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Pharmaceutics
Volume 16
Issue 12
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Pharmaceutics, Volume 16, Issue 12 (December 2024) – 145 articles

Cover Story (view full-size image): There is a need for new therapies with distinct mechanisms to treat inflammatory bowel disease (IBD). IBD pathophysiology is complex and involves genetic susceptibility, environmental factors, and immune dysfunction. Certain microRNAs (miRNAs), like miR146a, play a role in IBD by regulating gene transcription. miR146a downregulates NF-kB nuclear translocation and inflammation, but its instability challenges therapeutic use. We stabilized miR146a for therapeutic use by conjugating it to cerium oxide nanoparticles (CNPs), which also scavenge free radicals and reduce reactive oxygen species. Furthermore, we have previously demonstrated the preclinical efficacy of intrarectal CNP-miR146a in acute colitis. In this study, we examine the preclinical efficacy of orally administered CNP-miR146a in a more clinically relevant model of chronic T cell-mediated colitis. View this paper
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17 pages, 3198 KiB  
Article
Development and Evaluation of Five-in-One Vaccine Microneedle Array Patch for Diphtheria, Tetanus, Pertussis, Hepatitis B, and Haemophilus influenzae Type b: Immunological Efficacy and Long-Term Stability
by In-Jeong Choi, Hye-Ran Cha, Danbi Kwon, Aram Kang, Ji Seok Kim, Jooyoung Kim, Jeong-Eun Choi, Hyeon Woo Chung, Sunghoon Park, Doo Hee Shim, Tae-Hyun Kim, Seung-Ki Baek, Woon-Sung Na, Jae Myun Lee and Jung-Hwan Park
Pharmaceutics 2024, 16(12), 1631; https://doi.org/10.3390/pharmaceutics16121631 - 23 Dec 2024
Viewed by 1129
Abstract
Background and objectives: The development of a five-in-one vaccine microneedle patch (five-in-one MN patch) aims to address challenges in administering vaccines against Diphtheria (DT), Tetanus (TT), Pertussis (wP), Hepatitis B (HBsAg), and Haemophilus influenzae type b (Hib). Combining multiple vaccines into a [...] Read more.
Background and objectives: The development of a five-in-one vaccine microneedle patch (five-in-one MN patch) aims to address challenges in administering vaccines against Diphtheria (DT), Tetanus (TT), Pertussis (wP), Hepatitis B (HBsAg), and Haemophilus influenzae type b (Hib). Combining multiple vaccines into a single patch offers a novel solution to improve vaccine accessibility, stability, and delivery efficiency, particularly in resource-limited settings. Methods: The five-in-one MN patch consists of four distinct microneedle arrays: DT and TT vaccines are coated together on one array, while wP, HepB, and Hib vaccines are coated separately on individual arrays. The patch was tested for long-term stability (12 months at 25 °C) and evaluated for immunogenicity in mice and minipigs. Antibody titers were measured using ELISA to compare immune responses between microneedle-based delivery and traditional intramuscular (IM) injection. Results: The five-in-one MN patch demonstrated stable antigenicity for up to 12 months at room temperature. In animal studies, the patch induced antibody titers comparable to traditional IM injections for all vaccines. Notably, immunogenic responses to Pertussis and Haemophilus influenzae type b vaccines via microneedles were reported for the first time. The patch facilitated the simultaneous yet independent delivery of vaccines, preserving their immunogenicity without interference. Conclusions: The five-in-one MN patch represents a significant advancement in vaccine delivery by enabling stable, minimally invasive, and efficient immunization. Its innovative design addresses the critical limitations of combination vaccines and has the potential to enhance vaccine accessibility in low- and middle-income countries. Future studies will focus on optimizing patch application techniques and evaluating broader clinical applicability. Full article
(This article belongs to the Special Issue Microarray Patches for Transdermal Drug Delivery)
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20 pages, 3753 KiB  
Article
Twin Screw Melt Granulation of Simvastatin: Drug Solubility and Dissolution Rate Enhancement Using Polymer Blends
by Rasha M. Elkanayati, Indrajeet Karnik, Prateek Uttreja, Nagarjuna Narala, Sateesh Kumar Vemula, Krizia Karry and Michael A. Repka
Pharmaceutics 2024, 16(12), 1630; https://doi.org/10.3390/pharmaceutics16121630 - 23 Dec 2024
Viewed by 1083
Abstract
Background/Objectives: This study evaluates the efficacy of twin screw melt granulation (TSMG), and hot-melt extrusion (HME) techniques in enhancing the solubility and dissolution of simvastatin (SIM), a poorly water-soluble drug with low bioavailability. Additionally, the study explores the impact of binary polymer blends [...] Read more.
Background/Objectives: This study evaluates the efficacy of twin screw melt granulation (TSMG), and hot-melt extrusion (HME) techniques in enhancing the solubility and dissolution of simvastatin (SIM), a poorly water-soluble drug with low bioavailability. Additionally, the study explores the impact of binary polymer blends on the drug’s miscibility, solubility, and in vitro release profile. Methods: SIM was processed with various polymeric combinations at a 30% w/w drug load, and a 1:1 ratio of binary polymer blends, including Soluplus® (SOP), Kollidon® K12 (K12), Kollidon® VA64 (KVA), and Kollicoat® IR (KIR). The solid dispersions were characterized using modulated differential scanning calorimetry (M-DSC), powder X-ray diffraction (PXRD), and Fourier-transform infrared spectroscopy (FTIR). Dissolution studies compared the developed formulations against a marketed product. Results: The SIM-SOP/KIR blend showed the highest solubility (34 µg/mL), achieving an approximately 5.5-fold enhancement over the pure drug. Dissolution studies showed that SIM-SOP/KIR formulations had significantly higher release profiles than the physical mixture (PM) and pure drug (p < 0.01). Additionally, their release was similar to a marketed formulation, with 100% drug release within 30 min. In contrast, the SIM-K12/KIR formulation exhibited strong miscibility, but limited solubility and slower release rates, suggesting that high miscibility does not necessarily correlate with improved solubility. Conclusions: This study demonstrates the effectiveness of TSMG, and HME as effective continuous manufacturing technologies for improving the therapeutic efficacy of poorly water-soluble drugs. It also emphasizes the complexity of polymer–drug interactions and the necessity of carefully selecting compatible polymers to optimize the quality and performance of pharmaceutical formulations. Full article
(This article belongs to the Special Issue Improving the Bioavailability and Solubility of Pharmaceutical Formulations)
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16 pages, 1017 KiB  
Article
Vedolizumab Clearance as a Surrogate Marker for Remission in Inflammatory Bowel Disease Patients: Insights from Real-World Pharmacokinetics
by Srđan Marković, Đorđe Kralj, Petar Svorcan, Tamara Knežević Ivanovski, Olga Odanović, Sanja Obradović, Ana Homšek, Marija Jovanović, Rada Savić and Katarina M. Vučićević
Pharmaceutics 2024, 16(12), 1629; https://doi.org/10.3390/pharmaceutics16121629 - 23 Dec 2024
Viewed by 612
Abstract
Background/Objectives: Vedolizumab (VDZ) is approved in the treatment of patients with moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD). VDZ exhibits considerable variability in its pharmacokinetic (PK) profile, and its exposure-response relationship is not yet fully understood. The aim was to [...] Read more.
Background/Objectives: Vedolizumab (VDZ) is approved in the treatment of patients with moderate to severe ulcerative colitis (UC) or Crohn’s disease (CD). VDZ exhibits considerable variability in its pharmacokinetic (PK) profile, and its exposure-response relationship is not yet fully understood. The aim was to investigate the variability in VDZ trough levels and PK parameters, to assess the relationship between VDZ PK and biochemical response, as well as clinical and endoscopic outcomes. Methods: We included 61 UC and 45 CD patients. Patients’ data and trough VDZ concentrations were retrospectively obtained. Population PK analysis was performed using non-linear mixed-effects modelling with NONMEM (version 7.5). Graphs and statistical analyses were performed using R (version 4.1.3). Results: In total, 116 trough VDZ concentrations from 106 patients were described by a two-compartment model. For a typical patient, clearance (CL) was estimated at 0.159 L/day, while in patients previously treated with anti-TNFα agents, VDZ CL increased by 26.4% on average. In univariate binary logistic regression, VDZ trough concentration was not statistically significant predictor of remission, whereas CL was. Moreover, combined CL and faecal calprotectin (FCP) were a statistically significant predictors of remission. The hazard ratio (HR) for CL above 0.1886 L/day was 0.35 (p = 0.05) and for FCP below 250 µg/g was 2.66 (p = 0.02) in a time-to-event analysis. Conclusions: Our population PK model incorporates the effect of prior anti-TNFα agents on CL, suggesting its association with more severe forms of IBD. VDZ CL emerged as a more robust and clinically relevant predictor of remission in IBD patients than trough concentration. Full article
(This article belongs to the Special Issue Population Pharmacokinetics and Its Clinical Applications)
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16 pages, 1914 KiB  
Article
Molecular Docking and Antihypertensive Activity of Eupalitin 3-O-β-D-galactopyranoside Isolated from Boerhavia diffusa Linn
by Ilyas Uoorakkottil, Rashid Koottangodan, Kamal Y. Thajudheen, Saad Ali Alsheri and Mohammed Muqtader Ahmed
Pharmaceutics 2024, 16(12), 1628; https://doi.org/10.3390/pharmaceutics16121628 - 23 Dec 2024
Viewed by 539
Abstract
Background: Angiotensin-converting enzyme (ACE) is a key regulator of blood pressure, and ACE inhibition is an essential part of the treatment of hypertension. We used a molecular docking approach to find the interaction of ACE with an active flavonoid isolated from Boerhavia diffusa [...] Read more.
