Pharmaceutics

46 pages, 1520 KiB

Open AccessReview

Unveiling the Future: Opportunities in Long-Acting Injectable Drug Development for Veterinary Care

by HariPriya Koppisetti, Sadikalmahdi Abdella, Deepa D. Nakmode, Fatima Abid, Franklin Afinjuomo, Sangseo Kim, Yunmei Song and Sanjay Garg

Pharmaceutics 2025, 17(5), 626; https://doi.org/10.3390/pharmaceutics17050626 - 8 May 2025

Abstract

Long-acting injectable (LAI) formulations have revolutionized veterinary pharmaceuticals by improving patient compliance, minimizing dosage frequency, and improving therapeutic efficacy. These formulations utilize advanced drug delivery technologies, including microspheres, liposomes, oil solutions/suspensions, in situ-forming gels, and implants to achieve extended drug release. Biodegradable polymers [...] Read more.

Long-acting injectable (LAI) formulations have revolutionized veterinary pharmaceuticals by improving patient compliance, minimizing dosage frequency, and improving therapeutic efficacy. These formulations utilize advanced drug delivery technologies, including microspheres, liposomes, oil solutions/suspensions, in situ-forming gels, and implants to achieve extended drug release. Biodegradable polymers such as poly(lactic-co-glycolic acid) (PLGA), and polycaprolactone (PCL) have been approved by the USFDA and are widely employed in the development of various LAIs, offering controlled drug release and minimizing the side effects. Various classes of veterinary medicines, including non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, and reproductive hormones, have been successfully formulated as LAIs. Some remarkable LAI products, such as ProHeart^® (moxidectin), Excede^® (ceftiofur), and POSILACTM (recombinant bovine somatotropin), show clinical relevance and commercial success. This review provides comprehensive information on the formulation strategies currently being used and the emerging technologies in LAIs for veterinary purposes. Additionally, challenges in characterization, in vitro testing, in vitro in vivo correlation (IVIVC), and safety concerns regarding biocompatibility are discussed, along with the prospects for next-generation LAIs. Continued advancement in the field of LAI in veterinary medicine is essential for improving animal health. Full article

(This article belongs to the Special Issue Long Acting Drug Delivery Formulations)

16 pages, 3686 KiB

Open AccessArticle

Hydrogels Powered by Nanoemulsion Technology for the Topical Delivery of Acmella oleracea Extract

by Eleonora Spinozzi, Marco Cespi, Marta Ferrati, Riccardo Petrelli, Filippo Maggi, Junbiao Wang, Sunday Segun Alimi, Diego Romano Perinelli and Giulia Bonacucina

Pharmaceutics 2025, 17(5), 625; https://doi.org/10.3390/pharmaceutics17050625 - 8 May 2025

Abstract

Background/Objectives: Natural products are gaining increasing importance due to the large variety of biological activities exerted by their constituents. Among these, the products deriving from Acmella oleracea (L.) R.K. Jansen can be exploited for their local anaesthetic, myorelaxant, anti-inflammatory/analgesic, and antifungal properties. [...] Read more.

Background/Objectives: Natural products are gaining increasing importance due to the large variety of biological activities exerted by their constituents. Among these, the products deriving from Acmella oleracea (L.) R.K. Jansen can be exploited for their local anaesthetic, myorelaxant, anti-inflammatory/analgesic, and antifungal properties. In this regard, there is a need to develop novel formulations for the topical delivery of A. oleracea-derived extracts to widen their use in the pharmaceutical and cosmetic fields. Methods: Nanoformulations, i.e., nanoemulsions (NEs) and microemulsions (MEs), were investigated as a strategy to encapsulate an extract from A. oleracea at the nanoscale level in water and then incorporated into xanthan gum-based hydrogels. Results: Only NEs provided a physically stable formulation, while the precipitation of solid hydrophobic components from the extract was observed during ME preparation under all tested conditions despite the use of ethyl oleate as an oily co-solvent. The optimized NE-based hydrogel remained physically stable over six months, as confirmed by rheological measurements and polarized optical microscope observation, without a phase separation phenomenon. Therefore, NEs resulted more suitable nanodispersed systems than MEs for the encapsulation of A. oleracea extract, which contains a large amount of hydrophobic constituents that are solid at room temperature. Furthermore, the sustained spilanthol release across an artificial membrane (Franz cell apparatus) and the cytotoxic profile on HaCaT cell line support its potential topical application. Conclusions: The outcomes of this study provided valuable insights into the formulation of A. oleracea extract, broadening its fields of applicability, including topical administration. Full article

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

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22 pages, 1906 KiB

Open AccessArticle

Preformulation Study of Carbamazepine Orally Disintegrating Tablets for Pediatric Patients Using Direct Compression and the SeDeM Diagram Tool: A Quality by Design Approach

by Ricard Canadell-Heredia, Khadija Rouaz-El-Hajoui, Natalia Franco-Piedrahita, Pilar Pérez-Lozano, Marc Suñé-Pou, Josep María Suñé-Negre and Encarna García-Montoya

Pharmaceutics 2025, 17(5), 624; https://doi.org/10.3390/pharmaceutics17050624 - 8 May 2025

Abstract

Background/Objectives: Carbamazepine is widely used as a first-line treatment for pediatric patients with benign epilepsy. However, most commercial formulations have doses of 100 mg or higher, limiting their suitability for pediatric use. The aim of this study was to develop mini orally disintegrating [...] Read more.

