical constituents, this study integrated ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) and network pharmacology, along with activity verification, to investigate the anti-psoriatic active components among the transdermal constituents of DC. Results: Forty-one chemical constituents were characterized in DC, including 26 transdermally permeable compounds, predominantly alkaloids and limonoids. Network pharmacological analysis revealed core targets, including MMP9 and TLR4, as well as multiple pathways related to inflammatory and immune responses. Molecular docking studies identified dictamnine, jangomolide, rutaevin, and other key transdermal constituents that exhibited high binding affinity to core targets. In vitro validation showed that these compounds significantly suppressed cellular proliferation (p < 0.05) and downregulated Ki67 mRNA expression (p < 0.05) in the psoriasis-like HaCaT cell model. Concurrently, they significantly reduced secretion of key pro-inflammatory cytokines, including IL-17A, IL-22, IL-1β, IL-6, and IL-8 (p < 0.05). Comprehensive comparative analyses confirmed that dictamnine exhibited ideal anti-psoriatic efficacy. Conclusions: These results provide a pharmacological substance basis for the development of external preparations of DC for treating psoriasis and provide novel research concepts for investigating the pharmacodynamic material basis of Traditional Chinese Medicine topical drugs. Full article
(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)
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16 pages, 2533 KB  
Article
Examining the Impact of Storage Conditions on the Stability of a Liquid Formulation of mRNA-Loaded Lipid Nanoparticles
by Mina Sato, Eleni Samaridou, Moritz Beck-Broichsitter, Masatoshi Maeki, Shunsuke Kita, Manabu Tokeshi, Katsumi Maenaka, Hideyoshi Harashima and Yusuke Sato
Pharmaceutics 2025, 17(9), 1194; https://doi.org/10.3390/pharmaceutics17091194 (registering DOI) - 14 Sep 2025
Abstract
Background/Objectives: This study investigated the effect of storage conditions on mRNA-LNPs in situ via identification of the formulation traits necessary for improving storage stability. Methods: We synthesized an ionizable lipid, namely TOT-28, which has a hydrolysis-susceptible ester bond in its hydrophilic [...] Read more.
Background/Objectives: This study investigated the effect of storage conditions on mRNA-LNPs in situ via identification of the formulation traits necessary for improving storage stability. Methods: We synthesized an ionizable lipid, namely TOT-28, which has a hydrolysis-susceptible ester bond in its hydrophilic head group that allows it to act as an indicator of the hydrophilic environment within the mRNA-LNPs. LNPs were stored either at 4 or 25 °C for up to 8 weeks to investigate the effect of pH and temperature on ester hydrolysis, internal mRNA integrity, physicochemical properties of the LNPs, and mRNA gene expression. Results: The results indicate that, at 25 °C, a lower buffer pH increases ester hydrolysis, whereas an opposite trend slightly occurs in ester hydrolysis with storage at 4 °C. We also found that TOT-28-based LNPs were less hydrated and microviscosity was higher at 4 °C compared with storage temperature at 25 °C. Therefore, TOT-28-based LNPs seem less sensitive to external buffer solutions because of a higher-order structure when stored at lower temperatures. In addition, we found that LNPs with different ionizable lipid structures exhibit distinct responses to pH changes at specific storage temperatures. Conclusions: Our findings provide novel insights into the appropriate conditions for long-term storage of the mRNA-LNPs as a liquid formulation. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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26 pages, 3111 KB  
Article
Improved Dual-Modality Bioequivalence Evaluation of Topical Formulations Within Human Skin Using Stimulated Raman Scattering Microscopy
by Dandan Tu, Nick-Sidney Lemberger, Kristin Wallmeier, Jackson Riseman, Benjamin A. Kuzma, Yuxiao Wei, Ting Chean Khoo, Elena Rantou, Priyanka Ghosh, Markham C. Luke, Sam G. Raney, Carsten Fallnich and Conor L. Evans
Pharmaceutics 2025, 17(9), 1193; https://doi.org/10.3390/pharmaceutics17091193 (registering DOI) - 13 Sep 2025
Abstract
Background: The use of optical microscopic techniques has gained increasing attention in recent years for studying the bioavailability (BA) and bioequivalence (BE) of topical drugs. Stimulated Raman scattering (SRS), one type of optical imaging technique, probes chemical-specific information and has excellent spatiotemporal resolution. [...] Read more.
Background: The use of optical microscopic techniques has gained increasing attention in recent years for studying the bioavailability (BA) and bioequivalence (BE) of topical drugs. Stimulated Raman scattering (SRS), one type of optical imaging technique, probes chemical-specific information and has excellent spatiotemporal resolution. It uses intrinsic molecular vibrational signatures, and therefore, labeling samples or other treatments is unnecessary to track a molecule. Because of its unique advantages, studies have used SRS for BA evaluations and, more recently, for BE evaluations. In BE evaluation, low data variance within a treatment group is important to ensure sensitivity and specificity in comparing treatment groups. Methods: When measuring forward-direction SRS signals transmitted through skin, the signal intensity is susceptible to variance due to several factors, such as the microscope system’s performance, the different optical features of topical drug products, and the heterogeneity of skin in transmitting light. This work closely investigated the effects of these factors on an SRS signal and developed solutions to reduce their effects on the data variance. Specifically, we constructed a method using a dual-modality detector built in-house, which simultaneously measured both the SRS signal and total light transmission synchronized in time and co-registered in space. Results: We developed equations to normalize SRS signals using the transmission intensity, and the results demonstrated a clear improvement in the SRS signal via a reduction in the signal variance (up to a 9.46% CV value decrease) that is otherwise caused by various factors associated with the use of topical drugs and the composition of the skin. We carried out an exploratory BE study using tretinoin-containing topical products and observed improvements in BE assessment with the developed method (could achieve a reduction of 0.11 in the CI value). Conclusions: This work has led to a better understanding of the factors that affect SRS imaging and has provided an effective method to compensate for these factors in BE assessments. This is a critical initial effort for better practical implementation of SRS in cutaneous pharmacokinetics (cPKs) studies of topical drugs. Full article
(This article belongs to the Section Physical Pharmacy and Formulation)
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28 pages, 5916 KB  
Review
Recent Advances in Supramolecular Systems for Precision Medicine: Structural Design, Functional Integration, and Clinical Translation Challenges
by Xiaomin Ma, Yazhe Xiao, Shuyu Li, Jianghai Du, Junjie Wang and Xingzhou Peng
Pharmaceutics 2025, 17(9), 1192; https://doi.org/10.3390/pharmaceutics17091192 (registering DOI) - 13 Sep 2025
Abstract
Non-covalent and dynamic covalent interactions enable supramolecular systems to function as adaptive platforms in biomedical research, offering novel strategies for precision medicine applications. This review examines five-year developments in supramolecular applications across precision medical domains, including disease diagnosis, bioimaging, targeted drug delivery, tissue [...] Read more.
Non-covalent and dynamic covalent interactions enable supramolecular systems to function as adaptive platforms in biomedical research, offering novel strategies for precision medicine applications. This review examines five-year developments in supramolecular applications across precision medical domains, including disease diagnosis, bioimaging, targeted drug delivery, tissue engineering, and gene therapy. The review begins by systematically categorizing supramolecular structures into dynamic covalent systems (e.g., disulfide bonds, boronate esters, and hydrazone bonds) and dynamic non-covalent systems (e.g., host–guest interactions, hydrogen-bond networks, metal coordination, and π–π stacking), highlighting current strategies employed to optimize their responsiveness, stability, and targeting efficiency. Representative case studies, such as cyclodextrin-based nanocarriers and metal–organic frameworks (MOFs), are thoroughly analyzed to illustrate how supramolecular systems can enhance precision in drug delivery and improve biocompatibility. Furthermore, this article critically discusses major challenges faced during clinical translation, encompassing structural instability, inadequate specificity of environmental responsiveness, pharmacokinetic and toxicity concerns, and difficulties in scalable manufacturing. Potential future directions to overcome these barriers are proposed, emphasizing biomimetic interface engineering and dynamic crosslinking strategies. Collectively, the continued evolution in structural optimization and functional integration within supramolecular systems holds great promise for achieving personalized diagnostic and therapeutic platforms, thereby accelerating their translation into clinical practice and profoundly shaping the future landscape of precision medicine. Full article
(This article belongs to the Special Issue Recent Insights Concerning the Use of Supramolecular Systems for Biomedical Applications)
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21 pages, 3539 KB  
Article
Sustained-Release Biodegradable Intracameral Implants Containing Dexamethasone and Moxifloxacin: Development and In Vivo Primary Assessment
by Pablo Miranda, Luis Ignacio Tártara, Analía Castro, Patricia Zimet, Ricardo Faccio, Santiago Daniel Palma, Álvaro W. Mombrú and Helena Pardo
Pharmaceutics 2025, 17(9), 1191; https://doi.org/10.3390/pharmaceutics17091191 (registering DOI) - 13 Sep 2025
Abstract
Background/Objectives: We report the development of a novel intraocular sustained-release implantable pharmaceutical formulation, designed to be placed in the anterior chamber of the eye after cataract surgery. The device is intended to reduce postoperative inflammation, and to prevent opportunistic bacterial infections that [...] Read more.