Background: Angiotensin-converting enzyme (ACE) is a key regulator of blood pressure, and ACE inhibition is an essential part of the treatment of hypertension. We used a molecular docking approach to find the interaction of ACE with an active flavonoid isolated from Boerhavia diffusa Linn, eupalitin 3-O-β-D-galactopyranoside, which leads to potential antihypertensive effects in methyl predenisolone-induced hypertensive rats. Additionally, the pharmacokinetic parameters of this compound are assessed. Methods:eupalitin-3-O-β-D-galactopyranoside was isolated from leaves of Boerhavia diffusa by sedimentation method. The compound was characterized by UPLC-MSMS, NMR, and UV spectroscopy to confirm the identity of the compound. Hypertension was induced in rats with methyl predenisolone (5 mg/kg/day) for 14 days. Systolic and diastolic blood pressure effects of eupalitin 3-O-β-D-galactopyranoside were assessed using a tail-cuff method. The blood plasma data for oral administration were used to determine various pharmacokinetic parameters from the bioavailability and serum concentration. Results: In methyl predenisolone-induced hypertensive rats, both systolic and diastolic blood pressures were significantly lower than that of the vehicle with treatment from eupalitin 3-O-β-D-galactopyranoside (p < 0.01). Conclusions: The pharmacokinetic process showed the moderate bioavailability of the compound; eupalitin 3-O-β-D-galactopyranoside induces powerful antihypertensive activity in methyl predenisolone-induced hypertensive rats, implying potential clinical application as a new therapeutic drug for hypertension. Full article
(This article belongs to the Special Issue Natural Product Pharmaceuticals)
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26 pages, 7186 KiB  
Article
Biomedical Application Prospects of Gadolinium Oxide Nanoparticles for Regenerative Medicine
by Ekaterina V. Silina, Natalia E. Manturova, Elena L. Chuvilina, Akhmedali A. Gasanov, Olga I. Andreeva, Maksim A. Pugachevskii, Aleksey V. Kochura, Alexey A. Kryukov, Yulia G. Suzdaltseva and Victor A. Stupin
Pharmaceutics 2024, 16(12), 1627; https://doi.org/10.3390/pharmaceutics16121627 - 23 Dec 2024
Viewed by 728
Abstract
Background/Objectives: The aim was to study the possibilities of biomedical application of gadolinium oxide nanoparticles (Gd2O3 NPs) synthesized under industrial conditions, and evaluate their physicochemical properties, redox activity, biological activity, and safety using different human cell lines. Methods: The powder [...] Read more.
Background/Objectives: The aim was to study the possibilities of biomedical application of gadolinium oxide nanoparticles (Gd2O3 NPs) synthesized under industrial conditions, and evaluate their physicochemical properties, redox activity, biological activity, and safety using different human cell lines. Methods: The powder of Gd2O3 NPs was obtained by a process of thermal decomposition of gadolinium carbonate precipitated from nitrate solution, and was studied using transmission electron microscopy (TEM), X-ray diffraction (XRD), Raman spectroscopy, mass spectrometry, and scanning electron microscopy (SEM) with energy dispersive X-ray analyzer (EDX). The redox activity of different concentrations of Gd2O3 NPs was studied by the optical spectroscopy (OS) method in the photochemical degradation process of methylene blue dye upon irradiation with an optical source. Biological activity was studied on different human cell lines (keratinocytes, fibroblasts, mesenchymal stem cells (MSCs)) with evaluation of the effect of a wide range of Gd2O3 NP concentrations on metabolic and proliferative cellular activity (MTT test, direct cell counting, dead cell assessment, and visual assessment of cytoarchitectonics). The test of migration activity assessment on a model wound was performed on MSC culture. Results: According to TEM data, the size of the NPs was in the range of 2–43 nm, with an average of 20 nm. XRD analysis revealed that the f Gd2O3 nanoparticles had a cubic structure (C-form) of Gd2O3 (Ia3)¯ with lattice parameter a = 10.79(9) Å. Raman spectroscopy showed that the f Gd2O3 nanoparticles had a high degree of crystallinity. By investigating the photooxidative degradation of methylene blue dye in the presence of f Gd2O3 NPs under red light irradiation, it was found that f Gd2O3 nanoparticles showed weak antioxidant activity, which depended on the particle content in the solution. At a concentration of 10−3 M, the highest antioxidant activity of f Gd2O3 nanoparticles was observed when the reaction rate constant of dye photodegradation decreased by 5.5% to 9.4 × 10−3 min−1. When the concentration of f Gd2O3 NPs in solution was increased to 10−2 M upon irradiation with a red light source, their antioxidant activity changed to pro-oxidant activity, accompanied by a 15% increase in the reaction rate of methylene blue degradation. Studies on cell lines showed a high level of safety and regenerative potential of Gd2O3 NPs, which stimulated fibroblast metabolism at a concentration of 10−3 M (27% enhancement), stimulated keratinocyte metabolism at concentrations of 10−3 M–10−5 M, and enhanced keratinocyte proliferation by an average of 35% at concentrations of 10−4 M. Furthermore, it accelerated the migration of MSCs, enhancing their proliferation, and promoting the healing of the model wound. Conclusions: The results of the study demonstrated the safety and regenerative potential of redox-active Gd2O3 NPs towards different cell lines. This may be the basis for further research to develop nanomaterials based on Gd2O3 NPs for skin wound healing and in regenerative medicine generally. Full article
(This article belongs to the Special Issue Functional Nanomaterials in Pharmaceutics: Current Uses and Potential Applications)
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17 pages, 2069 KiB  
Review
Use of Antimicrobial Photodynamic Therapy to Inactivate Multidrug-Resistant Klebsiella pneumoniae: Scoping Review
by Angélica R. Bravo, Felipe Alejandro Fuentealba, Iván A. González and Christian Erick Palavecino
Pharmaceutics 2024, 16(12), 1626; https://doi.org/10.3390/pharmaceutics16121626 - 23 Dec 2024
Viewed by 885
Abstract
Klebsiella pneumoniae is a Gram-negative bacillus responsible for a wide variety of potentially fatal infections and, in turn, constitutes a critical agent of healthcare-associated infections. Moreover, K. pneumoniae is characterized by multi-drug-resistant (MDR) bacteria, such as extended-spectrum beta-lactamases (ESBL) and carbapenemase (KPC) producer [...] Read more.
Klebsiella pneumoniae is a Gram-negative bacillus responsible for a wide variety of potentially fatal infections and, in turn, constitutes a critical agent of healthcare-associated infections. Moreover, K. pneumoniae is characterized by multi-drug-resistant (MDR) bacteria, such as extended-spectrum beta-lactamases (ESBL) and carbapenemase (KPC) producer strains, representing a significant health problem. Because resistances make it difficult to eradicate using antibiotics, antimicrobial photodynamic therapy (aPDT) promises to be a favorable approach to complementing conventional therapy against MDR bacteria. This study aims to provide relevant bibliographic information on the state of the art of application of aPDT against K. pneumoniae and MDR K. pneumoniae. Our methodology follows a protocol using the PRISMA extension for scoping reviews (PRISMA-ScR) guidelines, and the search consults the PubMed (MESH), Google Scholar, and Scopus databases from January 2012 to September 2024. The eligibility criteria were (1) original articles after 2012 referring to antimicrobial photodynamic activity in K. pneumoniae in vitro and in vivo: clinical applications and synergism with antibiotics, other antimicrobial drugs, or PS coupled to other particles, (2) articles in English, and (3) articles peer-reviewed. Results. Following two independent searches in databases, 298 records were found. After applying eligibility criteria and various filters, such as removing duplicates, 25 studies were included in this review. The evidence demonstrates the effectiveness of aPDT in vitro in eradicating sensitive or MDR-K. pneumoniae strains, including strains producing biofilms, ESBL, and KPC. Finally, it is concluded that aPDT is a recommended antimicrobial therapy, but more research in vivo is needed to support studies in humans. Full article
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21 pages, 12533 KiB  
Review
Recent Advances in Porphyrin-Based Covalent Organic Frameworks for Synergistic Photodynamic and Photothermal Therapy
by Cheng Qi, Jiayi Chen, Yijie Qu, Xuanxuan Luo, Weiqi Wang and Xiaohua Zheng
Pharmaceutics 2024, 16(12), 1625; https://doi.org/10.3390/pharmaceutics16121625 - 22 Dec 2024
Viewed by 1084
Abstract
Porphyrin’s excellent biocompatibility and modifiability make it a widely studied photoactive material. However, its large π-bond conjugated structure leads to aggregation and precipitation in physiological solutions, limiting the biomedical applications of porphyrin-based photoactive materials. It has been demonstrated through research that fabricating porphyrin [...] Read more.