Background/Objectives: Carbamazepine is widely used as a first-line treatment for pediatric patients with benign epilepsy. However, most commercial formulations have doses of 100 mg or higher, limiting their suitability for pediatric use. The aim of this study was to develop mini orally disintegrating tablets (ODTs) containing 50 mg of carbamazepine, utilizing direct compression technology, specifically tailored to meet the unique needs of pediatric patients. Methods: The development was carried out following a Quality by Design (QbD) approach, beginning with preformulation studies using the SeDeM expert system. Various co-processed excipients (PROSOLV^® ODT and PARTECK^® ODT) and non-co-processed excipients (L-HPC LH11 and L-HPC NBD-022) were evaluated. Additionally, modifications to the radius parameter of the SeDeM expert system were investigated to improve formulation design. Results: Optimized Formulations 13 and 14 achieved disintegration times below 1 min, hardness values between 25 and 60 N, and friability under 1%, fulfilling the predefined Critical Quality Attributes (CQAs). Tablets were successfully produced with a diameter of 5 mm and a weight below 100 mg. Moreover, reducing the SeDeM incidence radius from 5.0 to values between 4.0 and 3.5 proved viable, enabling the inclusion of excipients previously considered unsuitable and broadening formulation options without compromising quality. Conclusions: This study demonstrates the feasibility of producing small, fast-disintegrating, and mechanically robust 50 mg carbamazepine ODTs tailored for pediatric patients. It also validates the adjustment of SeDeM parameters as an effective strategy to expand excipient selection and enhance formulation flexibility in pediatric drug development. Full article

(This article belongs to the Special Issue Pharmaceutical Solid Dosage Forms: Manufacturing, Design, Development, and Biomedical Applications)

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24 pages, 922 KiB

Open AccessReview

Aspects and Implementation of Pharmaceutical Quality by Design from Conceptual Frameworks to Industrial Applications

by Shiwei Yang, Xingming Hu, Jinmiao Zhu, Bin Zheng, Wenjie Bi, Xiaohong Wang, Jialing Wu, Zimeng Mi and Yifei Wu

Pharmaceutics 2025, 17(5), 623; https://doi.org/10.3390/pharmaceutics17050623 - 8 May 2025

Abstract

Background/Objectives: Quality by Design (QbD) has revolutionized pharmaceutical development by transitioning from reactive quality testing to proactive, science-driven methodologies. Rooted in ICH Q8–Q11 guidelines, QbD emphasizes defining Critical Quality Attributes (CQAs), establishing design spaces, and integrating risk management to enhance product robustness and [...] Read more.

Background/Objectives: Quality by Design (QbD) has revolutionized pharmaceutical development by transitioning from reactive quality testing to proactive, science-driven methodologies. Rooted in ICH Q8–Q11 guidelines, QbD emphasizes defining Critical Quality Attributes (CQAs), establishing design spaces, and integrating risk management to enhance product robustness and regulatory flexibility. This review critically examines QbD’s theoretical frameworks, implementation workflows, and industrial applications, aiming to bridge academic research and commercial practices while addressing emerging challenges in biologics, advanced therapies, and personalized medicine. Methods: The review synthesizes regulatory guidelines, case studies, and multidisciplinary tools, including Design of Experiments (DoE), Failure Mode Effects Analysis (FMEA), Process Analytical Technology (PAT), and multivariate modeling. It evaluates QbD workflows—from Quality Target Product Profile (QTPP) definition to control strategies—and explores advanced technologies like AI-driven predictive modeling, digital twins, and continuous manufacturing. Results: QbD implementation reduces batch failures by 40%, optimizes dissolution profiles, and enhances process robustness through real-time monitoring (PAT) and adaptive control. However, technical barriers, such as nonlinear parameter interactions in complex systems, and regulatory disparities between agencies hinder broader adoption. Conclusions: QbD significantly advances pharmaceutical quality and efficiency, yet requires harmonized regulatory standards, lifecycle validation protocols, and cultural shifts toward interdisciplinary collaboration. Emerging trends, including AI-integrated design space exploration and 3D-printed personalized medicines, promise to address scalability and patient-centric needs. By fostering innovation and compliance, QbD remains pivotal in achieving sustainable, patient-focused drug development. Full article

(This article belongs to the Special Issue Aspects and Implementation of Pharmaceutical Quality by Design, 2nd Edition)

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26 pages, 6909 KiB

Open AccessArticle

Development of Voriconazole Proliposome Based Dry Powder for Inhalation: A Design of Experiment Approach

by Sanjeevani Deshkar, Alisha Vas, Roshani Pagar, Prabhanjan Giram, Asha Thomas and Vaishali Undale

Pharmaceutics 2025, 17(5), 622; https://doi.org/10.3390/pharmaceutics17050622 - 8 May 2025

Abstract

The present investigation aimed to formulate and optimize sustained release proliposome dry powder for inhalation of Voriconazole (VZ) and its in vitro and in vivo evaluation. The proliposome-based dry powder for inhalation was formulated by spray drying technique using Phospholipon 90H and cholesterol [...] Read more.