Background/Objectives: We report the development of a novel intraocular sustained-release implantable pharmaceutical formulation, designed to be placed in the anterior chamber of the eye after cataract surgery. The device is intended to reduce postoperative inflammation, and to prevent opportunistic bacterial infections that may lead to endophthalmitis. Methods: The implants were produced via hot-melt extrusion, using a twin-screw extruder to process a homogeneous mixture of polylactide-co-glycolic acid, moxifloxacin hydrochloride (MOX HCl) and dexamethasone (DEX). Quality control tests included drug content determination, release rate profile evaluation, and several instrumental characterization techniques (scanning electron microscopy (SEM), confocal Raman microscopy, differential scanning calorimetry, and X-ray diffraction). Long-term and accelerated stability tests were also performed, following ICH guidelines. Sterilization was achieved by exposing samples to gamma radiation. In vivo exploratory studies were carried out in healthy rabbits to evaluate the safety and overall performance of the implantable formulation. Results: In terms of quality control, drug content was found to be homogeneously distributed throughout the implants, and it also met the label claim. In vitro release rate was constant for MOX HCl, but non-linear for DEX, increasing over time. In vivo preliminary tests showed that the inserts completely biodegraded within approximately 20 days. No clinical signs of anterior segment toxic syndrome or statistically significant intraocular pressure differences were found between treatment and control groups. Conclusions: The implants developed in this study can act as sustained-release depots for the delivery of both DEX and MOX HCl, and are biocompatible with ocular structures. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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31 pages, 1519 KB  
Review
Personalized Therapeutic Advances in Erythropoietin Signaling: From Anemia Management to Extensive Clinical Applications
by Elena-Christen Creangă, Raluca Stan, Alina-Crenguţa Nicolae, Cristina Manuela Drăgoi and Ion-Bogdan Dumitrescu
Pharmaceutics 2025, 17(9), 1190; https://doi.org/10.3390/pharmaceutics17091190 (registering DOI) - 12 Sep 2025
Abstract
Erythropoietin (EPO) is a glycoprotein hormone essential for red blood cell production and a cornerstone therapy for anemia, particularly in chronic kidney disease. Beyond hematopoiesis, EPO exerts pleiotropic effects on metabolism, neuroprotection, and tissue regeneration. This review summarizes current insights into the molecular [...] Read more.
Erythropoietin (EPO) is a glycoprotein hormone essential for red blood cell production and a cornerstone therapy for anemia, particularly in chronic kidney disease. Beyond hematopoiesis, EPO exerts pleiotropic effects on metabolism, neuroprotection, and tissue regeneration. This review summarizes current insights into the molecular mechanisms, pharmacokinetics, and clinical applications of recombinant human EPO (rHuEPO) and its analogs, with emphasis on personalized therapeutic strategies. Emerging evidence highlights both therapeutic opportunities and risks, including resistance, cardiovascular complications, and misuse in sports doping. Advances in detection methods, pharmacogenomics, and the development of novel agents such as HIF-prolyl hydroxylase inhibitors are discussed, underscoring the expanding role of EPO in precision medicine. Full article
(This article belongs to the Special Issue Emerging Strategies in Drug Development and Clinical Care in the Era of Personalized and Precision Medicine, 2nd Edition)
33 pages, 4412 KB  
Article
Sprayable Hybrid Gel with Cannabidiol, Hyaluronic Acid, and Colloidal Silver: A Multifunctional Approach for Skin Lesion Therapy
by Geta-Simona Cîrloiu (Boboc), Adina-Elena Segneanu, Ludovic Everard Bejenaru, Marius Ciprian Văruţ, Roxana Maria Bălăşoiu, Daniela Călina, Andreea-Cristina Stoian, Georgiana Băluşescu, Dumitru-Daniel Herea, Maria Viorica Ciocîlteu, Andrei Biţă, George Dan Mogoşanu and Cornelia Bejenaru
Pharmaceutics 2025, 17(9), 1189; https://doi.org/10.3390/pharmaceutics17091189 (registering DOI) - 12 Sep 2025
Abstract
Background/Objectives: This study presents the development and characterization of a novel thermoresponsive hydrogel composed of hyaluronic acid (HA), poloxamer 407, cannabidiol (CBD), and colloidal silver (Ag), designed for topical antimicrobial therapy. Methods: The Ag-CBD complex was first synthesized and subsequently incorporated [...] Read more.
Background/Objectives: This study presents the development and characterization of a novel thermoresponsive hydrogel composed of hyaluronic acid (HA), poloxamer 407, cannabidiol (CBD), and colloidal silver (Ag), designed for topical antimicrobial therapy. Methods: The Ag-CBD complex was first synthesized and subsequently incorporated into a HA–poloxamer gel matrix to produce a stable, sprayable formulation with suitable physicochemical properties for dermal applications. Results: The HA-Ag-CBD hybrid gel exhibited a physiological pH, a gelation temperature compatible with skin surface conditions, and favorable rheological behavior, including thixotropy and shear thinning—critical for uniform application and retention under dynamic conditions. Release studies confirmed a sustained delivery profile, supporting prolonged local activity of CBD and colloidal Ag. Antimicrobial assays demonstrated that the HA-Ag-CBD hybrid gel retained potent activity against Staphylococcus aureus and Candida albicans, with minimum inhibitory and bactericidal concentrations (MIC/MBC) statistically comparable to those of the unencapsulated Ag-CBD complex. Against E. coli, the HA-Ag-CBD hydrogel exhibited primarily bacteriostatic activity, with a low MIC (9.24 μg/mL) but a substantially higher MBC (387.35 μg/mL), consistent with the intrinsic structural resistance of Gram-negative bacteria. In contrast, bactericidal activity was more pronounced against Gram-positive strains, reflecting differential susceptibility related to bacterial envelope properties. CBD consistently demonstrated superior antimicrobial efficacy to colloidal Ag, while the Ag-CBD combination produced slightly enhanced, mainly additive effects, likely due to complementary membrane disruption and intracellular Ag+ ion activity. Cytotoxicity assays on normal human dermal fibroblasts confirmed that the HA-Ag-CBD hybrid gel maintained >70% cell viability at therapeutically relevant concentrations, in accordance with ISO 10993-5:2009 guidelines, and effectively mitigated the inherent cytotoxicity of the Ag-CBD complex. Conclusions: The HA-Ag-CBD hybrid gel demonstrates strong potential as a biocompatible, multifunctional topical formulation for the treatment of infected wounds and skin lesions. Future work will focus on in vivo evaluation, assessment of skin permeation, and further development to support translational applications. Full article
(This article belongs to the Special Issue Advances in Bioactive Compounds and Nanotechnology: Sustainable Approaches for Pharmaceutical Applications)
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21 pages, 7555 KB  
Article
Quercetin Nanocrystal Gel: A Novel Topical Therapeutic Strategy for Androgenetic Alopecia
by Yaya Su, Yuwen Zhu, Lei Ren, Xiang Deng, Rui Song, Lingling Wu, Zhihui Yang and Hailong Yuan
Pharmaceutics 2025, 17(9), 1188; https://doi.org/10.3390/pharmaceutics17091188 - 12 Sep 2025
Abstract
Purpose: Androgenetic alopecia (AGA) is a common, chronic, non-cicatricial dermatological condition characterized by progressive miniaturization of hair follicles. Although AGA is a benign disorder, it has a considerable impact on patients’ quality of life and psychological health. The current treatment options often demonstrate [...] Read more.