Porphyrin’s excellent biocompatibility and modifiability make it a widely studied photoactive material. However, its large π-bond conjugated structure leads to aggregation and precipitation in physiological solutions, limiting the biomedical applications of porphyrin-based photoactive materials. It has been demonstrated through research that fabricating porphyrin molecules into nanoscale covalent organic frameworks (COFs) structures can circumvent issues such as poor dispersibility resulting from hydrophobicity, thereby significantly augmenting the photoactivity of porphyrin materials. Porphyrin-based COF materials can exert combined photodynamic and photothermal effects, circumventing the limitations of photodynamic therapy (PDT) due to hypoxia and issues in photothermal therapy (PTT) from heat shock proteins or the adverse impact of excessive heat on the protein activity of normal tissue. Furthermore, the porous structure of porphyrin COFs facilitates the circulation of oxygen molecules and reactive oxygen species and promotes sufficient contact with the lesion site for therapeutic functions. This review covers recent progress regarding porphyrin-based COFs in treating malignant tumors and venous thrombosis and for antibacterial and anti-inflammatory uses via combined PDT and PTT. By summarizing relevant design strategies, ranging from molecular design to functional application, this review provides a reference basis for the enhanced phototherapy application of porphyrin-based COFs as photoactive materials. This review aims to offer valuable insights for more effective biomedical applications of porphyrin-based COFs through the synthesis of existing experimental data, thereby paving the way for their future preclinical utilization. Full article
(This article belongs to the Special Issue Advanced Nanotechnology for Combination Therapy and Diagnosis)
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17 pages, 6661 KiB  
Article
A Multifunctional Nanozyme Hydrogel with Antibacterial, Antioxidative, and Photo-Induced Nitric Oxide-Supplying Properties for Promoting Infected Wound Healing
by Wen Zuo, Kunpeng Wei, Xinyi Zhang, Dongjing Wang, Haoyang Gong, Yanzhuo Zhang and Hui Wang
Pharmaceutics 2024, 16(12), 1624; https://doi.org/10.3390/pharmaceutics16121624 - 22 Dec 2024
Viewed by 863
Abstract
Objectives: To design a multifunctional nanozyme hydrogel with antibacterial, photo-responsive nitric oxide-releasing, and antioxidative properties for promoting the healing of infected wounds. Methods: We first developed ultra-small silver nanoparticles (NPs)-decorated sodium nitroprusside-doped Prussian blue (SNPB) NPs, referred to as SNPB@Ag NPs, which served [...] Read more.
Objectives: To design a multifunctional nanozyme hydrogel with antibacterial, photo-responsive nitric oxide-releasing, and antioxidative properties for promoting the healing of infected wounds. Methods: We first developed ultra-small silver nanoparticles (NPs)-decorated sodium nitroprusside-doped Prussian blue (SNPB) NPs, referred to as SNPB@Ag NPs, which served as a multifunctional nanozyme. Subsequently, this nanozyme, together with geniposide (GE), was incorporated into a thermo-sensitive hydrogel, formulated from Poloxamer 407 and carboxymethyl chitosan, creating a novel antibacterial wound dressing designated as GE/SNPB@Ag hydrogel. The physical properties of a GE/SNPB@Ag hydrogel were systematically investigated. Results: After embedding the nanozyme and GE, the resulting GE/SNPB@Ag hydrogel retains its thermosensitive properties and exhibits sustained release characteristics. In addition to its catalase-like activity, the nanozyme demonstrates high photothermal conversion efficiency, photo-induced nitric oxide release, and antibacterial activity. In addition, the hydrogel exhibits favorable antioxidant properties and high biocompatibility. The results of animal experiments demonstrate that the composite hydrogel combined with laser irradiation is an effective method for promoting infected wound healing. Conclusions: In vitro and in vivo studies indicate that the resulting GE/SNPB@Ag hydrogel holds significant potential for the treatment of infected wounds and for further clinical applications. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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16 pages, 3140 KiB  
Article
Cationic Hydroxyethyl Cellulose Nanocomplexes and RANK siRNA/Zoledronate Co-Delivery Systems for Osteoclast Inhibition
by Sohyun Lee, Seoyeon Park and Tae-il Kim
Pharmaceutics 2024, 16(12), 1623; https://doi.org/10.3390/pharmaceutics16121623 - 22 Dec 2024
Viewed by 512
Abstract
Background/Objectives: In this study, HECP2k polymer, polyethylenimine2k (PEI2k)-modified hydroxyethyl cellulose (HEC) was utilized to form the nanocomplexes with receptor activator of nuclear factor k-B (RANK) siRNA and zoledronate (Zol) for osteoclast inhibition. HECP2k/(RANK siRNA + Zol) nanocomplexes prepared by simple mixing were anticipated [...] Read more.
Background/Objectives: In this study, HECP2k polymer, polyethylenimine2k (PEI2k)-modified hydroxyethyl cellulose (HEC) was utilized to form the nanocomplexes with receptor activator of nuclear factor k-B (RANK) siRNA and zoledronate (Zol) for osteoclast inhibition. HECP2k/(RANK siRNA + Zol) nanocomplexes prepared by simple mixing were anticipated to overcome the low transfection efficiency of siRNA and the low bioavailability of Zol. Methods: The characterization of both HECP2k/(pDNA + Zol) nanocomplexes and HECP2k/(RANK siRNA + Zol) nanocomplexes was performed. Results: The nanocomplexes were successfully formed even in the presence of Zol, showing about 200 nm sizes and about 20 mV of positive zeta potential values suitable for efficient cellular uptake. They also possessed high endosome buffering ability by PEI and Zol, suggesting the potential for efficient endosomal escape. It was found that the low cytotoxic nanocomplexes (>90% cell viability) displayed greater transfection efficiency than PEI25k and even HECP2k polyplexes. Finally, it was found by tartrate-resistant acid phosphatase (TRAP) assay and qPCR analysis that HECP2k/(RANK siRNA + Zol) nanocomplexes could inhibit the TRAP to about 50% value and another characteristic osteoclastic gene expression, increasing FAS gene expression to about 16 times higher than control and more efficiently (about 3 times and 5 times higher, respectively) than HECP2k/siRNA polyplexes and Zol only. Conclusions: HECP2k/(RANK siRNA + Zol) nanocomplexes formed by simple mixing showed great potential for inhibiting osteoclast differentiation and osteoclast activity, inducing the apoptosis via combinatorial effects of RANK siRNA and Zol. Full article
(This article belongs to the Special Issue Drug Nanocarriers for Pharmaceutical Applications)
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19 pages, 1816 KiB  
Review
Forty Years of the Use of Cells for Cartilage Regeneration: The Research Side
by Livia Roseti, Carola Cavallo, Giovanna Desando, Martina D’Alessandro and Brunella Grigolo
Pharmaceutics 2024, 16(12), 1622; https://doi.org/10.3390/pharmaceutics16121622 - 22 Dec 2024
Viewed by 942
Abstract
Background: The treatment of articular cartilage damage has always represented a problem of considerable practical interest for orthopedics. Over the years, many surgical techniques have been proposed to induce the growth of repairing tissue and limit degeneration. In 1994, the turning point occurred: [...] Read more.
Background: The treatment of articular cartilage damage has always represented a problem of considerable practical interest for orthopedics. Over the years, many surgical techniques have been proposed to induce the growth of repairing tissue and limit degeneration. In 1994, the turning point occurred: implanted autologous cells paved the way for a new treatment option based more on regeneration than repair. Objectives: This review aims to outline biological and clinical advances, from the use of mature adult chondrocytes to cell-derived products, going through progenitor cells derived from bone marrow or adipose tissue and their concentrates for articular cartilage repair. Moreover, it highlights the relevance of gene therapy as a valuable tool for successfully implementing current regenerative treatments, and overcoming the limitations of the local delivery of growth factors. Conclusions: Finally, this review concludes with an outlook on the importance of understanding the role and mechanisms of action of the different cell compounds with a view to implementing personalized treatments. Full article
(This article belongs to the Special Issue Osteoarthritis and Cartilage Biologics)
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21 pages, 19072 KiB  
Article
Early-Stage IM Treatment with the Host-Derived Immunostimulant CPDI-02 Increases Curative Protection of Healthy Outbred Mice Against Subcutaneous Infection with Community-Acquired Methicillin-Resistant Staphylococcus aureus USA300
by Jason P. Stewart, Caleb M. Sandall, Jacob E. Parriott, Stephen M. Curran, Russell J. McCulloh, Donald R. Ronning, Joy A. Phillips, Robin Schroeder, Christy Neel, Kelly F. Lechtenberg, Samuel M. Cohen, Yazen Alnouti, Sohel Daria, D. David Smith and Joseph A. Vetro
Pharmaceutics 2024, 16(12), 1621; https://doi.org/10.3390/pharmaceutics16121621 - 21 Dec 2024
Viewed by 1216
Abstract
Background/Objectives: Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) greatly complicates the treatment of skin and soft tissue infections (SSTI). It was previously found that subcutaneous (SQ) treatment with the mononuclear phagocyte (MP)-selective activator complement peptide-derived immunostimulant-02 (CPDI-02; formerly EP67) increases prophylaxis of outbred CD-1 [...] Read more.