The present investigation aimed to formulate and optimize sustained release proliposome dry powder for inhalation of Voriconazole (VZ) and its in vitro and in vivo evaluation. The proliposome-based dry powder for inhalation was formulated by spray drying technique using Phospholipon 90H and cholesterol in the lipid phase, mannitol as a carrier, and L-leucine as a dispersing agent. A face-centered central composite design was used to study the influence of factors on responses, vesicle size, VZ entrapment efficiency, and drug release. The optimized formulation was further characterized by FTIR, FESEM, DSC, XRD, and evaluated for in vitro drug release, in vitro aerosol deposition, and in vivo lung retention study in Wistar rats. For the optimized batch F-5 proliposome formulation, vesicle size was observed as 191.7 ± 0.049 nm with PDI 0.328 ± 0.009, entrapment efficiency as 72.94 ± 0.56%, and cumulative drug release after 8 h of dissolution was 82.0 ± 0.14%. The median mass aerodynamic diameter (MMAD) generated by optimized formulation F5 was significantly lower (3.85 ± 0.15 µm, p < 0.0001) as compared to spray-dried voriconazole (SD-VZ) (8.35 ± 0.23 µm). In vivo studies demonstrated a profound enhancement in lung retention (3.8-fold) compared to SD-VZ and oral VZ dispersion. Conclusively, proliposome formulation of voriconazole is a plausible and convincing approach for pulmonary fungal infections, considering its sustained release behaviour and prolonged lung retention. Full article

(This article belongs to the Special Issue Advanced Spray Drying Technology in Pharmaceutical Formulations: Novel Applications Using Polymeric and Lipidic Excipients)

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15 pages, 2319 KiB

Open AccessArticle

Nifuroxazide and 4-Hydroxybenzhydrazone Derivatives as New Antiparasitic (Trypanosoma cruzi and Leishmania mexicana) and Anti-Mycobacterium tuberculosis Agents

by Timoteo Delgado-Maldonado, Diana V. Navarrete-Carriola, Lenci K. Vázquez-Jiménez, Alma D. Paz-González, Baojie Wan, Scott Franzblau, Othman Mueen Mohammed, Lorena Rodríguez-Páez, Charmina Aguirre-Alvarado, Verónica Alcántara-Farfán, Joaquín Cordero-Martínez, Debasish Bandyopadhyay, Adriana Moreno-Rodríguez and Gildardo Rivera

Pharmaceutics 2025, 17(5), 621; https://doi.org/10.3390/pharmaceutics17050621 - 7 May 2025

Abstract

Background/Objectives: Nifuroxazide (Nfz) is a drug that has been used as a scaffold for designing antimicrobial and antiparasitic agents. This study aimed to synthesize and evaluate in vitro of Nfz and twenty-five 4-hydroxybenzhydrazone derivatives as potential anti-Trypanosoma cruzi, anti-Leishmania mexicana [...] Read more.

Background/Objectives: Nifuroxazide (Nfz) is a drug that has been used as a scaffold for designing antimicrobial and antiparasitic agents. This study aimed to synthesize and evaluate in vitro of Nfz and twenty-five 4-hydroxybenzhydrazone derivatives as potential anti-Trypanosoma cruzi, anti-Leishmania mexicana, and anti-Mycobacterium tuberculosis agents. Methods: The compounds were synthesized by condensing 4-hydroxybenzhydrazide with appropriate aldehydes in acidic conditions and structurally confirmed by spectroscopic techniques. All compounds were evaluated in vitro against T. cruzi strains (NINOA and A1), L. mexicana (M379 and FCQEPS strains), and M. tuberculosis (H37Rv strain), followed by enzymatic assays against T. cruzi cysteine proteases. Results: Compound Nfz-24 (IC₅₀ = 6.8 μM) had better trypanocidal activity than the reference drugs benznidazole (IC₅₀ > 30 μM) and nifurtimox (IC₅₀ > 7 μM) against the NINOA strain, and Nfz-8 (IC₅₀ = 7.2 μM) was the compound most active against the A1 strain with a high inhibition of T. cruzi cysteine proteases (IC₅₀ = 4.6 μM) and low cytotoxic effects (CC₅₀ >100 μM). On the other hand, compound Nfz-5 (IC₅₀ = 5.2 μM) had a 25-fold better leishmanicidal effect than glucantime (IC₅₀ > 125 μM) against the L. mexicana M379 strain, and compound Nfz-13 had the best leishmanicidal effects (IC₅₀ = 10.2 μM) against the FCQEPS strain. Finally, Nfz, Nfz-1, and Nfz-2 had minimum inhibitory concentration (MIC) values of 12.3, 5.1, and 18.8 μg/mL against M. tuberculosis, respectively. Conclusions: In summary, these results suggest that the compounds Nfz-1, Nfz-2, Nfz-5, Nfz-8, Nfz-10, Nfz-15, Nfz-24, and Nfz-25 are candidates for further studies to develop new and more potent anti-T. cruzi, anti-leishmaniasis, and anti-M. tuberculosis agents. Full article

(This article belongs to the Special Issue Advances in Antiparasitic Agents)

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28 pages, 6539 KiB

Open AccessArticle

Hydrogel–Nanolipid Formulations for the Complex Anti-Inflammatory and Antimicrobial Therapy of Periodontitis

by Rabia Ashfaq, Nóra Tóth, Anita Kovács, Szilvia Berkó, Gábor Katona, Rita Ambrus, Tamás Ferenc Polgár, Mária Szécsényi, Katalin Burián and Mária Budai-Szűcs

Pharmaceutics 2025, 17(5), 620; https://doi.org/10.3390/pharmaceutics17050620 - 7 May 2025

Abstract

Objectives: This study aimed to develop and evaluate nanostructured lipid carriers (NLCs) loaded with meloxicam (Melox) and a therapeutic antibacterial and anti-inflammatory liquid lipid, clove oil (CO) for periodontitis treatment, a complex inflammatory condition necessitating advanced drug delivery systems. The NLC–Melox formulation [...] Read more.