Purpose: Androgenetic alopecia (AGA) is a common, chronic, non-cicatricial dermatological condition characterized by progressive miniaturization of hair follicles. Although AGA is a benign disorder, it has a considerable impact on patients’ quality of life and psychological health. The current treatment options often demonstrate limited efficacy and are frequently associated with undesirable side effects. This study aimed to co-mill two natural compounds, quercetin (QT) and glycyrrhizic acid (GL), to develop follicle-targeted nanocrystals (NCs), thereby enhancing local accumulation, improving the pathological follicular microenvironment associated with AGA, and promoting hair regrowth. Methods: QT nanocrystals (QT-NCs) were fabricated using a top–down wet media milling technique with GL as a bioactive stabilizer. The resulting QT-NCs were characterized regarding their particle size, crystallinity, morphology, and stability. The skin permeation properties of the QT-NCs were further evaluated in vitro, and their therapeutic efficacy was assessed in a dihydrotestosterone (DHT)-induced AGA mouse model. Results: The QT-NCs exhibited an irregular structure with a particle size ranging from 200 to 300 nm, demonstrating uniform dimensions and excellent storage stability. In vitro permeation studies revealed a 2.27-fold increase in cumulative penetration and a 2.47-fold enhancement in skin retention compared to raw QT. In the DHT-induced AGA mouse model, QT-NCs significantly reduced local DHT levels while concurrently modulating the follicular microenvironment, resulting in markedly improved therapeutic outcomes. Notably, when co-administered, QT and GL demonstrated synergistic pharmacological effects, suggesting potential combinatory benefits. Conclusions: This study presents the first demonstration of QT-NCs for AGA treatment, establishing a novel therapeutic strategy with substantial potential for clinical translation. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
27 pages, 2849 KB  
Article
Development of pH-Sensitive Multiparticulates for Orally Disintegrating Tablets of Proton Pump Inhibitors: Physicochemical Characterization and Drug Release Studies
by Mahendra Singh, Punna Reddy Ullapu, Arokia Vijaya Anand Mariadoss, Satyender Kumar and Sung Gu Kang
Pharmaceutics 2025, 17(9), 1187; https://doi.org/10.3390/pharmaceutics17091187 - 12 Sep 2025
Abstract
Background/Objectives: Enteric coating protects active pharmaceutical ingredients from gastric degradation, but conventional tablets may present swallowing difficulties in geriatric and pediatric patients. Hence, this study intended to develop pH-responsive multiparticulates, formulated into orally disintegrating tablets (ODTs), for targeted intestinal drug delivery in individuals [...] Read more.
Background/Objectives: Enteric coating protects active pharmaceutical ingredients from gastric degradation, but conventional tablets may present swallowing difficulties in geriatric and pediatric patients. Hence, this study intended to develop pH-responsive multiparticulates, formulated into orally disintegrating tablets (ODTs), for targeted intestinal drug delivery in individuals with dysphagia. Methods: Multiparticulates were developed via sequential seal coating, drug layering, sub-coating, and enteric coating on inert cores using a fluidized bed coater (Pam Glatt, India; bottom spray). Selected enteric-coated batches were directly compressed into ODTs using microcrystalline cellulose (Avicel PH102) and mannitol (Pearlitol SD 160) as fillers, with Explotab®, Ac-Di-Sol®, or crospovidone M® as superdisintegrants. Results: Multiparticulates exhibited mean diameters of 197.671–529.511 μm and span values of 0.603–0.838. Span value < 1, indicating a narrow size distribution. Electron microscopy confirmed the spherical morphology of Batches 7a and b. Enteric-coated batches (5b, 6, 7a, 7b) released ≤10% of the drug in 0.1 N HCl at 2 h. Optimized formulation ODT 7b released 7.904% of the drug under gastric conditions and 79.749% in phosphate buffer (pH 6.8) within 2.5 h, following first-order drug release kinetics. ODT 7b demonstrated hardness (2.538 ± 0.144 kg/cm2), wetting time (11.17 ± 1.051 s), friability (0.712%), and drug content (99.81 ± 1.01%) within acceptable limits. Conclusions: The pH-dependent multiparticulates provided sustained intestinal drug release and, when incorporated into ODTs, yielded a dosage form with a rapid wetting time and acceptable mechanical properties. This dosage form can offer a promising approach for improving compliance and therapeutic efficacy in patients with swallowing difficulties (dysphagia). Full article
(This article belongs to the Special Issue Paediatric and Neonatal Specific Dosage Forms and Administration)
30 pages, 3041 KB  
Review
Machine Learning for Multi-Target Drug Discovery: Challenges and Opportunities in Systems Pharmacology
by Xueyuan Bi, Yangyang Wang, Jihan Wang and Cuicui Liu
Pharmaceutics 2025, 17(9), 1186; https://doi.org/10.3390/pharmaceutics17091186 - 12 Sep 2025
Abstract
Multi-target drug discovery has become an essential strategy for treating complex diseases involving multiple molecular pathways. Traditional single-target approaches often fall short in addressing the multifactorial nature of conditions such as cancer and neurodegenerative disorders. With the rise in large-scale biological data and [...] Read more.
Multi-target drug discovery has become an essential strategy for treating complex diseases involving multiple molecular pathways. Traditional single-target approaches often fall short in addressing the multifactorial nature of conditions such as cancer and neurodegenerative disorders. With the rise in large-scale biological data and algorithmic advances, machine learning (ML) has emerged as a powerful tool to accelerate and optimize multi-target drug development. This review presents a comprehensive overview of ML techniques, including advanced deep learning (DL) approaches like attention-based models, and highlights their application in multi-target prediction, from traditional supervised learning to modern graph-based and multi-task learning frameworks. We highlight real-world applications in oncology, central nervous system disorders, and drug repurposing, showcasing the translational potential of ML in systems pharmacology. Major challenges are discussed, such as data sparsity, lack of interpretability, limited generalizability, and integration into experimental workflows. We also address ethical and regulatory considerations surrounding model transparency, fairness, and reproducibility. Looking forward, we explore promising directions such as generative modeling, federated learning, and patient-specific therapy design. Together, these advances point toward a future of precision polypharmacology driven by biologically informed and interpretable ML models. This review aims to provide researchers and practitioners with a roadmap for leveraging ML in the development of safer and more effective multi-target therapeutics. Full article
(This article belongs to the Special Issue Advanced Algorithms for Small-Molecule Therapeutics Development)
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17 pages, 1329 KB  
Article
Optimizing Dose Conversion from IR-Tac to LCP-Tac Formulations in Renal Transplant Recipients: A Population Pharmacokinetic Modeling Study
by Zeyar Mohammed Ali, Beatriz Fernández-Alarcón, Pere Fontova, Anna Vidal-Alabró, Raul Rigo-Bonnin, Edoardo Melilli, Nuria Montero, Anna Manonelles, Ana Coloma, Alexandre Favà, Josep M. Grinyó, Josep M. Cruzado, Helena Colom and Nuria Lloberas
Pharmaceutics 2025, 17(9), 1185; https://doi.org/10.3390/pharmaceutics17091185 - 12 Sep 2025
Viewed by 55
Abstract
Background/Objectives: Tacrolimus dosing remains challenging due to its narrow therapeutic index and high inter- and intra-patient variability. The extended-release once-daily tacrolimus (LCP-Tac) formulation provides enhanced bioavailability and a sustained pharmacokinetic profile compared to the immediate-release twice-daily tacrolimus (IR-Tac) formulation. Although a general [...] Read more.
Background/Objectives: Tacrolimus dosing remains challenging due to its narrow therapeutic index and high inter- and intra-patient variability. The extended-release once-daily tacrolimus (LCP-Tac) formulation provides enhanced bioavailability and a sustained pharmacokinetic profile compared to the immediate-release twice-daily tacrolimus (IR-Tac) formulation. Although a general conversion ratio of 1:0.7 is widely recommended when switching between formulations, current guidelines do not account for pharmacogenetic variability. This study aimed to determine whether CYP3A5 genotype influences the conversion ratio in Caucasian renal transplant recipients using population pharmacokinetic (PopPK) modeling. Methods: A PopPK model was developed in NONMEM using full PK profiles (10–18 samples per patient) from 30 stable renal transplant patients treated with both IR-Tac and LCP-Tac. Results: Tacrolimus pharmacokinetics were best described by a two-compartment model with first-order absorption and linear elimination with distinct absorption rate constants and lag times for each formulation. Including circadian rhythm in the apparent clearance (CL/F) and Ka of IR-Tac significantly improved the model. CYP3A5 polymorphism was the most powerful covariate explaining variability on CL/F. CYP3A5*1 expressers showed higher clearance and lower exposure requiring a more pronounced dose reduction upon conversion to LCP-Tac. Simulations indicated optimal conversion ratios of 1:0.6 for CYP3A5*1 expressers and 1:0.7 for non-expressers. Conclusions: These findings highlight the need to move beyond a one-size-fits-all conversion ratio and adopt genotype-informed strategies. LCP-Tac’s enhanced bioavailability requires dose reduction, greater in expressers when switching from IR-Tac. These genotype-specific recommendations provide clinically actionable guidance to complement therapeutic drug monitoring and support more individualized conversion protocols in renal transplantation. Full article
(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)
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34 pages, 9678 KB  
Article
Invasomes and Nanostructured Lipid Carriers for Targeted Delivery of Ceftazidime Combined with N-Acetylcysteine: A Novel Approach to Treat Pseudomonas aeruginosa-Induced Keratitis
by Mina Josef, Menna M. Abdellatif, Rehab Abdelmonem, Mohamed A. El-Nabarawi, Mahmoud Teaima, Hadeer M. Bedair and Alshaimaa Attia
Pharmaceutics 2025, 17(9), 1184; https://doi.org/10.3390/pharmaceutics17091184 - 11 Sep 2025
Viewed by 109
Abstract
Objectives: This study was designed to optimize a ceftazidime (CTZ)-loaded nanocarrier that could efficiently permeate across corneal tissues. Moreover, N-acetylcysteine (NAC) was combined with an optimized CTZ-loaded formula to augment the antimicrobial activity and facilitate the efficient healing of Pseudomonas aeruginosa-induced [...] Read more.