Background/Objectives: Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) greatly complicates the treatment of skin and soft tissue infections (SSTI). It was previously found that subcutaneous (SQ) treatment with the mononuclear phagocyte (MP)-selective activator complement peptide-derived immunostimulant-02 (CPDI-02; formerly EP67) increases prophylaxis of outbred CD-1 mice against SQ infection with CA-MRSA. Here, we determined if treatment with CPDI-02 also increases curative protection. Methods: Female CD-1 mice were challenged SQ with CA-MRSA USA300 LAC, then CPDI-02 or inactive scCPDI-02 was administered by a topical, SQ, IM, or IV route at 6 or 24 h post-challenge. Abscess sizes were compared over 10 days and CA-MRSA burden, neutrophils, MP, and pro-inflammatory cytokines were compared in subcutaneous abscesses. CPDI-02 PK and distribution in female CD-1 mice were compared after IM or IV dosing and CPDI-02 toxicity in male and female CD-1 mice was determined by IM dose escalation and repeat IM dosing. Results: Repeat IM treatment starting at 6 h post-challenge decreased maximum abscess surface area, CA-MRSA burden, and time to resolution, whereas repeat treatment by a topical, SQ, or IV route had no effect. Repeat treatment starting at 24 h post-challenge was ineffective by the current routes. Single IM treatment starting at 6 h post-challenge was as effective as repeat IM treatment, increased systemic exposure to CPDI-02, and, in subcutaneous abscesses, initially decreased IL-1β and increased MP. CPDI-02 was tolerated between 130 and 170 mg/kg after IM dose escalation and between 65 and 130 mg/kg after repeat IM dosing with males being more tolerant. Conclusions: Single early-stage IM treatment with CPDI-02 may increase curative protection against SSTI caused by CA-MRSA and/or other pathogens controlled by activated MP. Full article
(This article belongs to the Section Pharmacokinetics and Pharmacodynamics)
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23 pages, 13175 KiB  
Article
C118P Suppresses Gastric Cancer Growth via Promoting Autophagy–Lysosomal Degradation of RAB1A
by Shihui Wei, Jing Zhang, Hai Wu, Zhengguang Liao, Zhengrui Liu, Yuhang Hou, Danyu Du, Jingwei Jiang, Li Sun, Shengtao Yuan and Mei Yang
Pharmaceutics 2024, 16(12), 1620; https://doi.org/10.3390/pharmaceutics16121620 - 21 Dec 2024
Viewed by 707
Abstract
Background/Objectives: Gastric cancer (GC) is the leading cause of cancer-related deaths worldwide. C118P, a microtubule inhibitor with anti-angiogenic and vascular-disrupting activities, was proven to be cytotoxic to various cancer cell lines. This study aimed to explore the anti-tumor effect of C118P against [...] Read more.
Background/Objectives: Gastric cancer (GC) is the leading cause of cancer-related deaths worldwide. C118P, a microtubule inhibitor with anti-angiogenic and vascular-disrupting activities, was proven to be cytotoxic to various cancer cell lines. This study aimed to explore the anti-tumor effect of C118P against gastric cancer and identify its potential target. Methods: The MTT assay, colony formation assay, and EdU incorporation assay were used to evaluate the effect of C118P on GC cell proliferation. Cell cycle and cell apoptosis were measured using flow cytometry. Molecular docking, a microscale thermophoresis (MST) analysis, and the cellular thermal shift assay (CETSA) were used to investigate the binding of C118P to RAB1A. Autophagy-related effects were evaluated by using the MDC staining assay, immunofluorescence assay, and immunoblotting assay. The SGC-7901 cell line xenograft mouse model was used to confirm the anti-tumor efficacy of C118P. Results: C118P dramatically inhibited proliferation, induced G2/M cell cycle arrest, and triggered apoptosis in GC cell lines HGC-27 and SGC-7901. Mechanistically, C118P was demonstrated to bind with RAB1A and reduce the RAB1A protein level, accompanied by the inhibition of mTORC1 signaling. Moreover, C118P induced autophagosome formation and promoted RAB1A protein degradation in an autophagy–lysosomal-dependent manner. The in vivo study verified that C118P inhibits GC growth by inhibiting the RAB1A-mTOR axis. Conclusions: Our findings suggested that C118P inhibits GC growth by promoting the autophagy–lysosomal-dependent degradation of RAB1A and modulating mTOR C1 signaling. C118P shows potential as being a small molecule drug effective in the treatment of gastric cancer via targeting RAB1A. Full article
(This article belongs to the Section Drug Targeting and Design)
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37 pages, 2140 KiB  
Systematic Review
Clinical Pharmacokinetics of Fexofenadine: A Systematic Review
by Maryam Batool, Ammara Zamir, Faleh Alqahtani, Tanveer Ahmad, Hamid Saeed and Muhammad Fawad Rasool
Pharmaceutics 2024, 16(12), 1619; https://doi.org/10.3390/pharmaceutics16121619 - 20 Dec 2024
Viewed by 1445
Abstract
Background/Objectives: Fexofenadine hydrochloride is a widely prescribed drug for treating histamine-mediated allergic reactions. This review systematically collates existing research on the clinical pharmacokinetics (PK) of fexofenadine, with a copious emphasis on examining the impact of stereoisomerism, disease states, and drug interactions. Methods: The [...] Read more.
Background/Objectives: Fexofenadine hydrochloride is a widely prescribed drug for treating histamine-mediated allergic reactions. This review systematically collates existing research on the clinical pharmacokinetics (PK) of fexofenadine, with a copious emphasis on examining the impact of stereoisomerism, disease states, and drug interactions. Methods: The search engines PubMed, Science Direct, Google Scholar, and Cochrane were scanned systematically for articles concerning the clinical PK of fexofenadine in humans. The extensive literature search yielded 85 articles meeting the inclusion standards. Results: The PK parameters of fexofenadine showed a linear correlation between increasing doses and proportional elevations in PK parameters such as area under the curve from time 0 to infinity (AUC0–∞) and maximum plasma concentration (Cmax). Under fed conditions, its bioavailability was reduced by approximately 50%. Findings from patients with end-stage renal disease (ESRD) displayed a 63% decline in oral clearance (CL/F) of fexofenadine. A drug–food interaction study has displayed that grapefruit juice decreased Cmax (201 ng/mL vs. 128 ng/mL), accompanied by a 30% reduction in the bioavailability of fexofenadine. Furthermore, a drug–herb interaction study with St John’s Wort (SJW) has reported a reduction in CL/F by 10% after a single dose, but long-term administration reversed this effect, resulting in elevated CL/F by 17% of fexofenadine. Conclusions: Since no prior systematic review on the PK of this drug exists, this review amalgamates all pertinent PK parameters in humans by pooling up-to-date data from published studies. This detailed literature review can be advantageous for researchers who want to develop and assess PK models. Full article
(This article belongs to the Special Issue Precision Dosing in Clinical Therapeutics: The Application of Pharmacokinetics and Pharmacometrics)
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21 pages, 7521 KiB  
Article
Potential of Cricket Chitosan for Nanoparticle Development Through Ionotropic Gelation: Novel Source for Cosmeceutical Delivery Systems
by Jirasit Inthorn, Pratthana Chomchalao, Puracheth Rithchumpon, Saranya Juntrapirom, Watchara Kanjanakawinkul, Thomas Rades and Wantida Chaiyana
Pharmaceutics 2024, 16(12), 1618; https://doi.org/10.3390/pharmaceutics16121618 - 20 Dec 2024
Viewed by 1004
Abstract
Background/Objectives: Crickets are recognized as an alternative source of chitosan. This study aimed to assess the potential of cricket-derived chitosan as a natural source to develop chitosan nanoparticles (CNPs). Methods: Chitosan were isolated from different cricket species, including Gryllus bimaculatus, Teleogryllus mitratus [...] Read more.
Background/Objectives: Crickets are recognized as an alternative source of chitosan. This study aimed to assess the potential of cricket-derived chitosan as a natural source to develop chitosan nanoparticles (CNPs). Methods: Chitosan were isolated from different cricket species, including Gryllus bimaculatus, Teleogryllus mitratus, and Acheta domesticus. The isolated chitosan were characterized by their functional groups, crystallographic and thermal properties, molecular structure, morphology, water solubility, molecular weight, binding capacity, irritation potential, and cytotoxicity in comparison to commercial shrimp-based chitosan. CNPs were developed through an ionotropic gelation method, followed by the evaluation of particle size, polydispersity index (PDI), and zeta potential. Results: The findings of this study indicate that chitosan can be successfully isolated from the three cricket species, with yields ranging from 4.35% to 5.22% w/w of the dried material. The characteristics of cricket-based chitosan were similar to those of commercial chitosan, except that the cricket-based chitosan displayed a higher crystallinity and a lower molecular weight. Additionally, CPNs were successfully produced from cricket-based chitosan using sodium citrate as a crosslinking agent. All cricket-based chitosan exhibited no irritation or cytotoxicity. Chitosan derived from A. domesticus however was found to be the most suitable to develop CPNs, as it produced the smallest particle size (522.0 ± 12.1 nm) with a comparatively narrow PDI (0.388 ± 0.026) and an acceptable positive zeta potential (34.2 ± 4.4 mV). Conclusions: Cricket-derived chitosan compares favorably with crustacean-derived chitosan and showed potential for a range of applications, including the use as a nanocosmeceutical delivery system in topical and cosmetic formulations. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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13 pages, 1531 KiB  
Article
Sustained-Release Solid Dispersions of Fenofibrate for Simultaneous Enhancement of the Extent and Duration of Drug Exposure
by Seong-Jin Park, Gyu Lin Kim and Hyo-Kyung Han
Pharmaceutics 2024, 16(12), 1617; https://doi.org/10.3390/pharmaceutics16121617 - 20 Dec 2024
Viewed by 739
Abstract
Background/Objectives: A sustained-release formulation of fenofibrate while enhancing drug dissolution with minimal food effect is critical for maximizing the therapeutic benefits of fenofibrate. Therefore, this study aimed to develop an effective solid dispersion formulation of fenofibrate for simultaneous enhancement in the extent and [...] Read more.