Objectives: This study aimed to develop and evaluate nanostructured lipid carriers (NLCs) loaded with meloxicam (Melox) and a therapeutic antibacterial and anti-inflammatory liquid lipid, clove oil (CO) for periodontitis treatment, a complex inflammatory condition necessitating advanced drug delivery systems. The NLC–Melox formulation was integrated into three hydrogels, hypromellose (HPMC), zinc hyaluronate (ZnHA), and sodium hyaluronate (NaHA), to conduct a comparative analysis focusing on enhanced localized drug delivery, improved mucoadhesion, prolonged retention, and significant therapeutic outcomes. Methods: NLC–Melox was prepared by homogenization and characterized by dynamic light scattering (DLS). Subsequently, NLC–Melox-loaded gels were subjected to transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), Raman spectroscopy, and rheological analysis. In vitro drug release, anti-inflammatory activity (BSA denaturation assay), and antibacterial efficacy (MIC, MBC) were investigated to assess therapeutic potential. Results: DLS revealed a particle size of 183 nm with a polydispersity index of 0.26, indicating homogeneity. TEM confirmed consistent morphology and uniform nanoparticle distribution. DSC and XRD demonstrated the amorphous nature of Melox, enhancing solubility and stability. Spectroscopy confirmed no chemical interactions between components. Rheological studies identified ZnHA as the most mucoadhesive and structurally stable gel. In vitro release studies showed sustained drug release over 24 h. Melox and CO-loaded formulations demonstrated significant anti-inflammatory activity and notable antibacterial efficacy due to the antibacterial oil. Conclusions: The study highlighted the potential of NLC-based mucoadhesive hydrogels as an effective strategy for periodontitis treatment. The formulation offered improved drug solubility, therapeutic efficacy, mucoadhesivity, and prolonged delivery, making it a promising candidate for localized therapy. Full article

(This article belongs to the Special Issue Recent Insights Concerning the Use of Supramolecular Systems for Biomedical Applications)

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24 pages, 564 KiB

Open AccessReview

Pharmacokinetics of Different Tacrolimus Formulations in the Early Post-Liver Transplant Period: A Scoping Review

by Paloma Barriga-Rodríguez, Marta Falcón-Cubillo, Marta Mejías-Trueba, Pablo Ciudad-Gutiérrez, Ana Belén Guisado-Gil, Miguel Ángel Gómez-Bravo, Manuel Porras-López, María Victoria Gil-Navarro and Laura Herrera-Hidalgo

Pharmaceutics 2025, 17(5), 619; https://doi.org/10.3390/pharmaceutics17050619 - 6 May 2025

Abstract

Background: Tacrolimus (TAC) is the cornerstone of immunosuppression after liver transplantation (LT). TAC has a narrow therapeutic index and high inter- and intra-individual pharmacokinetic (PK) variability, requiring dose individualization. This variability is more noticeable in the early post-LT period. Objectives: This study aimed [...] Read more.

Background: Tacrolimus (TAC) is the cornerstone of immunosuppression after liver transplantation (LT). TAC has a narrow therapeutic index and high inter- and intra-individual pharmacokinetic (PK) variability, requiring dose individualization. This variability is more noticeable in the early post-LT period. Objectives: This study aimed to compare the PK of different TAC formulations in the early post-LT period and describe the main PK characteristics and plasma levels obtained with each TAC formulation used. Methods: The search was conducted in MEDLINE (PubMed) and EMBASE in accordance with PRISMA-ScR guidelines. The main inclusion criteria were clinical trials and observational studies focusing on the PK parameters of TAC in LT recipients during the first month post-transplant. Results: A total of 2169 articles were identified, of which 23 met the inclusion criteria. Various PK parameters were analyzed after LT for the different TAC formulations: intravenous (iv) and oral forms, such as immediate-release (IRT), prolonged-release (PRT), and extended-release (LCPT) formulations. PK variability was higher in the initial days after LT, with different TAC exposure between formulations. IV TAC allows the rapid attainment of therapeutic levels, but it has fallen into disuse. Regarding oral formulations, IRT reaches target levels faster than PRT and LCPT. PRT and LCPT exposure seem more stable during the first month post-LT than when using IRT. Conclusions: TAC formulations exhibit relevant differences in their PK profile in the early post-LT period. PK differences might influence the dose regimen and the time to achieve PK targets. Given these variations, therapeutic drug monitoring (TDM) is essential for optimizing treatment. Full article

(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)

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18 pages, 14056 KiB

Open AccessArticle

Collagen–Chitosan Composites Enhanced with Hydroxytyrosol for Prospective Wound Healing Uses

by Miguel P. Batista, Margarida Pimenta, Naiara Fernández, Ana Rita C. Duarte, Maria do Rosário Bronze, Joana Marto and Frédéric Bustos Gaspar

Pharmaceutics 2025, 17(5), 618; https://doi.org/10.3390/pharmaceutics17050618 - 6 May 2025

Abstract

Background/Objectives: Recent studies highlight the excellent wound-healing properties of collagen and chitosan materials. Combining these polymers with a bioactive compound could enhance their effectiveness as next-generation wound dressings. Hydroxytyrosol (HT), an antioxidant derived from olive oil, may aid wound healing due to its [...] Read more.