Objectives: This study was designed to optimize a ceftazidime (CTZ)-loaded nanocarrier that could efficiently permeate across corneal tissues. Moreover, N-acetylcysteine (NAC) was combined with an optimized CTZ-loaded formula to augment the antimicrobial activity and facilitate the efficient healing of Pseudomonas aeruginosa-induced keratitis. Methods: Different CTZ-loaded invasomes (INVs) and CTZ-loaded nanostructured lipid carriers (NLC) were fabricated and fully characterized via the determination of the entrapment efficiency (EE%), particle size (PS), surface charge, and percentage of CTZ release. Next, NAC was added to the optimized formulae from each nanocarrier, which were further assessed through ex vivo corneal permeation and in vitro antimicrobial activity studies. Finally, an in vivo evaluation of the optimal nanocarrier in the presence of NAC was performed. Results: Both nanocarriers showed nanoscale PS with sufficient surface charges. CTZ-loaded NLC formulae showed a higher EE% range with a sustained drug release profile. Both optimized formulae showed a spherical shape and excellent stability. Moreover, the antibacterial activity and biofilm inhibition assessments confirmed the synergistic effects of NAC when combined with different CTZ-loaded nanocarriers. However, the optimized CTZ-loaded INV formula achieved higher corneal permeation and deposition compared to the optimized CTZ-loaded NLC formula. Finally, the in vivo assessment confirmed the dominance of the optimized CTZ-loaded INV formula combined with NAC, where the microbiological, histopathological, and immunohistopathological examinations showed the rapid eradication of keratitis. Conclusions: Recent strategies for the incorporation of antibiotics into nanocarriers, combined with mucolytic agents, can offer a promising platform to boost the therapeutic efficiency of antibiotics and prevent antimicrobial resistance. Full article
(This article belongs to the Special Issue Nano-Based Delivery Systems for Topical Applications)
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50 pages, 1057 KB  
Review
Formulation of Recombinant Therapeutic Proteins: Technological Innovation, Regulations, and Evolution Towards Buffer-Free Formulations
by Tomas Gabriel Bas
Pharmaceutics 2025, 17(9), 1183; https://doi.org/10.3390/pharmaceutics17091183 - 11 Sep 2025
Viewed by 317
Abstract
Background/Objectives: Formulating recombinant therapeutic proteins is essential to ensure their safety, efficacy, and stability. A growing trend in biopharmaceutical development is the move toward buffer-free formulations, which aim to reduce immunogenicity, improve tolerability, and simplify production. This review explores technological advances, regulatory [...] Read more.
Background/Objectives: Formulating recombinant therapeutic proteins is essential to ensure their safety, efficacy, and stability. A growing trend in biopharmaceutical development is the move toward buffer-free formulations, which aim to reduce immunogenicity, improve tolerability, and simplify production. This review explores technological advances, regulatory perspectives, and safety considerations related to this shift. Methods: A systematic documentary review was conducted using the PSALSAR framework. Scientific publications, patents, and regulatory documents (2020–2025) were retrieved from PubMed, Scopus, Web of Science, and regulatory databases (FDA, EMA). Inclusion criteria focused on recombinant proteins, buffer-free formulations, and regulatory alignment. Results: The findings reveal an increasing adoption of self-buffering strategies in high-concentration subcutaneous biologics. Technologies such as Fc-fusion, PASylation, and XTENylation enhance stability without conventional buffers. Regulatory bodies are progressively accepting minimalist formulations, provided safety and biosimilarity are demonstrated. However, intellectual property barriers limit formulation transparency. A synthesis of recent FDA and EMA approvals illustrates this formulation evolution. Conclusions: Buffer-free formulations offer a promising alternative for therapeutic protein development by improving patient experience and reducing formulation complexity. They align with biosimilar goals and regulatory trends, although long-term transparency and safety assessments remain critical for widespread adoption. Full article
(This article belongs to the Special Issue Formulation of Recombinant Therapeutic Proteins)
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19 pages, 1068 KB  
Article
Liposomal Encapsulation of Pine Green Cone Essential Oil: The Influence of the Carrier on the Enhancement of Anti-Inflammatory Activity
by Snježana Mirković, Vanja Tadić, Marina Tomović, Anica Petrović, Marijana Andjić, Jovana Bradić, Sanja Perać, Aleksandar Radojković, Jelena Jovanović and Ana Žugić
Pharmaceutics 2025, 17(9), 1182; https://doi.org/10.3390/pharmaceutics17091182 - 11 Sep 2025
Viewed by 166
Abstract
Background/Objectives: This study aimed to investigate the traditionally claimed anti-inflammatory effect of essential oil (EO) derived from pine green cones per se and after encapsulation into liposomes, which is expected to enhance its bioactivity and stability. Methods: The chemical profiling of EO [...] Read more.
Background/Objectives: This study aimed to investigate the traditionally claimed anti-inflammatory effect of essential oil (EO) derived from pine green cones per se and after encapsulation into liposomes, which is expected to enhance its bioactivity and stability. Methods: The chemical profiling of EO was conducted using GC/GC-MS. The physico-chemical characterization of the liposomal formulation (LEO) included encapsulation efficiency, FTIR spectroscopy, and AFM imaging. Additionally, parameters such as mean particle diameter, polydispersity index, zeta potential, pH, and electrical conductivity were evaluated and reassessed after 30 days and 1 year to determine formulation stability. The in vivo anti-inflammatory effect of the EO and LEO was examined using a carrageenan-induced rat paw edema model. Results: The Pinus halepensis EO contained 14 components, mainly, α-pinene, myrcene, and (E)-caryophyllene. Encapsulation efficiency was 97.35%. AFM analyses confirmed the nanoscale dimensions and spherical shape of liposomes, while FTIR indicated successful encapsulation through overlapping functional groups. The droplet size of blank liposomes (L) ranged from 197.4 to 217 nm, while adding the EO decreased the droplet size and electrical conductivity. The polydispersity index (PDI) remained below 0.2. The zeta potential of the liposomes was between −35.61 and −49.43 mV, while the pH value was in the range of 4.35 to 5.01. These results indicate satisfactory stability across repeated measurements. Administration of LEO significantly inhibited paw edema relative to the controls, with a percentage inhibition of approximately 69%, which does not significantly differ from the effect of hydrocortisone, which was used as a positive control. Conclusions: This is the first study to report liposomal encapsulation and in vivo anti-inflammatory activity of an EO derived specifically from green cones of P. halepensis. Our findings demonstrate that EO-loaded liposomes exhibited favorable physico-chemical properties and notable anti-inflammatory activity, comparable to that of hydrocortisone. These results support their potential application in the development of effective topical anti-inflammatory formulations. Full article
(This article belongs to the Special Issue Natural Bioactive Compounds in Micro- and Nanocarriers)
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17 pages, 1758 KB  
Article
Evaluation of Permeation Enhancers for Vaginal Delivery of Buserelin Acetate Using a Validated Chromatographic Method and Ex Vivo Porcine Model
by AHM Musleh Uddin, Roy N. Kirkwood, Kiro R. Petrovski, Souha H. Youssef, Baljinder Singh, Songhita Mukhopadhyay, Yunmei Song and Sanjay Garg
Pharmaceutics 2025, 17(9), 1181; https://doi.org/10.3390/pharmaceutics17091181 - 11 Sep 2025
Viewed by 167
Abstract
Background/Objectives: This study aimed to enhance the vaginal permeation of buserelin acetate (BA), a synthetic gonadotropin-releasing hormone (GnRH) analogue, by evaluating various permeation enhancers (PEs) using a validated reversed-phase high-performance liquid chromatography (RP-HPLC) method and an ex vivo porcine vaginal model. Methods [...] Read more.