Background/Objectives: A sustained-release formulation of fenofibrate while enhancing drug dissolution with minimal food effect is critical for maximizing the therapeutic benefits of fenofibrate. Therefore, this study aimed to develop an effective solid dispersion formulation of fenofibrate for simultaneous enhancement in the extent and duration of drug exposure. Methods: Fenofibrate-loaded solid dispersions (FNSDs) were prepared using poloxamer 407 and Eudragit® RSPO at varied ratios via solvent evaporation. In vitro/in vivo characteristics of FNSDs were examined in comparison with untreated drugs. Results: Based on dissolution profiles of FNSDs in aqueous media, the weight ratio of fenofibrate: poloxamer 407: Eudragit® RSPO at 1:1:4 (FNSD2) was selected as the optimal composition for achieving sustained drug release while maximizing the drug dissolution. The enhanced and sustained drug release of FNSD2 was also confirmed in a buffer transition system mimicking the pH change in the gastrointestinal tract. FNSD2 achieved approximately 66% drug release over 12 h, while pure drug exhibited only 12%. Furthermore, FNSD2 maintained similar release rates under fed and fasted conditions, while the entire drug dissolution slightly increased in the fed state. Structural analysis by x-ray diffraction showed that fenofibrate remained crystalline in FNSD2. Pharmacokinetic studies in rats revealed that orally administered FNSD2 significantly improved the extent and duration of systemic drug exposure. Compared to pure drugs, the FNSD2 formulation increased the oral bioavailability of fenofibrate by 22 folds with the delayed Tmax of 4 h in rats. Conclusion: FNSD2 formulation is effective in improving the extent and duration of drug exposure simultaneously. Full article
(This article belongs to the Collection Advanced Pharmaceutical Science and Technology in Korea)
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26 pages, 1719 KiB  
Review
Nanoscale Prussian Blue and Its Analogues: Design and Applications in Infection Control, Wound Healing and Beyond
by Nayanika Chakraborty, Indrajit Roy, Pradeep Kumar, Swati Singh, Rajiv Pathak, Vibhav Gautam and Hemant K. Gautam
Pharmaceutics 2024, 16(12), 1616; https://doi.org/10.3390/pharmaceutics16121616 - 20 Dec 2024
Viewed by 1085
Abstract
Prussian blue nanoparticles (PBNPs) have gained significant attraction in the field of nanomedicine due to their excellent biocompatibility, potential for nanoscale production, exceptional photothermal conversion ability, and multi-enzyme mimicking capabilities. PBNPs have made considerable advancements in their application to biomedical fields. This review [...] Read more.
Prussian blue nanoparticles (PBNPs) have gained significant attraction in the field of nanomedicine due to their excellent biocompatibility, potential for nanoscale production, exceptional photothermal conversion ability, and multi-enzyme mimicking capabilities. PBNPs have made considerable advancements in their application to biomedical fields. This review embarks with a comprehensive understanding of the physicochemical properties and chemical profiling of PB-based nanoparticles, discussing systematic approaches to tune their dimensions, shapes, and sizes, as well as their biomedical properties. Subsequently, the use of PB-based NPs in the biomedical sector is extensively discussed and categorized based on the various features of modified PBNPs, either in combination with drugs or their analogues. Finally, the article highlights the existing challenges associated with current studies and explores the latest developments in these rapidly evolving PB-based nanoplatforms and their therapeutic potentials. Overall, this review aims to deepen the understanding of PB-based NPs and provide crucial insights into their rational design in disease treatment. Full article
(This article belongs to the Section Nanomedicine and Nanotechnology)
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16 pages, 1548 KiB  
Article
Pharmacodynamic Model of the Hemodynamic Effects of Propofol and Remifentanil and Their Interaction with Noxious Stimulation
by Maite Garraza-Obaldia, Sebastian Jaramillo, Zinnia P. Parra-Guillen, José F. Valencia, Pedro L. Gambús and Iñaki F. Trocóniz
Pharmaceutics 2024, 16(12), 1615; https://doi.org/10.3390/pharmaceutics16121615 - 19 Dec 2024
Viewed by 682
Abstract
Background: Despite the known impact of propofol and remifentanil on hemodynamics and patient outcomes, there is a lack of comprehensive quantitative analysis, particularly in surgical settings, considering the influence of noxious stimuli. The aim of this study was to develop a quantitative [...] Read more.
Background: Despite the known impact of propofol and remifentanil on hemodynamics and patient outcomes, there is a lack of comprehensive quantitative analysis, particularly in surgical settings, considering the influence of noxious stimuli. The aim of this study was to develop a quantitative semi-mechanistic population model that characterized the time course changes in mean arterial pressure (MAP) and heart rate (HR) due to the effects of propofol, remifentanil, and different types of noxious stimulation related to the clinical routine. Methods: Data from a prospective study were used; the study analyzed the effects of propofol and remifentanil general anesthesia on female patients in physical status of I-II according to the American Society of Anesthesiologists (ASA I-II) undergoing gynecology surgery. Patients were consecutively assigned to different administration schemes of propofol and remifentanil targeted at different effect-site concentrations. Esophageal instrumentation, laryngeal mask airway insertion, hysteroscopy, and tetanus stimuli were applied. Data from patients with chronic hypertension were discarded. Results: MAP and HR observations from 77 patients were analyzed. The hemodynamic effects were described using turn-over models incorporating feedback mechanisms. Analyses revealed that propofol and remifentanil elicited effects on the turn-over of MAP and HR, respectively, with estimates of plasma drug concentrations causing an inhibition-half of the maximum effect (C50) of 8.79 µg∙mL−1 and 4.57 ng∙mL−1. Hysteroscopy exerted an increase in MAP (but not in HR), which was well-characterized by the model, with a predicted typical increase of 28 mmHg and a dissipation half-life of 33 min. The impact of other noxious stimuli on MAP or HR could not be identified. Model simulations indicated that propofol and remifentanil, titrated to inhibit the motor response to noxious stimuli, regardless of dose combinations, cause a significant risk of hypotension, especially following induction and at the end of surgery (when surgical intervention is completed, before the awakening phase). Conclusions: The developed semi-mechanistic and fully identifiable model provides quantitative information on how propofol, remifentanil, and surgical stimulus (hysteroscopy) interact to produce the hemodynamic changes (of MAP and HR) commonly observed in clinical practice. Full article
(This article belongs to the Special Issue Mechanism-Based Pharmacokinetic and Pharmacodynamic Modeling)
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16 pages, 10924 KiB  
Article
Building of CuO2@Cu-TA@DSF/DHA Nanoparticle Targets MAPK Pathway to Achieve Synergetic Chemotherapy and Chemodynamic for Pancreatic Cancer Cells
by Jiaru Zhang, Zuoping Li, Zhenzhen Xie, Shiwan You, Yanbing Chen, Yuling Zhang, Jing Zhang, Na Zhao, Xiling Deng and Shiguo Sun
Pharmaceutics 2024, 16(12), 1614; https://doi.org/10.3390/pharmaceutics16121614 - 19 Dec 2024
Viewed by 726
Abstract
Background/Objectives: With the increase of reactive oxygen species (ROS) production, cancer cells can avoid cell death and damage by up-regulating antioxidant programs. Therefore, it will be more effective to induce cell death by using targeted strategies to further improve ROS levels and drugs [...] Read more.
Background/Objectives: With the increase of reactive oxygen species (ROS) production, cancer cells can avoid cell death and damage by up-regulating antioxidant programs. Therefore, it will be more effective to induce cell death by using targeted strategies to further improve ROS levels and drugs that inhibit antioxidant programs. Methods: Considering that dihydroartemisinin (DHA) can cause oxidative damage to protein, DNA, or lipids by producing excessive ROS, while, disulfiram (DSF) can inhibit glutathione (GSH) levels and achieve the therapeutic effect by inhibiting antioxidant system and amplifying oxidative stress, they were co-loaded onto the copper peroxide nanoparticles (CuO2) coated with copper tannic acid (Cu-TA), to build a drug delivery system of CuO2@Cu-TA@DSF/DHA nanoparticles (CCTDD NPs). In response to the tumor microenvironment, DHA interacts with copper ion (Cu2+) to produce ROS, and a double (diethylthiocarbamate)-copper (II) (CuET) is generated by the complexation of DSF and Cu2+, which consumes GSH and inhibits antioxidant system. Meanwhile, utilizing the Fenton-like effect induced by the multi-copper mode can achieve ROS storm, activate the MAPK pathway, and achieve chemotherapy (CT) and chemodynamic (CDT). Results: Taking pancreatic cancer cell lines PANC-1 and BxPC-3 as the research objects, cell line experiments in vitro proved that CCTDD NPs exhibit efficient cytotoxicity on cancer cells. Conclusions: The CCTDD NPs show great potential in resisting pancreatic cancer cells and provides a simple strategy for designing powerful metal matrix composites. Full article
(This article belongs to the Special Issue Biocompatible Polymers for Drug Delivery)
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14 pages, 4542 KiB  
Article
Novel Cyclic Peptide–Drug Conjugate P6-SN38 Toward Targeted Treatment of EGFR Overexpressed Non-Small Cell Lung Cancer
by Andrii Bazylevich, Ayala Miller, Iryna Tkachenko, Maia Merlani, Leonid Patsenker, Gary Gellerman and Bat Chen R. Lubin
Pharmaceutics 2024, 16(12), 1613; https://doi.org/10.3390/pharmaceutics16121613 - 19 Dec 2024
Viewed by 837
Abstract
Background/Objectives: Here, we report on the synthesis and biological evaluation of a novel peptide–drug conjugate, P6-SN38, which consists of the EGFR-specific short cyclic peptide, P6, and the Topo I inhibitor SN38, which is a bioactive metabolite of the anticancer drug irinotecan. Methods: SN38 [...] Read more.