Background/Objectives: Recent studies highlight the excellent wound-healing properties of collagen and chitosan materials. Combining these polymers with a bioactive compound could enhance their effectiveness as next-generation wound dressings. Hydroxytyrosol (HT), an antioxidant derived from olive oil, may aid wound healing due to its anti-inflammatory, antimicrobial, and angiogenesis-stimulating properties, making it a beneficial addition to collagen–chitosan dressings. It could be a beneficial addition to collagen–chitosan dressings, thus improving their therapeutic effects. This study screens the potential of collagen–chitosan composites with HT for wound-healing applications and assesses the influence of the compound’s incorporation on the materials’ properties. Methods: The material production involved incorporating chitosan and HT into a marine collagen extract. The resulting collagen–chitosan–HT material was obtained through freeze-drying. Prototype dressing characterization included morphology by scanning electron microscopy, solid and hydrated state by textural and rheological studies, and in vitro HT release studies. The materials’ cytocompatibility screening was assessed using a mouse fibroblast cell line, and the antibacterial activity was evaluated against microorganisms commonly implicated in wound infections. Results: Burst strength, viscosity, frequency sweep test, tackiness, and adhesion results indicate that chitosan contributes to the material’s mechanical robustness by maintaining a high viscosity and preserving the material’s gel structure. The in vitro release studies suggest an HT-controlled release profile with a maximum release (70%) achieved after 10 h. Biological experiments confirmed the materials’ cytocompatibility with skin cells and very promising antibacterial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa. Conclusions: In conclusion, HT was successfully incorporated into a collagen–chitosan matrix, enhancing the therapeutic prospect of the resultant material. The collagen–chitosan–HT composite presents a promising potential as an advanced wound-healing material. Full article

(This article belongs to the Special Issue Drug Delivery of Natural Active Principles: Focus on Topical and Oral Applications, 2nd Edition)

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3 pages, 149 KiB

Open AccessEditorial

ADME Properties in Drug Delivery

by Luciana Scotti and Marcus Tullius Scotti

Pharmaceutics 2025, 17(5), 617; https://doi.org/10.3390/pharmaceutics17050617 - 6 May 2025

Abstract

In recent decades, the identification of thousands of lead compounds, through development of analytical, synthetic, and computational techniques has occurred [...] Full article

(This article belongs to the Special Issue ADME Properties in the Drug Delivery)

4 pages, 152 KiB

Open AccessEditorial

Advances in the Oral Delivery of Protein and Peptide Drugs

by Guanyu Chen

Pharmaceutics 2025, 17(5), 616; https://doi.org/10.3390/pharmaceutics17050616 - 6 May 2025

Abstract

Protein and peptide drugs (PPDs) are highly effective therapies for a wide range of diseases, including cancer, diabetes, and autoimmune disorders [...] Full article

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

23 pages, 7191 KiB

Open AccessArticle

Interleukin-15Rα-Sushi-Fc Fusion Protein Co-Hitchhikes Interleukin-15 and Pheophorbide A for Cancer Photoimmunotherapy

by Zhe Li, Jiaojiao Xu, Hongzheng Lin, Sheng Yu, Jingwen Sun, Chen Zhang, Sihang Zhang, Tingting Li, Afeng Yang and Wei Lu

Pharmaceutics 2025, 17(5), 615; https://doi.org/10.3390/pharmaceutics17050615 - 5 May 2025

Abstract

Background: Interleukin-15 (IL-15) stimulates the proliferation of natural killer cells or T cells, which, in combination with photodynamic therapy (PDT), has emerged as an effective strategy for cancer photoimmunotherapy. Instead of direct cytokine receptor activation, IL-15 necessitates first binding to the IL-15 [...] Read more.

Background: Interleukin-15 (IL-15) stimulates the proliferation of natural killer cells or T cells, which, in combination with photodynamic therapy (PDT), has emerged as an effective strategy for cancer photoimmunotherapy. Instead of direct cytokine receptor activation, IL-15 necessitates first binding to the IL-15 receptor α chain subunit (IL-15Rα), followed by trans-presentation to the IL-15 receptor β/γ chain subunit on the effector cells for pharmacologic activation. Therefore, the delivery of IL-15 remains a major challenge owing to its short half-life, its lack of targeting activity, and the limited availability of IL-15Rα. Methods: A co-hitchhiking delivery approach using recombinant IL-15 (rIL-15) and a photosensitizer, pheophorbide A (PhA), is developed for enhanced combinatorial cancer immunotherapy with PDT. A recombinant IL-15Rα-sushi-Fc fusion protein (rILR-Fc) is designed to load rIL-15 through the IL-15Rα sushi domain, which mimics its trans-presentation. Moreover, the Fc moiety of rILR-Fc can load PhA based on its high binding affinity. Results: Through self-assembly, rILR-Fc/PhA/rIL-15 nanoparticles (NPs) are formulated to co-hitchhike PhA and rIL-15, which improves the tumor accumulation of PhA and rIL-15 through receptor-mediated transcytosis. Moreover, the nanoparticles prolong the blood half-life of rIL-15 but do not alter the elimination rate of PhA from the blood. The rILR-Fc/PhA/rIL-15 NPs effectively elicit potent systemic antitumor immunity and long-lasting immune memory against tumor rechallenge in model mice bearing orthotopic colon tumors. Conclusions: The enhanced antitumor therapeutic effect demonstrates that the co-hitchhiking delivery strategy, optimizing the pharmacokinetics of both the photosensitizer and IL-15, provides a promising strategy for combinatorial photodynamic and IL-15 immunotherapy. Full article

(This article belongs to the Section Nanomedicine and Nanotechnology)

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26 pages, 14079 KiB

Open AccessArticle

Neutrophil-Camouflaged Stealth Liposomes for Photothermal-Induced Tumor Immunotherapy Through Intratumoral Bacterial Activation

by Xinxin Chen, Jiang Sun, Tingxian Ye and Fanzhu Li

Pharmaceutics 2025, 17(5), 614; https://doi.org/10.3390/pharmaceutics17050614 - 5 May 2025

Abstract

Objective: F. nucleatum, a tumor-resident bacterium colonizing breast cancer (BC), results in an immunosuppressive microenvironment and facilitates tumor growth and metastasis. This study aimed to develop a neutrophil-based liposome delivery system designed for dual-targeted elimination of tumor cells and F. nucleatum [...] Read more.