Background/Objectives: This study aimed to enhance the vaginal permeation of buserelin acetate (BA), a synthetic gonadotropin-releasing hormone (GnRH) analogue, by evaluating various permeation enhancers (PEs) using a validated reversed-phase high-performance liquid chromatography (RP-HPLC) method and an ex vivo porcine vaginal model. Methods: A robust RP-HPLC method was developed and validated according to ICH Q2 (R2) guidelines to enable accurate quantification of BA in permeation samples. The analytical method demonstrated high specificity, linearity (R2 = 0.9999), accuracy (98–102%), precision (%RSD < 2%), robustness, and stability. Using this method, ex vivo permeation studies were conducted with six different PEs: 2-hydroxypropyl-β-cyclodextrin, sodium dodecyl sulfate, poloxamer 188, Span 80, Tween 80, and chitosan. Results: Among all tested PEs, chitosan demonstrated the best enhancement of BA permeation. It achieved the highest flux (J) (0.64 ± 0.03 × 10−2 µg/cm2·h) and apparent permeability coefficient (Papp) (16.20 ± 0.84 × 10−5 cm/h), both of which were statistically significantly higher (p < 0.05) than those of all other enhancer groups. Kinetic modelling indicated a non-Fickian, biphasic permeation mechanism best described by the Makoid–Banakar model. Conclusions: These findings highlight chitosan’s potential as an effective intravaginal delivery vehicle for peptide therapeutics and establish the validated HPLC method as a reliable platform for future formulation development and translational studies in mucosal drug delivery. Full article
(This article belongs to the Special Issue Methods of Potentially Improving Drug Permeation and Bioavailability)
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23 pages, 2028 KB  
Review
Nanoencapsulation of Biotics: Feasibility to Enhance Stability and Delivery for Improved Gut Health
by Pedro Brivaldo Viana da Silva, Thiécla Katiane Osvaldt Rosales and João Paulo Fabi
Pharmaceutics 2025, 17(9), 1180; https://doi.org/10.3390/pharmaceutics17091180 - 11 Sep 2025
Viewed by 201
Abstract
The human gastrointestinal tract contains a complex and diverse community of microorganisms, referred to as the gut microbiota. Due to their close proximity to human cells, these microorganisms play a crucial role in maintaining the host’s health, influencing various metabolic processes, and providing [...] Read more.
The human gastrointestinal tract contains a complex and diverse community of microorganisms, referred to as the gut microbiota. Due to their close proximity to human cells, these microorganisms play a crucial role in maintaining the host’s health, influencing various metabolic processes, and providing protection against potentially harmful agents and pathogens. The disruption in this microbial ecosystem, known as dysbiosis, is associated with inflammatory and metabolic diseases, as well as certain types of cancer. Strategies to modulate the microbiota toward a state of homeostasis through the use of “biotics” (probiotics, prebiotics, synbiotics, and postbiotics) have increased. However, challenges such as low stability, loss of microbial viability, and difficulties in delivery to the intestine significantly decrease the progress of their clinical and nutritional applications. Microencapsulation and nanoencapsulation technologies offer potential solutions to enhance the stability, bioavailability, and controlled release of microorganisms and/or bioactive compounds within the gastrointestinal tract. Considering these aspects, this review provides a comprehensive overview of recent advances in nanoencapsulation techniques for biotics, highlighting their mechanisms of action, potential health benefits, and applications in functional foods and targeted therapies. Furthermore, it addresses existing limitations, evaluates feasibility, and discusses the future potential of these technologies in promoting gut health and disease prevention. Further research, especially through clinical studies, is mandatory to verify the safety and effectiveness of nanoencapsulated biotics and to obtain regulatory approval. Full article
(This article belongs to the Special Issue Biomedical Applications of Nanocarriers in Targeted Delivery of Bioactive Compounds)
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19 pages, 6473 KB  
Article
Identification of Variable Lymphocyte Receptors That Target the Human Blood–Brain Barrier
by Moriah E. Katt, Elizabeth A. Waters, Benjamin D. Gastfriend, Brantley R. Herrin, Max D. Cooper and Eric V. Shusta
Pharmaceutics 2025, 17(9), 1179; https://doi.org/10.3390/pharmaceutics17091179 - 10 Sep 2025
Viewed by 142
Abstract
Background/Objectives: Receptor-mediated transcytosis utilizing the native transporters at the blood–brain barrier (BBB) is a growing strategy for the delivery of therapeutics to the brain. One of the major challenges in identifying appropriate human transcytosis targets is that there is a species-specific transporter [...] Read more.
Background/Objectives: Receptor-mediated transcytosis utilizing the native transporters at the blood–brain barrier (BBB) is a growing strategy for the delivery of therapeutics to the brain. One of the major challenges in identifying appropriate human transcytosis targets is that there is a species-specific transporter expression profile at the BBB, complicating translation of successful preclinical candidates into humans. In an effort to overcome this obstacle and identify proteins capable of binding human-relevant BBB ligands, we generated and screened a BBB-targeting library against human-induced pluripotent stem cell-derived brain microvascular endothelial-like cells (iPSC-derived BMEC-like cells). As targeting molecules, we used lamprey antibodies, known as variable lymphocyte receptors (VLRs), and generated a VLR library by immunizing lamprey with iPSC-derived BMEC-like cells, and inserting the resultant VLR repertoire into the yeast surface display system. Methods: The yeast displayed VLR library was then panned against human iPSC-derived BMEC-like cells and lead VLRs were validated using human in vitro models and mouse and human ex vivo brain tissue sections. Results: Finally, brain uptake for a set of VLRs was validated in mice. Of the 15 lead VLR candidates, 14 bound to human BBB antigens, and 10 bound to the murine BBB. Pharmacodynamic testing using the neuroactive peptide neurotensin indicated that the lead candidate, VLR2G, could cross the mouse BBB after intravenous injection and deliver sufficient neurotensin payload to generate a pharmacological response and lower systemic body temperature. Conclusions: Together, these results demonstrate the application of a novel screening technique capable of identifying a VLR with human relevance that can cross the BBB and deliver a payload. Full article
(This article belongs to the Special Issue Advancements and Innovations in Antibody Drug Conjugates)
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33 pages, 3114 KB  
Review
Advances in Second Near-Infrared Window Photothermal Agents and Photothermal Therapy for Tumors in Interdisciplinary Medical Research
by Runxuan Zhou, Yufei Chen, Shuxi Yao, Weiyun Zhang and Dawei Ye
Pharmaceutics 2025, 17(9), 1178; https://doi.org/10.3390/pharmaceutics17091178 - 10 Sep 2025
Viewed by 323
Abstract
Cancer continues to pose a significant threat to human health. While early diagnosis has improved survival rates for many cancer patients, a substantial number still do not achieve the desired treatment outcomes. Therefore, it is imperative to develop novel therapeutic approaches for tumor [...] Read more.
Cancer continues to pose a significant threat to human health. While early diagnosis has improved survival rates for many cancer patients, a substantial number still do not achieve the desired treatment outcomes. Therefore, it is imperative to develop novel therapeutic approaches for tumor management. Second near-infrared window photothermal therapy has garnered considerable attention from researchers due to its effective tumor-killing capabilities and minimal side effects. This review commences by summarizing the advancements in second near-infrared photothermal agents, alongside an evaluation of the advantages and disadvantages of various photothermal agents. Subsequently, we highlight the benefits of combining photothermal therapy with other treatment modalities. Finally, we present a compilation of reports detailing the application of photothermal therapy in the treatment of various tumor types in clinical settings. In the conclusion, we underscore the challenges and potential research directions associated with photothermal therapy. Our article aims to facilitate interdisciplinary research in the fields of nanomedicine and clinical medicine. Full article
(This article belongs to the Special Issue Nanotechnology Applied in Prevention, Diagnosis and Treatment of Cancer)
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23 pages, 1233 KB  
Review
Recent Advances in Nose-to-Brain Gene Delivery for Central Nervous System Disorders
by Flávia Nathiely Silveira Fachel, Angélica Salatino-Oliveira, Willian da Silva Carniel, Rafaela Zimmermann, Ursula Matte, Helder Ferreira Teixeira, Guilherme Baldo and Roselena Silvestri Schuh
Pharmaceutics 2025, 17(9), 1177; https://doi.org/10.3390/pharmaceutics17091177 - 10 Sep 2025
Viewed by 294
Abstract
The nasal route represents a promising non-invasive technique for the direct delivery of nucleic acids to the central nervous system (CNS) disorders, effectively bypassing the blood–brain barrier. This route offers several advantages, including ease of administration, enhanced patient compliance, rapid therapeutic onset, and [...] Read more.