Background/Objectives: Here, we report on the synthesis and biological evaluation of a novel peptide–drug conjugate, P6-SN38, which consists of the EGFR-specific short cyclic peptide, P6, and the Topo I inhibitor SN38, which is a bioactive metabolite of the anticancer drug irinotecan. Methods: SN38 is attached to the peptide at position 20 of the E ring’s tertiary hydroxyl group via a mono-succinate linker. Results: The developed peptide–drug conjugate (PDC) exhibited sub-micromolar anticancer activity on EGFR-positive (EGFR+) cell lines but no effect on EGFR-negative (EGFR−) cells. In vivo studies have shown that this PDC specifically accumulates in EGFR+ non-small cell lung cancer (NSCLC) xenografts and presents superior anticancer activity compared to the EGFR-specific antibody cetuximab (ErbituxTM) and free SN38. The 10 mg/kg dose of P6-SN38 in a side-by-side EGFR+/EGFR− xenograft shows eradication of the EGFR+ tumor with good tolerance, but no inhibition of tumor growth of the EGFR− counterpart. Conclusions: The PDC examined in this study was proven to be highly efficient for NSCLC, broadening its utilization for targeted cancer therapy in EGFR overexpressed cancers. Full article
(This article belongs to the Section Drug Targeting and Design)
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23 pages, 2054 KiB  
Article
Characterization and Safety Assessment of a Novel Antioxidant Excipient from Sustainable Recovery of Grape Processing Waste Bentonite Designed to Develop a Thermosensitive Buccal Spray for Oral Cavity Wellness
by Giulia Di Prima, Elena Belfiore, Cecilia La Mantia, Serena Indelicato, Giuseppe Avellone and Viviana De Caro
Pharmaceutics 2024, 16(12), 1612; https://doi.org/10.3390/pharmaceutics16121612 - 19 Dec 2024
Cited by 1 | Viewed by 548
Abstract
Background/Objectives: Nowadays, sustainability efforts focus on extracting natural cosmeceutical ingredients, such as polyphenols, from agri-food waste, for example, black bentonite (BB). The aims of this work were to validate an antioxidant cosmetic ingredient obtained from the waste BB and embed it into an [...] Read more.
Background/Objectives: Nowadays, sustainability efforts focus on extracting natural cosmeceutical ingredients, such as polyphenols, from agri-food waste, for example, black bentonite (BB). The aims of this work were to validate an antioxidant cosmetic ingredient obtained from the waste BB and embed it into an ad hoc designed oromucosal spray intended for oral cavity wellness. Methods: Focusing on sustainability, the study tested PEG200, propylene glycol, and their mixtures as unconventional and green extraction solvents, aligned with a waste-to-market approach. The extracts obtained by maceration were characterized through HPLC-DAD and HPLC-MS analyses, DPPH, Bradford, and Folin–Ciocalteu assays. The best P extract was further subjected to OECD-compliant in vitro validation as novel cosmetic raw material and used to prepare a thermosensitive buccal spray for oral daily care. Results: PEG200 enabled the obtainment of a cost-effective polyphenol-rich extract, which was validated as a safe, high value-added cosmetic secondary raw material. The extract was incorporated into a liquid thermosensitive buccal formulation, able to gel once at body temperature and enhance polyphenol accumulation into the oral mucosae even with short contact times. Conclusions: BB is confirmed as a valuable source of polyphenols, and PEG200 represents an effective extraction solvent leading to a novel functional liquid excipient characterized by an OECD-compliant variegate pool of phenols. The buccal spray then proposed represents a valuable, friendly solution for daily oral care, as it is simple to use, as well as the in vitro and ex vivo tests carried out suggested its effectiveness. Full article
(This article belongs to the Special Issue Pharmaceuticals Based on or Loaded with Natural Products)
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32 pages, 1270 KiB  
Review
Drug Delivery Across the Blood–Brain Barrier: A New Strategy for the Treatment of Neurological Diseases
by Yimai Jiao, Luosen Yang, Rujuan Wang, Guoqiang Song, Jingxuan Fu, Jinping Wang, Na Gao and Hui Wang
Pharmaceutics 2024, 16(12), 1611; https://doi.org/10.3390/pharmaceutics16121611 - 19 Dec 2024
Viewed by 1108
Abstract
The blood–brain barrier (BBB) serves as a highly selective barrier between the blood and the central nervous system (CNS), and its main function is to protect the brain from foreign substances. This physiological property plays a crucial role in maintaining CNS homeostasis, but [...] Read more.
The blood–brain barrier (BBB) serves as a highly selective barrier between the blood and the central nervous system (CNS), and its main function is to protect the brain from foreign substances. This physiological property plays a crucial role in maintaining CNS homeostasis, but at the same time greatly limits the delivery of drug molecules to the CNS, thus posing a major challenge for the treatment of neurological diseases. Given that the high incidence and low cure rate of neurological diseases have become a global public health problem, the development of effective BBB penetration technologies is important for enhancing the efficiency of CNS drug delivery, reducing systemic toxicity, and improving the therapeutic outcomes of neurological diseases. This review describes the physiological and pathological properties of the BBB, as well as the current challenges of trans-BBB drug delivery, detailing the structural basis of the BBB and its role in CNS protection. Secondly, this paper reviews the drug delivery strategies for the BBB in recent years, including physical, biological and chemical approaches, as well as nanoparticle-based delivery technologies, and provides a comprehensive assessment of the effectiveness, advantages and limitations of these delivery strategies. It is hoped that the review in this paper will provide valuable references and inspiration for future researchers in therapeutic studies of neurological diseases. Full article
(This article belongs to the Special Issue Advanced Drug Delivery across the Blood–Brain Barrier)
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17 pages, 3020 KiB  
Article
A New Heteroleptic Zn(II) Complex with Schiff Bases Sensitizes Triple-Negative Breast Cancer Cells to Doxorubicin and Paclitaxel
by Raiane Aparecida dos Santos Machado, Raoni Pais Siqueira, Fernanda Cardoso da Silva, André Carlos Pereira de Matos, Dayanne Silva Borges, Gislaine Gonçalves Rocha, Thais Cristina Prado de Souza, Rafael Aparecido Carvalho Souza, Clayton Rodrigues de Oliveira, Antônio G. Ferreira, Pedro Ivo da Silva Maia, Victor Marcelo Deflon, Carolina Gonçalves Oliveira and Thaise Gonçalves Araújo
Pharmaceutics 2024, 16(12), 1610; https://doi.org/10.3390/pharmaceutics16121610 - 18 Dec 2024
Viewed by 819
Abstract
Background/Objectives: Triple-negative breast cancer (TNBC) is the most challenging molecular subtype of breast cancer (BC) in clinical practice, associated with a worse prognosis due to limited treatment strategies and its insensitivity to conventional drugs. Zinc is an important trace element for homeostasis, [...] Read more.
Background/Objectives: Triple-negative breast cancer (TNBC) is the most challenging molecular subtype of breast cancer (BC) in clinical practice, associated with a worse prognosis due to limited treatment strategies and its insensitivity to conventional drugs. Zinc is an important trace element for homeostasis, and its Schiff base metal complexes have shown promise in treating advanced tumors. In this study, four new heteroleptic Zn(II) complexes (1–4) with Schiff bases were synthesized, characterized, and evaluated for their activity in BC cells. Methods: Compounds were synthesized, characterized, and their crystal structures were determined. Biological activity was assessed using MTT, clonogenic, scratch wound healing, caspase 3 and 8 activity, qPCR, and chemosensitization assays. Results: The complexes exhibited cytotoxicity against MCF-7 (luminal BC), MDA-MB-453 (HER2-positive BC), and MDA-MB-231 (TNBC) cell lines, with IC50 values ranging from 0.01 to 20 µM. Complex 4 showed reduced cytotoxicity toward non-tumor cell lines. This, complexation with Zn(II) increased the cytotoxicity of the ligands, a trend not observed for complexes 1–3. Due to its favorable profile, complex 4 was selected for further assays, in which it inhibited colony formation and the cell migration of TNBC cells in a dose-dependent manner. Furthermore, this compound induced cell death independently of caspases, decreasing the activity of caspase 8. Interestingly, complex 4 sensitized TBNC cells to doxorubicin and paclitaxel, possibly modulating the epithelial–mesenchymal transition mechanism, as evidenced by increased CDH1 expression. Conclusions: Results suggest the potential of complex 4 in sensitizing aggressive BC cells to chemotherapy, proving to be a promising alternative in cases of therapeutic failure. Full article
(This article belongs to the Section Drug Targeting and Design)
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15 pages, 7714 KiB  
Article
Gemcitabine-Loaded Microbeads for Transarterial Chemoembolization of Rabbit Renal Tumor Monitored by 18F-FDG Positron Emission Tomography/X-Ray Computed Tomography Imaging
by Xiaoli Zhang, Tingting Li, Jindong Tong, Meihong Zhou, Zi Wang, Xingdang Liu, Wei Lu, Jingjing Lou and Qingtong Yi
Pharmaceutics 2024, 16(12), 1609; https://doi.org/10.3390/pharmaceutics16121609 - 17 Dec 2024
Viewed by 892
Abstract
Background/Objectives: The purpose of this study was to develop the gemcitabine-loaded drug-eluting beads (G-DEBs) for transarterial chemoembolization (TACE) in rabbit renal tumors and to evaluate their antitumor effect using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography/X-ray computed tomography (18F-FDG PET/CT). Methods: DEBs were prepared [...] Read more.