Objective: F. nucleatum, a tumor-resident bacterium colonizing breast cancer (BC), results in an immunosuppressive microenvironment and facilitates tumor growth and metastasis. This study aimed to develop a neutrophil-based liposome delivery system designed for dual-targeted elimination of tumor cells and F. nucleatum, while simultaneously upregulating pathogen-associated molecular patterns and damage-associated molecular patterns to potentiate tumor immunotherapy. Methods: The liposomes (PD/GA-LPs) loaded with the perylene diimide complex (PD) and gambogic acid (GA) were fabricated via the extrusion method. Subsequently, comprehensive evaluations including physicochemical characteristics, antibacterial activity, antitumor effect, and immunomodulatory effect evaluation were systematically conducted to validate the feasibility of this delivery system. Results: The resulting PD/GA-LPs exhibited a dynamic size (121.3 nm, zeta potential −44.1 mV) and a high encapsulation efficiency of approximately 78.1% (PD) and 91.8% (GA). In addition, the optimized PD/GA-LPs exhibited excellent photothermal performance and antibacterial efficacy. In vitro cellular experiments revealed that PD/GA-LPs exhibited enhanced internalization by neutrophils, followed by extracellular trap-mediated release, ultimately significantly inhibiting tumor cell proliferation and inducing immunogenic cell death. During in vivo treatment, PD/GA-LPs exhibited targeted tumor accumulation, where F. nucleatum-driven PD reduction activated near-infrared-responsive photothermal ablation. When combined with GA, this delivery system effectively eliminated tumor cells and F. nucleatum, while facilitating the subsequent T-cell infiltration. Conclusions: This strategy amplified the antitumor immune response, thus leading to effective treatment of BC and prevention of metastasis. In summary, this approach, grounded in the distinct microecology of tumor and normal tissues, offers novel insights into the development of precise and potent immunotherapies for BC. Full article

(This article belongs to the Special Issue Cutting-Edge Liposome Innovations for Precision Delivery and Cancer Treatment)

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19 pages, 5644 KiB

Open AccessArticle

3D Printing of PVA Capsular Devices for Applications in Compounding Pharmacy: Stability Evaluation and In Vivo Performance

by Juan Francisco Peña, Daniel Andrés Real, Juan Pablo Real, Santiago Daniel Palma, María del Pilar Zarazaga, Nicolás Javier Litterio, Loreana Gallo and Ivana Maria Cotabarren

Pharmaceutics 2025, 17(5), 613; https://doi.org/10.3390/pharmaceutics17050613 - 5 May 2025

Abstract

Background: The personalization of medication through 3D printing enables the development of capsular devices (CDs) tailored to patient-specific needs. This study aimed to evaluate the stability and in vivo performance of 3D-printed polyvinyl alcohol (PVA) CDs with 0.4 and 0.9 mm width [...] Read more.

Background: The personalization of medication through 3D printing enables the development of capsular devices (CDs) tailored to patient-specific needs. This study aimed to evaluate the stability and in vivo performance of 3D-printed polyvinyl alcohol (PVA) CDs with 0.4 and 0.9 mm width wall thicknesses (WT) compared to traditional hard gelatin capsules (HGCs). Methods: Capsules were tested for swelling, erosion, adhesion, water sorption, and in vitro disintegration. Additionally, the release of the model drug (losartan potassium) from CDs was evaluated. In vivo capsule opening times were assessed in dogs using X-ray imaging. Stability studies were conducted under natural (25 ± 2 °C, 60 ± 5% RH) and accelerated (40 ± 2 °C, 75 ± 5% RH) storage conditions. Results: CDs with 0.4 mm WT (CD–0–0.4) exhibited higher swelling and erosion, lower adhesion, and faster disintegration, leading to a more immediate drug release, comparable to HGCs. A strong correlation was found between in vitro and in vivo disintegration behavior. Water sorption tests revealed lower moisture affinity for PVA CDs compared to HGC. Stability studies showed that CD–0–0.4 retained its physical and chemical properties. Instead, CDs with 0.9 mm WT (CD–0–0.9) were sensitive to storage, particularly under accelerated aging, which affected their integrity and release profile. Conclusions: These findings highlight the potential of PVA-CDs, especially the 0.4 mm design, as a promising and stable alternative for compounding pharmacy applications, offering an effective platform for personalized oral drug delivery. Full article

(This article belongs to the Special Issue 3D Printing—Current Pharmaceutical Applications and Future Directions)

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17 pages, 1522 KiB

Open AccessPerspective

From Patterns to Pills: How Informatics Is Shaping Medicinal Chemistry

by Alexander Trachtenberg and Barak Akabayov

Pharmaceutics 2025, 17(5), 612; https://doi.org/10.3390/pharmaceutics17050612 - 5 May 2025

Abstract

In today’s information-driven era, machine learning is revolutionizing medicinal chemistry, offering a paradigm shift from traditional, intuition-based, and often bias-prone methods to the prediction of chemical properties without prior knowledge of the basic principles governing drug function. This perspective highlights the growing importance [...] Read more.