The nasal route represents a promising non-invasive technique for the direct delivery of nucleic acids to the central nervous system (CNS) disorders, effectively bypassing the blood–brain barrier. This route offers several advantages, including ease of administration, enhanced patient compliance, rapid therapeutic onset, and increased availability. Nonetheless, challenges such as mucociliary clearance, enzymatic degradation, and the low permeability of cell membranes to large molecules remain obstacles to the effectiveness of this approach. To address these limitations and achieve targeted nose-to-brain delivery with optimized therapeutic outcomes, various technological solutions have been explored, such as nanotechnology-based delivery systems and mucoadhesive formulations. These innovations aim to enhance the permeability of the nasal mucosa, extend the residence time of therapeutic agents in the nasal cavity, and improve overall treatment effectiveness. While the nasal gene delivery to the brain is still relatively new, it holds considerable potential for expanding treatment options for a range of CNS disorders. In this context, this review examines the anatomy and physiology of the nasal route, the mechanisms of biomolecule transport from nose to brain, the potential of gene delivery vectors, key preclinical advancements, and clinical perspectives for the nasal delivery of nucleic acids in CNS disorders. Full article
(This article belongs to the Special Issue Development of Vectors for Drug and Gene Delivery via the Nasal Route)
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26 pages, 3759 KB  
Review
3D Bioprinted Neural Tissues: Emerging Strategies for Regeneration and Disease Modeling
by Taekyung Choi, Jinseok Park, Suvin Lee, Hee-Jae Jeon, Byeong Hee Kim, Hyun-Ouk Kim and Hyungseok Lee
Pharmaceutics 2025, 17(9), 1176; https://doi.org/10.3390/pharmaceutics17091176 - 10 Sep 2025
Viewed by 356
Abstract
Three-dimensional (3D) bioprinting has emerged as a versatile platform in regenerative medicine, capable of replicating the structural and functional intricacies of the central and peripheral nervous systems (CNS and PNS). Beyond structural repair, it enables the construction of engineered tissues that closely recapitulate [...] Read more.
Three-dimensional (3D) bioprinting has emerged as a versatile platform in regenerative medicine, capable of replicating the structural and functional intricacies of the central and peripheral nervous systems (CNS and PNS). Beyond structural repair, it enables the construction of engineered tissues that closely recapitulate neural microenvironments. This review provides a comprehensive and critical synthesis of current bioprinting strategies for neural tissue engineering, with particular emphasis on comparing natural, synthetic, and hybrid polymer-based bioinks from mechanistic and translational perspectives. Distinctively, it highlights gradient-based modulation of Schwann cell behavior and axonal pathfinding using mechanically and chemically patterned constructs. Special attention is given to printing modalities such as extrusion, inkjet, and electrohydrodynamic jet printing, examining their respective capacities for controlling spatial organization and microenvironmental cues. Representative applications include brain development models, neurodegenerative disease platforms, and glioblastoma scaffolds with integrated functional properties. Furthermore, this review identifies key translational barriers—including host tissue integration and bioink standardization—and explores emerging directions such as artificial intelligence-guided biofabrication and organ-on-chip integration, to enhance the fidelity and therapeutic potential of neural bioprinted constructs. Full article
(This article belongs to the Special Issue 3D Bioprinting: Current Advances and Future Directions in Drug Delivery)
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37 pages, 3899 KB  
Review
Integrating Microorganism-Based Therapy and Emerging Biotechnology in the Treatment of Intracranial Central Nervous System Diseases
by Zifan Li, Shihua Yang and Lida Su
Pharmaceutics 2025, 17(9), 1175; https://doi.org/10.3390/pharmaceutics17091175 - 9 Sep 2025
Viewed by 235
Abstract
The development of drug delivery systems for the treatment of intracranial central nervous system (CNS) diseases remains one of the most intractable medical problems in modern society, owing to the special physiological structure of the brain, including the existence of the blood-brain barrier [...] Read more.
The development of drug delivery systems for the treatment of intracranial central nervous system (CNS) diseases remains one of the most intractable medical problems in modern society, owing to the special physiological structure of the brain, including the existence of the blood-brain barrier (BBB), the CNS’s immune privilege, and its high complexity and vulnerability. Recently, a leading approach in the CNS drug delivery domain has been to employ or simulate the physiological behavior of microorganisms to overcome the BBB and remodel the pathological immune microenvironment in intracranial tissue. Considering the exceptional advancements in microorganism-based CNS drug delivery systems, it is imperative to review the latest breakthroughs. Herein, we summarize the emerging trends at the intersection of microorganism-based drug delivery systems and emerging biomedical technology for the treatment of CNS diseases, with a particular focus on preclinical research into microorganism-based drug delivery systems to combat CNS diseases, aiming to describe a credible landscape for further clinical trials. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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24 pages, 1731 KB  
Article
Modeling and Design of Chitosan–PCL Bi-Layered Microspheres for Intravitreal Controlled Release
by Eduardo A. Chacin Ruiz, Samantha L. Carpenter, Katelyn E. Swindle-Reilly and Ashlee N. Ford Versypt
Pharmaceutics 2025, 17(9), 1174; https://doi.org/10.3390/pharmaceutics17091174 - 9 Sep 2025
Viewed by 209
Abstract
Background/Objectives: Chronic retinal diseases usually require repetitive local dosing. Depending on factors such as dosing frequency, mode of administration, and associated costs, this can result in poor patient compliance. A better alternative involves using controlled-release drug delivery systems to reduce the frequency of [...] Read more.
Background/Objectives: Chronic retinal diseases usually require repetitive local dosing. Depending on factors such as dosing frequency, mode of administration, and associated costs, this can result in poor patient compliance. A better alternative involves using controlled-release drug delivery systems to reduce the frequency of intravitreal dosing and extend drug release. However, reaching the market stage is a time-consuming process. Methods: In this study, we employed two computational approaches to model and estimate the parameters governing the diffusion-controlled drug release from bi-layered microspheres. The case study involved microspheres composed of a chitosan core and a polycaprolactone (PCL) shell. The model drugs were bovine serum albumin and bevacizumab (an agent that slows neovascularization due to retinal disorders). Drug release from the microspheres is described by a mathematical model that was solved numerically using the finite difference and the finite element approaches. The parameter estimation was performed by nonlinear least-squares regression. Results: We used the estimated parameters to simulate the cumulative release under various conditions and optimize the device design to guide future experimental efforts and improve the duration of release beyond a target daily therapeutic release rate from the microspheres. Conclusions: We investigated the effects of polymeric layer sizes on drug release and provided recommendations for optimal sizes. We provide straightforward computational tools for others to reuse in designing bi-layered microspheres for intravitreal drug delivery needs in the treatment of chronic ocular neovascularization. Full article
(This article belongs to the Special Issue Drug Delivery Systems for Ocular Diseases)
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17 pages, 3561 KB  
Review
Etrog Citron (Citrus medica) as a Novel Source of Antiviral Agents: Overview of Its Bioactive Phytochemicals and Delivery Approaches
by Arik Dahan, Ludmila Yarmolinsky, Faina Nakonechny, Olga Semenova, Boris Khalfin, Sigal Fleisher-Berkovich and Shimon Ben-Shabat
Pharmaceutics 2025, 17(9), 1173; https://doi.org/10.3390/pharmaceutics17091173 - 9 Sep 2025
Viewed by 277
Abstract
The recent COVID-19 pandemic highlighted the significant challenge of insufficient antiviral pharmacological options. Edible plants offer a promising avenue for developing novel antiviral drugs. Etrog citron (Citrus medica L.), which is a valuable edible and medicinal plant, contains various antiviral phytochemicals, mainly [...] Read more.
The recent COVID-19 pandemic highlighted the significant challenge of insufficient antiviral pharmacological options. Edible plants offer a promising avenue for developing novel antiviral drugs. Etrog citron (Citrus medica L.), which is a valuable edible and medicinal plant, contains various antiviral phytochemicals, mainly flavonoids, coumarins, and terpenes. However, the therapeutic application of these compounds remains limited by factors such as poor solubility, limited bioavailability, and unclear mechanisms of action. The aim of the present article is to offer a comprehensive analysis of the antiviral phytochemicals extracted from various parts of Citrus medica, emphasizing their mode of action and delivery strategies that may allow turning these compounds into new antiviral drugs. Full article
(This article belongs to the Special Issue Plant Extracts and Their Biomedical Applications)
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17 pages, 2201 KB  
Article
Electrospun PMVEMA Nanofibers Developed as a Fast-Release Platform for Antineoplastic Drugs Tested in Glioblastoma Primary Cultures
by Pedro Valentín Badía-Hernández, Joan Moll Carrió, María Fuentes-Baile, María Losada-Echeberría, Rocío Díaz-Puertas, Amalia Mira, Miguel Saceda, Pilar García-Morales and Ricardo Mallavia
Pharmaceutics 2025, 17(9), 1172; https://doi.org/10.3390/pharmaceutics17091172 - 8 Sep 2025
Viewed by 322
Abstract
Background/Objectives: The local release of antineoplastic drugs in post-surgical treatments is an alternative way to improve their effectiveness against glioblastoma reappearance. Thus, it was proposed to develop a local delivery system based on electrospun PMVEMA-derived nanofibers for the administration of carmustine (BCNU), [...] Read more.