Background/Objectives: The purpose of this study was to develop the gemcitabine-loaded drug-eluting beads (G-DEBs) for transarterial chemoembolization (TACE) in rabbit renal tumors and to evaluate their antitumor effect using 2-deoxy-2-[(18)F]fluoro-D-glucose positron emission tomography/X-ray computed tomography (18F-FDG PET/CT). Methods: DEBs were prepared by polyvinyl alcohol-based macromer crosslinked with N-acryl tyrosine and N,N′-methylenebis(acrylamide). Gemcitabine was loaded through ion change to obtain G-DEBs. Their particle size and drug release profile were characterized. VX2 tumors were implanted in the right kidney of rabbits to establish the renal tumor model. The tumor-bearing rabbits received pre-scan by 18F-FDG PET/CT, followed by targeted transarterial injection of G-DEBs under digital subtraction angiography (DSA) guidance. The rabbits received another 18F-FDG PET/CT scan 10 or 14 days after the treatment. The therapeutic effect was further validated by histopathological analysis of the dissected tumors. Results: The average particle size of the microspheres was 58.06 ± 0.50 µm, and the polydisperse index was 0.26 ± 0.002. The maximum loading rate of G-DEBs was 18.09 ± 0.35%, with almost 100% encapsulation efficiency. Within 24 h, GEM was eluted from G-DEBs rapidly and completely, and more than 20% was released in different media. DSA illustrated that G-DEBs were delivered to rabbit renal tumors. Compared with the untreated control group with increased tumor volume and intense 18F -FDG uptake, the G-DEBs group showed significant reductions in tumor volume and maximum standard uptake value (SUVmax) 10 or 14 days after the treatment. Histopathological analysis confirmed that the proliferating area of tumor cells was significantly reduced in the G-DEBs group. Conclusions: Our results demonstrated that G-DEBs are effective in TACE treatment of rabbit VX2 renal tumors, and 18F-FDG PET/CT provides a non-invasive imaging modality to monitor the antitumor effects of TACE in renal tumors. Full article
(This article belongs to the Section Drug Targeting and Design)
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4 pages, 162 KiB  
Editorial
Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 85th Birthday, Recognizing His Outstanding Achievements in Advancing the Field of Dendrimers
by Anne-Marie Caminade
Pharmaceutics 2024, 16(12), 1608; https://doi.org/10.3390/pharmaceutics16121608 - 17 Dec 2024
Viewed by 592
Abstract
As the main pioneer in the field of dendrimers, a term that he coined in 1985 in reference to their tree-like structure, Prof. Donald A. Tomalia has inspired several generations of researchers worldwide [...] Full article
(This article belongs to the Special Issue Dendrimers: A Themed Issue in Honor of Professor Donald A. Tomalia on the Occasion of His 85th Birthday for His Outstanding Achievements in Advancing the Field of Dendrimers)
32 pages, 9784 KiB  
Article
Discovery of Non-Peptide GLP-1 Positive Allosteric Modulators from Natural Products: Virtual Screening, Molecular Dynamics, ADMET Profiling, Repurposing, and Chemical Scaffolds Identification
by Mohamed S. Gomaa, Mansour S. Alturki, Nada Tawfeeq, Dania A. Hussein, Faheem H. Pottoo, Abdulaziz H. Al Khzem, Mohammad Sarafroz and Samar Abubshait
Pharmaceutics 2024, 16(12), 1607; https://doi.org/10.3390/pharmaceutics16121607 - 17 Dec 2024
Cited by 1 | Viewed by 790
Abstract
Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor is currently one of the most explored targets exploited for the management of diabetes and obesity, with many aspects of its mechanisms behind cardiovascular protection yet to be fully elucidated. Research dedicated towards the development of oral GLP-1 [...] Read more.
Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor is currently one of the most explored targets exploited for the management of diabetes and obesity, with many aspects of its mechanisms behind cardiovascular protection yet to be fully elucidated. Research dedicated towards the development of oral GLP-1 therapy and non-peptide ligands with broader clinical applications is crucial towards unveiling the full therapeutic capacity of this potent class of medicines. Methods: This study describes the virtual screening of a natural product database consisting of 695,133 compounds for positive GLP-1 allosteric modulation. The database, obtained from the Coconut website, was filtered according to a set of physicochemical descriptors, then was shape screened against the crystal ligand conformation. This filtered database consisting of 26,325 compounds was used for virtual screening against the GLP-1 allosteric site. Results: The results identified ten best hits with the XP score ranging from −9.6 to −7.6 and MM-GBSA scores ranging from −50.8 to −32.4 and another 58 hits from docked pose filter and a second round of XP docking and MM-GBSA calculation followed by molecular dynamics. The analysis of results identified hits from various natural products (NPs) classes, to whom attributed antidiabetic and anti-obesity effects have been previously reported. The results also pointed to β-lactam antibiotics that may be evaluated in drug repurposing studies for off-target effects. The calculated ADMET properties for those hits revealed suitable profiles for further development in terms of bioavailability and toxicity. Conclusions: The current study identified several NPs as potential GLP-1 positive allosteric modulators and revealed common structural scaffolds including peptidomimetics, lactams, coumarins, and sulfonamides with peptidomimetics being the most prominent especially in indole and coumarin cores. Full article
(This article belongs to the Special Issue Computer-Aided Development: Recent Advances and Expectations)
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14 pages, 3790 KiB  
Article
Natural Gomesin-like Peptides with More Selective Antifungal Activities
by Ilia A. Bolosov, Ekaterina I. Finkina, Ivan V. Bogdanov, Victoria N. Safronova, Pavel V. Panteleev and Tatiana V. Ovchinnikova
Pharmaceutics 2024, 16(12), 1606; https://doi.org/10.3390/pharmaceutics16121606 - 17 Dec 2024
Viewed by 759
Abstract
Background: Antimicrobial peptides are generally considered promising drug candidates for combating resistant bacterial infections. However, the selectivity of their action may vary significantly. Natural gomesin, isolated from haemocytes of the tarantula Acanthoscurria gomesiana, demonstrates a broad spectrum of antimicrobial activities, being [...] Read more.
Background: Antimicrobial peptides are generally considered promising drug candidates for combating resistant bacterial infections. However, the selectivity of their action may vary significantly. Natural gomesin, isolated from haemocytes of the tarantula Acanthoscurria gomesiana, demonstrates a broad spectrum of antimicrobial activities, being the most effective against pathogenic fungi. Methods: Here, we searched for variants of natural gomesin-like peptides and produced their recombinant analogs in the bacterial expression system. The antimicrobial activities of the obtained peptides were tested against a panel of bacterial and yeast strains, and their toxicity towards human cells was examined. Results: Most of the new analogs of gomesin have primary structures homologous to that of the natural gomesin; however, they have fewer amino acid residues and post-translational modifications. One of the discovered analogs, the His-rich shorter peptide from the spider Dysdera sylvatica, designated as DsGom, displays antifungal activity comparable with that of natural gomesin. In the process of the structural–functional study of DsGom, it was shown that this analog retains a basic mechanism of action similar to that of natural gomesin. The DsGom analog has a significantly better toxicity profile as compared to gomesin. At the same time, the loss of the first Arg residue reduces, but does not annul, the antifungal activity of DsGom. Moreover, the acidification of the growth medium reduces the loss of the antifungal activity of this analog. Conclusions: The discovered natural gomesin-like peptides display more selective antifungal activities as compared to gomesin. The low cytotoxicity of DsGom, combined with its high antifungal activity and stability, allows us to consider it a promising drug candidate for the treatment of fungal infections, especially those caused by fungi of the Candida genus. Full article
(This article belongs to the Special Issue Advances in Bioactive Peptides from Natural Sources: Characterization, Biological Targets and Promising Applications)
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18 pages, 9603 KiB  
Article
High Carbonyl Graphene Oxide Suppresses Colorectal Cancer Cell Proliferation and Migration by Inducing Ferroptosis via the System Xc−/GSH/GPX4 Axis
by Xiecheng Zhou, Qixing Zhang, Haoran Zhu, Guangxiong Ouyang, Xin Wang and Yuankun Cai
Pharmaceutics 2024, 16(12), 1605; https://doi.org/10.3390/pharmaceutics16121605 - 17 Dec 2024
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Abstract
Background/Objectives: Colorectal cancer (CRC) is characterized by a high rate of both incidence and mortality, and its treatment outcomes are often affected by recurrence and drug resistance. Ferroptosis, an iron-dependent programmed cell death mechanism triggered by lipid peroxidation, has recently gained attention as [...] Read more.