In today’s information-driven era, machine learning is revolutionizing medicinal chemistry, offering a paradigm shift from traditional, intuition-based, and often bias-prone methods to the prediction of chemical properties without prior knowledge of the basic principles governing drug function. This perspective highlights the growing importance of informatics in shaping the field of medicinal chemistry, particularly through the concept of the “informacophore”. The informacophore refers to the minimal chemical structure, combined with computed molecular descriptors, fingerprints, and machine-learned representations of its structure, that are essential for a molecule to exhibit biological activity. Similar to a skeleton key unlocking multiple locks, the informacophore points to the molecular features that trigger biological responses. By identifying and optimizing informacophores through in-depth analysis of ultra-large datasets of potential lead compounds and automating standard parts in the development process, there will be a significant reduction in biased intuitive decisions, which may lead to systemic errors and a parallel acceleration of drug discovery processes. Full article

(This article belongs to the Special Issue Advancements in AI and Pharmacokinetics)

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38 pages, 10556 KiB

Open AccessArticle

Augmented Marshmallow Extract Lipid Nanoparticles with Clove Oil Embedded in Collagen Sponge for Ultimate Antimicrobial Healing of Diabetic Mouth Ulcer

by Sammar Fathy Elhabal, Ahmed Mohsen Faheem, Sandra Hababeh, Jakline Nelson, Nahla A. Elzohairy, Yasmine F. Ibrahim, Tassneim M. Ewedah, Ibrahim S. Mousa, Khaled M. Allam and Ahmed Mohsen Elsaid Hamdan

Pharmaceutics 2025, 17(5), 611; https://doi.org/10.3390/pharmaceutics17050611 - 5 May 2025

Abstract

Background/Objectives: Diabetic mouth ulcers are a pathological condition of the oral mucosa leading to increases in susceptibility to infection and prolonged wound healing time. Still, there is a lack of natural formulations for treating this condition. Our principal objective was to formulate [...] Read more.

Background/Objectives: Diabetic mouth ulcers are a pathological condition of the oral mucosa leading to increases in susceptibility to infection and prolonged wound healing time. Still, there is a lack of natural formulations for treating this condition. Our principal objective was to formulate solid lipid nanoparticles (SLNs) that contained Althaea officinalis (marshmallow) (M.) extract with clove oil (CO.), subsequently integrated into a collagen sponge for enhancing stability, solubility, sustained release, antimicrobial efficacy, and healing power when targeting diabetic oral ulcers. Methods: A factorial design of 34 trials was established to evaluate the influence of lipid concentration (A), SAA concentration (B), lipid type (C), and SAA type (D). The optimized M-CO-SLNs was selected using Design Expert^®, the based Poly dispersibility index (Y2), zeta potential (MV) (Y3), and encapsulation efficiency (%) (Y4). The optimized SLNs were integrated into a collagen sponge matrix and tested for their antibacterial and antifungal efficacy against Pseudomonas aeruginosa, Escherichia coli, and Candida albicans, respectively. Moreover, they were tested for their wound healing power in a diabetic mouth ulcer model. Results: The optimized formula (Run 16: 5% lipid concentration, 4% SAA concentration, capric acid) demonstrated P.S (110 ± 0.76 nm), ZP (−24 ± 0.32 mV), PDI (0.18 ± 0.05), and EE% (90 ± 0.65%.). The optimized M-CO-SLNs formula was incorporated into a cross-linked collagen sponge and showed superior antimicrobial efficacy, an increased swelling ratio, and was effective in an in vivo oral ulcer study, as evidenced by ELISA biomarkers, gene expression analysis, and histological analysis. Conclusions: M-CO-SLNs embedded in collagen sponges is a promising therapeutic formula for clinical application against diabetic mouth ulcers. Full article

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

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24 pages, 4850 KiB

Open AccessReview

Anti-Cancer Drugs: Trends and Insights from PubMed Records

by Ferdinando Spagnolo, Silvia Brugiapaglia, Martina Perin, Simona Intonti and Claudia Curcio

Pharmaceutics 2025, 17(5), 610; https://doi.org/10.3390/pharmaceutics17050610 - 4 May 2025

Abstract

Background: In recent years, there has been an exponential growth in global anti-cancer drug research, prompting the necessity for comprehensive analyses of publication output and thematic shifts. Methods: This study utilized a comprehensive set of PubMed records from 1962 to 2024 and [...] Read more.

Background: In recent years, there has been an exponential growth in global anti-cancer drug research, prompting the necessity for comprehensive analyses of publication output and thematic shifts. Methods: This study utilized a comprehensive set of PubMed records from 1962 to 2024 and examined growth patterns, content classification, and co-occurrence of key pharmacological and molecular terms. Results: Our results highlight an exponential rise in publications, with an annual compound growth rate of over 14%, influenced by advancements in digital knowledge sharing and novel therapeutic breakthroughs. A pronounced surge occurred during the COVID-19 pandemic, suggesting a sustained shift in research dynamics. The content analyses revealed a strong emphasis on classical chemotherapeutic agents—often studied in combination with targeted therapies or immunotherapies—and a growing focus on immune checkpoint inhibitors and vaccine platforms. Furthermore, co-occurrence networks indicated robust links between chemotherapy and supportive care, as well as emerging synergies between immuno-oncology, precision medicine approaches. Conclusions: Our study suggests that while novel modalities are reshaping treatment paradigms, chemotherapy remains central, underscoring the value of integrative regimens. This trend toward personalized, combination-based strategies indicates a transformative era in oncology research, where multidimensional data assessment is instrumental in guiding future therapeutic innovations. Full article

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22 pages, 2643 KiB

Open AccessReview

Immune Modulation with Oral DNA/RNA Nanoparticles

by Ulpan Kart, Aigul Raimbekova, Sergey Yegorov and Gonzalo Hortelano

Pharmaceutics 2025, 17(5), 609; https://doi.org/10.3390/pharmaceutics17050609 - 4 May 2025

Abstract

The oral delivery of DNA/RNA nanoparticles represents a transformative approach in immunotherapy and vaccine development. These nanoparticles enable targeted immune modulation by delivering genetic material to specific cells in the gut-associated immune system, triggering both mucosal and systemic immune responses. Unlike parenteral administration, [...] Read more.