Background/Objectives: The local release of antineoplastic drugs in post-surgical treatments is an alternative way to improve their effectiveness against glioblastoma reappearance. Thus, it was proposed to develop a local delivery system based on electrospun PMVEMA-derived nanofibers for the administration of carmustine (BCNU), temozolomide (TMZ), and doxorubicin (DOX). Methods: Electrospun nanofibers were prepared using PMVEMA-monoethyl ester (PMVEMA-Es) and PMVEMA-acid (PMVEMA-Ac), loading BCNU, TMZ, and DOX at 1% or 8% (w/w). Their morphology, encapsulation efficiency, and release profiles were characterized by FESEM, confocal microscopy, and HPLC. Their biological effects were evaluated through cell viability, cell cycle, and intracellular accumulation assays in established cell lines from glioblastoma patients (HGUE-GB) and human astrocytes (HAs). Results: The nanofibers were optimized without defects, and encapsulation efficiencies were above 80%. The release studies showed a rapid initial release in the first hour, being DOX > TMZ > BCNU, while the second release rate was sustained in the cases of PMVEMA-Ac/TMZ (0.14%/h) and PMVEMA-Es/BCNU (1.2%/h), highlighting that, after 24 h under physiological conditions, the degradation of the loaded drug was lower than its free state, comparable to the Gliadel release system. Furthermore, it was confirmed that there was a dose-dependent decrease in cell viability for PMVEMA-Es/BCNU and PMVEMA-Ac/DOX, with higher cytotoxicity than free DOX. Finally, the lowest concentration tested had a relatively low effect on HAs compared with its effect on glioblastoma cells. Conclusion: PMVEMA-based electrospun nanofibers are effective in encapsulating and releasing antineoplastic drugs, suggesting their potential as a local delivery system to improve glioblastoma post-surgical treatment efficacy. Full article
(This article belongs to the Special Issue Nano-Based Technology for Glioblastoma)
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15 pages, 1527 KB  
Article
The Preservation of the Therapeutic Efficacy of the Secretome of Adipose Mesenchymal Stem Cells, Produced in the Presence of Antioxidant and Anti-Inflammatory Drugs
by Sofia Martinez-Rodriguez, Nahla Jemni-Damer, Atocha Guedan-Duran, Girish K. Srivastava and Fivos Panetsos
Pharmaceutics 2025, 17(9), 1171; https://doi.org/10.3390/pharmaceutics17091171 - 8 Sep 2025
Viewed by 268
Abstract
Background/Objectives: Inflammatory processes, both acute and chronic, encompass a wide range of autoimmune, metabolic, and neurodegenerative conditions. Conventional treatments, primarily anti-inflammatories and immunosuppressants, provide partial relief but are often hampered by adverse effects and limited durability. Mesenchymal stem cells (MSCs) have emerged as [...] Read more.
Background/Objectives: Inflammatory processes, both acute and chronic, encompass a wide range of autoimmune, metabolic, and neurodegenerative conditions. Conventional treatments, primarily anti-inflammatories and immunosuppressants, provide partial relief but are often hampered by adverse effects and limited durability. Mesenchymal stem cells (MSCs) have emerged as a powerful new treatment due to their immunomodulatory and anti-inflammatory properties, primarily mediated through their secretome, which is a complex mixture of bioactive factors. Secretome-based therapeutic strategies show strong potential for controlling inflammation, mitigating oxidative stress, and supporting tissue regeneration and repair. However, the therapeutic efficacy of MSCs’ secretome is subject to modification by concurrent anti-inflammatory drug regimens used in clinical settings. Methods: To evaluate the effect of combinatorial treatment strategies on the secretome of the MSCs, we employed an in vitro retinal inflammation model to investigate whether the exposure of the MSCs to five representative anti-inflammatory drugs (ketorolac, diclofenac, α-lipoic acid, N-acetyl-L-cysteine, and nicotinamide) impacts the functionality of the resulting secretome. Specifically, we evaluated the effect of the above-mentioned drugs on the anti-inflammatory properties of the secretome in relation to the secreted levels of two main MSC secretome factors—the Brain-Derived Neurotrophic Factor (BDNF) and the Vascular Endothelial Growth Factor (VEGF)—and on the secretome’s pro-metabolic activity. Results: Our findings provide evidence that the presence of any of the tested drugs during MSC secretome production does not compromise its anti-inflammatory activity; BDNF and VEGF levels remain stable, and the secretome retains a high degree of its pro-metabolic effect. Conclusions: These results underscore the robustness and clinical resilience of MSC-based therapies, even when administered alongside pharmacological agents. This work advances the translational viability of MSC therapies for inflammatory diseases and supports the development of safe, combinatorial treatment strategies. Full article
(This article belongs to the Section Gene and Cell Therapy)
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15 pages, 1434 KB  
Article
In Vitro Antifungal Activity of Amphotericin B-Encapsulated Silk Fibroin-Chitosan Nanoparticles Against Fusarium solani Isolates from Keratitis Patients
by Rossukon Khotcharrat, Sangly P. Srinivas, Yordhathai Thongsri and Wanachat Thongsuk
Pharmaceutics 2025, 17(9), 1170; https://doi.org/10.3390/pharmaceutics17091170 - 8 Sep 2025
Viewed by 359
Abstract
Background: Fungal keratitis is a serious ophthalmic problem due to low antifungal medication penetration and bioavailability at the ocular surface, necessitating novel delivery strategies for successful therapeutic outcomes. This study created amphotericin B-loaded silk fibroin nanoparticles (AmB-SFNs) as a targeted drug delivery platform [...] Read more.
Background: Fungal keratitis is a serious ophthalmic problem due to low antifungal medication penetration and bioavailability at the ocular surface, necessitating novel delivery strategies for successful therapeutic outcomes. This study created amphotericin B-loaded silk fibroin nanoparticles (AmB-SFNs) as a targeted drug delivery platform for long-term ocular antifungal therapy. Methods: Silk fibroin-chitosan nanoparticles were produced using a precipitation technique, with chitosan coating for mucoadhesion and polyethylene glycol-400 surface stability. Clinical fungal isolates from keratitis patients were identified as species by morphological and molecular analysis, followed by in vitro antifungal susceptibility testing. Results: The optimized formulation produced spherical AmB-SFNs with an average diameter of 220 nm, a positive zeta potential of +34 mV, and a maximum amphotericin B entrapment effectiveness of 76%. Molecular identification confirmed that all five clinical isolates were Fusarium solani. AmB-SFNs showed strong antifungal activity against all tested isolates, with a minimum inhibitory dose of 50 μg/mL (0.25% w/v). Conclusions: The developed nanoparticulate system has optimal characteristics for enhanced corneal drug delivery, such as appropriate particle size for tissue penetration and mucoadhesive properties for prolonged ocular residence time, suggesting that this nanoparticulate system warrants further investigation in vivo to evaluate its potential for clinical translation in treating Fusarium keratitis and as a platform for topical ophthalmic therapies. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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41 pages, 2093 KB  
Review
Cracking the Blood–Brain Barrier Code: Rational Nanomaterial Design for Next-Generation Neurological Therapies
by Lucio Nájera-Maldonado, Mariana Parra-González, Esperanza Peralta-Cuevas, Ashley J. Gutierrez-Onofre, Igor Garcia-Atutxa and Francisca Villanueva-Flores
Pharmaceutics 2025, 17(9), 1169; https://doi.org/10.3390/pharmaceutics17091169 - 6 Sep 2025
Viewed by 851
Abstract
This review provides a mechanistic framework to strategically design nanoparticles capable of efficiently crossing the blood–brain barrier (BBB), a critical limitation in neurological treatments. We systematically analyze nanoparticle–BBB transport mechanisms, including receptor-mediated transcytosis, adsorptive-mediated transcytosis, and transient barrier modulation. Essential nanoparticle parameters (size, [...] Read more.