Background/Objectives: Colorectal cancer (CRC) is characterized by a high rate of both incidence and mortality, and its treatment outcomes are often affected by recurrence and drug resistance. Ferroptosis, an iron-dependent programmed cell death mechanism triggered by lipid peroxidation, has recently gained attention as a potential therapeutic target. Graphene oxide (GO), known for its oxygen-containing functional groups, biocompatibility, and potential for functionalization, holds promise in cancer treatment. However, its role in ferroptosis induction in CRC remains underexplored. The objective of this study was to investigate the effects of High Carbonyl Graphene Oxide (HC-GO) on ferroptosis in CRC and elucidate the underlying mechanisms. Methods: In vitro assays were conducted to evaluate the impact of HC-GO on CRC cell proliferation, mitochondrial function, iron accumulation, lipid peroxidation, and reactive oxygen species (ROS) production. The ferroptosis inhibitor Fer-1 was used to confirm the role of ferroptosis in HC-GO’s anti-tumor effects. In vivo, the anti-tumor activity of HC-GO was assessed in a CRC xenograft model, with organ toxicity evaluated. Results: HC-GO significantly inhibited CRC cell proliferation, induced mitochondrial damage, and enhanced iron accumulation, lipid peroxidation, and ROS production. It also downregulated the ferroptosis-inhibiting proteins GPX4 and SLC7A11, which were reversed by Fer-1, confirming the involvement of ferroptosis in HC-GO’s anti-cancer effects. In vivo, HC-GO significantly suppressed tumor growth without noticeable toxicity to vital organs. Conclusions: HC-GO triggered ferroptosis in CRC cells by suppressing the System Xc−/GSH/GPX4 pathway, providing a novel therapeutic strategy for CRC treatment. These findings suggest HC-GO as a promising nanomedicine for clinical application, warranting further investigation to explore its potential in CRC therapy. Full article
(This article belongs to the Special Issue Carbon Nanomaterials in Pharmaceutical Sciences: Exploring Antibacterial, Antiviral, and Anticancer Properties)
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22 pages, 3006 KiB  
Review
How to Fabricate Hyaluronic Acid for Ocular Drug Delivery
by Martha Kim, Mi-Young Jung, Do-Yeon Lee, So Min Ahn, Gyeong Min Lee and Choul Yong Park
Pharmaceutics 2024, 16(12), 1604; https://doi.org/10.3390/pharmaceutics16121604 - 16 Dec 2024
Viewed by 887
Abstract
This review aims to examine existing research on the development of ocular drug delivery devices utilizing hyaluronic acid (HA). Renowned for its exceptional biocompatibility, viscoelastic properties, and ability to enhance drug bioavailability, HA is a naturally occurring biopolymer. The review discussed specific mechanisms [...] Read more.
This review aims to examine existing research on the development of ocular drug delivery devices utilizing hyaluronic acid (HA). Renowned for its exceptional biocompatibility, viscoelastic properties, and ability to enhance drug bioavailability, HA is a naturally occurring biopolymer. The review discussed specific mechanisms by which HA enhances drug delivery, including prolonging drug residence time on ocular surfaces, facilitating controlled drug release, and improving drug penetration through ocular tissues. By focusing on these unique functionalities, this review highlights the potential of HA-based systems to revolutionize ocular treatment. Various fabrication techniques for HA-based ocular drug delivery systems, including hydrogels, nanoparticles, and microneedles, are discussed, highlighting their respective advantages and limitations. Additionally, this review explores the clinical applications of HA-based devices in treating a range of ocular diseases, such as dry eye syndrome, glaucoma, retinal disorders, and ocular infections. By comparing the efficacy and safety profiles of these devices with traditional ocular drug delivery methods, this review aims to provide a comprehensive understanding of the potential benefits and challenges associated with HA-based systems. Moreover, this review discusses current limitations and future directions in the field, such as the need for standardized fabrication protocols, long-term biocompatibility studies, and large-scale clinical trials. The insights and advancements presented in this review aim to guide future research and development efforts, ultimately enhancing the effectiveness of ocular drug delivery and improving patient outcomes. Full article
(This article belongs to the Section Drug Delivery and Controlled Release)
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17 pages, 1668 KiB  
Article
Zein Nanoparticles-Loaded Flavonoids-Rich Fraction from Fridericia platyphylla: Potential Antileishmanial Applications
by Monica Araujo das Neves, Caroline Martins de Jesus, Jhones Luiz de Oliveira, Samuel dos Santos Soares Buna, Lucilene Amorim Silva, Leonardo Fernandes Fraceto and Cláudia Quintino da Rocha
Pharmaceutics 2024, 16(12), 1603; https://doi.org/10.3390/pharmaceutics16121603 - 16 Dec 2024
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Abstract
Background/Objectives: Leishmaniasis, caused by protozoa of the genus Leishmania, is a major global health issue due to the limitations of current treatments, which include low efficacy, high costs, and severe side effects. This study aimed to develop a more effective and less [...] Read more.
Background/Objectives: Leishmaniasis, caused by protozoa of the genus Leishmania, is a major global health issue due to the limitations of current treatments, which include low efficacy, high costs, and severe side effects. This study aimed to develop a more effective and less toxic therapy by utilizing zein nanoparticles (ZNPs) in combination with a nonpolar fraction (DCMF) from Fridericia platyphylla (Syn. Arrabidaea brachypoda), a plant rich in dimeric flavonoids called brachydins. Methods: Zein nanoparticles were used as carriers to encapsulate DCMF. The system was characterized by measuring particle diameter, polydispersity index, zeta potential, and encapsulation efficiency. Analytical techniques such as FTIR, DSC, and AFM were employed to confirm the encapsulation and stability of DCMF. Antileishmanial activity was assessed against Leishmania amazonensis promastigotes and amastigotes, while cytotoxicity was tested on RAW264.7 macrophages. Results: The ZNP-DCMF system exhibited favorable properties, including a particle diameter of 141 nm, a polydispersity index below 0.2, and a zeta potential of 11.3 mV. DCMF was encapsulated with an efficiency of 94.6% and remained stable for 49 days. In antileishmanial assays, ZNP-DCMF inhibited the viability of promastigotes with an IC50 of 36.33 μg/mL and amastigotes with an IC50 of 0.72 μg/mL, demonstrating higher selectivity (SI = 694.44) compared to DCMF alone (SI = 43.11). ZNP-DCMF was non-cytotoxic to RAW264.7 macrophages, with a CC50 > 500 μg/mL. Conclusions: Combining F. platyphylla DCMF with zein nanoparticles as a carrier presents a promising approach for leishmaniasis treatment, offering improved efficacy, reduced toxicity, and protection of bioactive compounds from degradation. Full article
(This article belongs to the Special Issue Anti-parasitic Applications of Nanoparticles)
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14 pages, 3511 KiB  
Article
Drug–Phospholipid Co-Amorphous Formulations: The Role of Preparation Methods and Phospholipid Selection
by Keyoomars Khorami, Sam Darestani Farahani, Anette Müllertz and Thomas Rades
Pharmaceutics 2024, 16(12), 1602; https://doi.org/10.3390/pharmaceutics16121602 - 16 Dec 2024
Viewed by 689
Abstract
Background/Objectives: This study aims to broaden the knowledge on co-amorphous phospholipid systems (CAPSs) by exploring the formation of CAPSs with a broader range of poorly water-soluble drugs, celecoxib (CCX), furosemide (FUR), nilotinib (NIL), and ritonavir (RIT), combined with amphiphilic phospholipids (PLs), including [...] Read more.
Background/Objectives: This study aims to broaden the knowledge on co-amorphous phospholipid systems (CAPSs) by exploring the formation of CAPSs with a broader range of poorly water-soluble drugs, celecoxib (CCX), furosemide (FUR), nilotinib (NIL), and ritonavir (RIT), combined with amphiphilic phospholipids (PLs), including soybean phosphatidylcholine (SPC), hydrogenated phosphatidylcholine (HPC), and mono-acyl phosphatidylcholine (MAPC). Methods: The CAPSs were initially prepared at equimolar drug-to-phospholipid (PL) ratios by mechano-chemical activation-based, melt-based, and solvent-based preparation methods, i.e., ball milling (BM), quench cooling (QC), and solvent evaporation (SE), respectively. The solid state of the product was characterized by X-ray powder diffraction (XRPD), polarized light microscopy (PLM), and differential scanning calorimetry (DSC). The long-term physical stability of the CAPSs was investigated at room temperature under dry conditions (0% RH) and at 75% RH. The dissolution behavior of the CCX CAPS and RIT CAPS was studied. Results: Our findings indicate that SE consistently prepared CAPSs for CCX-PLs, FUR-PLs, and RIT-PLs, whereas the QC method could only form CAPSs for RIT-PLs, CCX-SPC, and CCX-MAPC. In contrast, the BM method failed to produce CAPSs, but all drugs alone could be fully amorphized. While the stability of each drug varied depending on the PLs used, the SE CAPS consistently demonstrated the highest stability by a significant margin. Initially, a 1:1 molar ratio was used for screening all systems, though the optimal molar ratio for drug stability remained uncertain. To address this, various molar ratios were investigated to determine the ratio yielding the highest amorphous drug stability. Our results indicate that all systems remained physically stable at a 1.5:1 ratio and with excess of PL. Furthermore, the CAPS formed by the SE significantly improves the dissolution behavior of CCX and RIT, whereas the PLs provide a slight precipitation inhibition for supersaturated CCX and RIT. Conclusions: These findings support the use of a 1:1 molar ratio in screening processes and suggest that CAPSs can be effectively prepared with relatively high drug loads compared to traditional drug–polymer systems. Furthermore, the study highlights the critical role of drug selection, the preparation method, and the PL type in developing stable and effective CAPSs. Full article
(This article belongs to the Special Issue Advances in the Preparation and Technology of Pharmaceutical Solid Dosage Forms)
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