The oral delivery of DNA/RNA nanoparticles represents a transformative approach in immunotherapy and vaccine development. These nanoparticles enable targeted immune modulation by delivering genetic material to specific cells in the gut-associated immune system, triggering both mucosal and systemic immune responses. Unlike parenteral administration, the oral route offers a unique immunological environment that supports both tolerance and activation, depending on the formulation design. This review explores the underlying mechanisms of immune modulation by DNA/RNA nanoparticles, their design and delivery strategies, and recent advances in their application. Emphasis is placed on strategies to overcome physiological barriers such as acidic pH, enzymatic degradation, mucus entrapment, and epithelial tight junctions. Special attention is given to the role of gut-associated lymphoid tissue in mediating immune responses and the therapeutic potential of these systems in oral vaccine platforms, food allergies, autoimmune diseases, and chronic inflammation. Despite challenges, recent advances in nanoparticle formulation support the translation of these technologies into clinical applications for both therapeutic immunomodulation and vaccination. Full article

(This article belongs to the Special Issue Nanoparticle-Based Gene Delivery)

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22 pages, 1650 KiB

Open AccessSystematic Review

Efficacy and Safety of Antibody-Drug Conjugates for Lung Cancer Therapy: A Systematic Review of Randomized and Non-Randomized Clinical Trials

by Matteo Gallina, Anna Carollo, Anna Gallina, Sofia Cutaia, Sergio Rizzo and Alessio Provenzani

Pharmaceutics 2025, 17(5), 608; https://doi.org/10.3390/pharmaceutics17050608 - 3 May 2025

Abstract

Background/Objectives: Lung cancer is the leading cause of cancer-related deaths worldwide. Non-Small-Cell Lung Cancer (NSCLC) accounts for 80–90% of all lung cancers. Antibody-Drug Conjugates (ADCs) represent an expanding targeted therapy option for the treatment of NSCLC. The aim is to perform a [...] Read more.

Background/Objectives: Lung cancer is the leading cause of cancer-related deaths worldwide. Non-Small-Cell Lung Cancer (NSCLC) accounts for 80–90% of all lung cancers. Antibody-Drug Conjugates (ADCs) represent an expanding targeted therapy option for the treatment of NSCLC. The aim is to perform a systematic literature review to evaluate the efficacy and safety profiles of ADCs currently undergoing clinical trials for the treatment of NSCLC. Methods: The study adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Literature searches were conducted in PubMed, ClinicalTrial.gov and Web of Science databases, covering the period from 2014 to 2024. Only randomized and non-randomized phase II-IV clinical trials focusing on ADC-based therapies for adult patients affected by NSCLC were selected. The Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2.0) and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) were used to evaluate the overall risk of bias in the included randomized and non-randomized studies, respectively. While GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology was used to assess the certainty of the evidence. Efficacy endpoints were categorized based on primary outcomes while safety was assessed through the frequency and severity of Treatment-Emergent Adverse Events (TEAEs), and a qualitative summary of the findings was conducted. Results: A total of seven studies, including three randomized, three non-randomized, and one without specific allocation, were included, comprising 1287 patients, with 693 (54%) men, and an average age of 63 years old. Two studies were deemed to have a low risk of bias, while six had a moderate risk or some concerns. Five ADCs were evaluated: trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1), telisotuzumab vedotin, patritumab deruxtecan, and datopotamab deruxtecan (Dato-DXd). T-DXd demonstrated superior efficacy in HER2-overexpressing and HER2-mutant NSCLC, with an ORR of 52.9% and 49.0%, respectively. However, HER2-mutant patients exhibited a longer median DOR (16.8 vs. 6.2 months) but a higher incidence of grade ≥ 3 TEAEs (38.6% vs. 22%). T-DM1 showed modest efficacy, with an ORR of 20% in HER2-overexpressing NSCLC and 6.7% in HER2-mutant patients. Dato-DXd demonstrated improved ORR (26.4% vs. 12.8%) and PFS (4.4 vs. 3.7 months) compared to docetaxel. Patritumab deruxtecan achieved an ORR of 39% in EGFR-mutant NSCLC, while telisotuzumab vedotin exhibited limited activity in c-MET-positive NSCLC (ORR 9%, median DOR 7.5 months). Frequency and severity of TEAEs varied across ADCs, with ILD being a major concern, highlighting the need for strict patient monitoring and early intervention to mitigate severe adverse events. Conclusions: ADCs represent a promising advancement in NSCLC treatment, offering targeted therapeutic options beyond conventional chemotherapy and immunotherapy. T-DXd has emerged as the most effective ADC for HER2-mutant NSCLC with manageable safety profile, whereas Dato-DXd provides a viable alternative for TROP2-expressing tumors. While ADCs offer significant clinical benefits, careful patient selection and proactive management of adverse events remain crucial. Ongoing and future trials will further refine the role of ADCs in personalized NSCLC treatment, potentially expanding their tumor-agnostic use to broader patient populations. Full article

(This article belongs to the Section Clinical Pharmaceutics)

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