This review provides a mechanistic framework to strategically design nanoparticles capable of efficiently crossing the blood–brain barrier (BBB), a critical limitation in neurological treatments. We systematically analyze nanoparticle–BBB transport mechanisms, including receptor-mediated transcytosis, adsorptive-mediated transcytosis, and transient barrier modulation. Essential nanoparticle parameters (size, shape, stiffness, surface charge, and biofunctionalization) are evaluated for their role in enhancing brain targeting. For instance, receptor-targeted nanoparticles can significantly enhance brain uptake, achieving levels of up to 17.2% injected dose per gram (ID/g) in preclinical glioma models. Additionally, validated preclinical models (human-derived in vitro systems, rodents, and non-human primates) and advanced imaging techniques crucial for assessing nanoparticle performance are discussed. Distinct from prior BBB nanocarrier reviews that primarily catalogue mechanisms, this work (i) derives quantitative ‘design windows’ (size 10–100 nm, aspect ratio ~2–5, near-neutral ζ) linked to transcytosis efficiency, (ii) cross-walks human-relevant in vitro/in vivo models (including TEER thresholds and NHP evidence) into a translational decision guide, and (iii) integrates regulatory/toxicology readiness (ISO 10993-4, FDA/EMA, ICH) into practical checklists. We also curate recent (2020–2025) %ID/g brain-uptake data across lipidic, polymeric, protein, inorganic, and hybrid vectors to provide actionable, evidence-based rules for BBB design. Full article
(This article belongs to the Special Issue Advances and Challenges in Nanomedicine: Translating Nanotechnology into Therapeutics for Cancer, Neurodegenerative, and Infectious Diseases)
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16 pages, 1161 KB  
Article
Development of 3D-Printed Gel-Based Supplement-Containing Tablets with Tailored Release Profiles for Neurological Pain Management
by Jurga Andreja Kazlauskaite, Inga Matulyte and Jurga Bernatoniene
Pharmaceutics 2025, 17(9), 1168; https://doi.org/10.3390/pharmaceutics17091168 - 6 Sep 2025
Viewed by 371
Abstract
Background/Objectives: Neuropathic pain, resulting from damage or pathology affecting the somatosensory nervous system, is a prevalent form of chronic pain that significantly impacts quality of life. Combined therapies are often utilised to manage this condition. Three-dimensional printing (3DP) offers a promising approach [...] Read more.
Background/Objectives: Neuropathic pain, resulting from damage or pathology affecting the somatosensory nervous system, is a prevalent form of chronic pain that significantly impacts quality of life. Combined therapies are often utilised to manage this condition. Three-dimensional printing (3DP) offers a promising approach for personalising medication doses and dosage forms to meet individual patient needs. Methods: In this study, a formulation suitable for 3D printing was developed using magnesium citrate, uridine monophosphate, vitamins B3 (niacin), B6 (pyridoxine), B12 (cobalamin), B9 (folic acid), and spermidine to create a novel gel-based oral tablet for the targeted treatment of neurological pain. The antioxidant potential of the active pharmaceutical ingredients (APIs) was assessed using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) methods. The physical properties of the tablets were evaluated using a texture analyser, while the in vitro release profiles were determined by high-performance liquid chromatography (HPLC). Results: Results demonstrated that pectin–gelatin tablets hardened over time, with higher citric acid concentrations further enhancing this effect. Formulation AVII exhibited good hardness and low stickiness. Formulation AV, however, showed poor performance across all physical parameters and lacked sufficient structural integrity for practical application. While uridine monophosphate, B12, and B9 showed no significant differences in the release profiles of the tablets, spermidine, B6, and B3 displayed statistically significant variations. Specifically, AVII outperformed AV in terms of spermidine and B6 release, and AV showed a higher release of B3 compared to AV. Conclusions: The AVII tablet demonstrates potential for use in combined therapy targeting neurological pain disorders. Full article
(This article belongs to the Special Issue 3D Printing in Personalized Drug Delivery)
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12 pages, 2470 KB  
Article
A Preliminary Study on the Accuracy of MRI-Guided Thalamic Infusion of AAV2-GFP and Biodistribution Analysis Using Cryo-Fluorescence Tomography in Nonhuman Primates
by Ernesto A. Salegio, Reinier Espinosa, Geary R. Smith, David Shoshan, Matthew Silva, Eli White and Jacob McDonald
Pharmaceutics 2025, 17(9), 1167; https://doi.org/10.3390/pharmaceutics17091167 - 6 Sep 2025
Viewed by 451
Abstract
Background: Adeno-associated viral (AAV) vectors are the leading platform for gene therapy, but common delivery routes show limited spread to distal cortical structures, hence the utility of direct, intrathalamic infusions for broader transgene distribution. In this preliminary study, we recapitulate previous studies targeting [...] Read more.
Background: Adeno-associated viral (AAV) vectors are the leading platform for gene therapy, but common delivery routes show limited spread to distal cortical structures, hence the utility of direct, intrathalamic infusions for broader transgene distribution. In this preliminary study, we recapitulate previous studies targeting the thalamus as a conduit to achieve cortical transgene spread and showcase novel data evaluating biodistribution of a green fluorescent protein (GFP) using cryo-fluorescence tomography (CFT). For the first time in nonhuman primates (NHPs) and coupled with magnetic resonance imaging (MRI)-guidance, we demonstrated the application of CFT as a powerful tool to map out vector distribution in the NHP brain. Methods: Briefly, a single thalamic infusion was performed in African green monkeys using ClearPoint’s navigational platform to deliver an AAV serotype 2 vector containing a GFP payload. Transgene biodistribution was assessed in the left and right hemispheres using CFT and histological analysis, respectively. Results: Infusions were successfully performed with sub-millimetric target accuracy and with minimal error, achieving ~86% thalamic coverage with the largest infusion volume. Histology confirmed the presence of the GFP transgene, with the strongest signal in the cerebral gray/white matter and internal capsule, while CFT allowed for the three-dimensional detection of the transgene starting at the site of infusion and spreading to multiple cortical regions. Conclusions: These findings suggest that by combining MRI-guided technology with CFT imaging, it is feasible to map whole-brain gene biodistribution in NHPs. This proof-of-concept study bridges the gap between cellular microscopy and MRI-guidance to provide a complete picture of disease and treatment with clinical applicability. Full article
(This article belongs to the Special Issue New Trends in the Controlled Release Systems of Medicinal Substances Used in the Treatment of Diseases of the Central Nervous System)
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Article
Bioavailability Enhancement of Curcumin by PEG-Based Gastroretentive System: Development and In Vitro Evaluation
by Orsolya Csendes, Gábor Vasvári, Ádám Haimhoffer, László Horváth, Monika Béresová, Attila Bényei, Ildikó Bácskay, Pálma Fehér, Zoltán Ujhelyi and Dániel Nemes
Pharmaceutics 2025, 17(9), 1166; https://doi.org/10.3390/pharmaceutics17091166 - 5 Sep 2025
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Abstract
Background/Objectives: Increasing the bioavailability of poorly absorbed drugs is a continuous challenge in modern pharmaceutical technology. This is due to the problematic nature of BCS class IV active pharmaceutical ingredients: these drugs possess poor solubility and membrane permeability. Moreover, many undergo immediate efflux [...] Read more.
Background/Objectives: Increasing the bioavailability of poorly absorbed drugs is a continuous challenge in modern pharmaceutical technology. This is due to the problematic nature of BCS class IV active pharmaceutical ingredients: these drugs possess poor solubility and membrane permeability. Moreover, many undergo immediate efflux and/or rapid systemic metabolism after absorption. This project aimed to improve the bioavailability of BCS class IV drugs by formulating gastroretentive self-emulsifying systems using curcumin as a model drug. Methods: The base of the systems was created by melting emulsifying agents, dissolution retardants, and PEGs together. Curcumin was added after the mixture was cooled slightly. Aqueous dispersions of several compositions were characterized by dynamic light scattering. After screening these results, the viscosities of the selected formulations were evaluated. Dissolution retardants were selected and added to the most superior samples, and their dissolution profiles were compared. Gastroretention of the final formulation was achieved by dispersing air in the molten system through melt foaming; internal structure was assessed by microCT, and physicochemical properties by PXRD and DSC. Cytotoxicity was measured in Caco-2 cells using MTT and Neutral Red assays, and transcellular transport was also studied. Results: Based on these results, a homogeneous gastric floating system was developed. We observed an advantageous cytotoxic profile and increased bioavailability. Conclusions: Overall, we were able to create a self-emulsifying gastroretentive formulation displaying extended release and gastric retention with a low amount of cost-efficient excipients. Full article
(This article belongs to the Special Issue Advances in Solid and Semi-Solid Dosage Form Design for Enhanced Biopharmaceutical Performance)
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