Membrane mimicking protein nanodiscs are nanoscale structures composed of a lipid bilayer and a scaffold protein that forms a circular disc-like structure. These NDs are designed to mimic the natural cell membrane and are used as a platform to study membrane-associated proteins, such as those involved in signal transduction or drug transport. In cancer therapeutics, NDs have been developed as a promising nano-formulation for delivering macromolecules, such as drugs or nucleic acids, to cancer cells. The NDs can be functionalized with targeting ligands, such as antibodies or peptides, to specifically bind to cancer cells and deliver therapeutic payloads. One advantage of ND-based formulations is their ability to protect macromolecules from degradation and enhance their pharmacokinetics and bioavailability. Additionally, the use of NDs as a delivery vehicle allows for the precise control of drug release, which can improve efficacy while reducing toxic side effects. Overall, membrane mimicking protein NDs show great potential as a versatile platform for macromolecular delivery in cancer therapeutics, with the ability to precisely target cancer cells and enhance the therapeutic effect of drugs or nucleic acids. In this review, we discuss the structural components, stability issues, synthetic strategies, limitations, therapeutic advancements, and future challenges associated with the clinical implication of ND’s anti-cancer therapies.
{"title":"Injectables Protein-Based Nanodiscs in Cancer Drug Delivery: From Bench to Clinical Potential","authors":"Vimal Patel, Jigar N. Shah, Saloni Dalwadi, Parv Barot, Darshan Vaghela, Megha Patel, Vijaykumar Sutariya","doi":"10.1208/s12249-025-03247-9","DOIUrl":"10.1208/s12249-025-03247-9","url":null,"abstract":"<div><p>Membrane mimicking protein nanodiscs are nanoscale structures composed of a lipid bilayer and a scaffold protein that forms a circular disc-like structure. These NDs are designed to mimic the natural cell membrane and are used as a platform to study membrane-associated proteins, such as those involved in signal transduction or drug transport. In cancer therapeutics, NDs have been developed as a promising nano-formulation for delivering macromolecules, such as drugs or nucleic acids, to cancer cells. The NDs can be functionalized with targeting ligands, such as antibodies or peptides, to specifically bind to cancer cells and deliver therapeutic payloads. One advantage of ND-based formulations is their ability to protect macromolecules from degradation and enhance their pharmacokinetics and bioavailability. Additionally, the use of NDs as a delivery vehicle allows for the precise control of drug release, which can improve efficacy while reducing toxic side effects. Overall, membrane mimicking protein NDs show great potential as a versatile platform for macromolecular delivery in cancer therapeutics, with the ability to precisely target cancer cells and enhance the therapeutic effect of drugs or nucleic acids. In this review, we discuss the structural components, stability issues, synthetic strategies, limitations, therapeutic advancements, and future challenges associated with the clinical implication of ND’s anti-cancer therapies.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145406398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-30DOI: 10.1208/s12249-025-03243-z
Eman Abdelhakeem, Sally A. Mohamed, Hanan H. Beherei, Mona Moaness, Doaa Hegazy
Chronic infected wounds with multi-drug resistant pathogens present severe therapeutic challenges, often leading to prolonged morbidity and impaired healing. To address this, we engineered a multifunctional wound dressing by integrating Voriconazole-loaded silver/zinc MOFs (VOR@Ag/Zn-MOFs) into a hyaluronic acid/polyvinylpyrrolidone (HA/PVP) matrix. The composite was prepared through sequential steps, including preparing a HA/PVP polymer blend via solvent dissolution, synthesizing bimetallic Ag/Zn-MOFs through chemical precipitation, loading VOR into MOF nanocages, and consolidating the composite via chemical crosslinking followed by freeze-drying. Comprehensive physicochemical characterization to confirm MOF stability was implemented through SEM/EDX, confirming uniform nanocage architecture and elemental distribution (Ag/Zn/F), while DLS revealed controlled particle dimensions, and optimal colloidal stability (PDI 0.694; ZP + 39.3 mV). FTIR confirmed structural integrity through preserved polymer peaks (O–H 3400–3200, C = O 1650 cm⁻1), VOR-specific C-F (1400–1200 cm⁻1), and MOF Zn–O bonds (1100–1000/400–600 cm⁻1), verifying non-covalent integration without degradation. XRD further verified the crystalline framework integrity. In-vitro release studies demonstrated sustained biphasic release (44.2% ± 5.9 burst within 6 h; up to 77.1% ± 1.8 controlled release over 360 h). The composite demonstrated exceptional antimicrobial synergy, including potent antifungal activity against Candida albicans (MFC 1.4 µg/mL, 214-fold lower than free VOR) with microscopically-confirmed cell wall disruption, and broad bacteriostatic activity (MIC range 8,500–17,000 µg/mL against Gram-positive and Gram-negative pathogens). Critically, it achieved complete fungal clearance within 24 h. Simultaneously, it accelerated tissue regeneration, showing outstanding fibroblast biocompatibility (IC₃₀ > 3,000 µg/mL; 6,000-fold safety margin) and enabling marked wound closure within 72 h in the wound healing study. By converging triple-action mechanisms, including metal ion synergy (Ag⁺/Zn2⁺), targeted azole delivery, and HA/PVP-mediated pro-regenerative signaling, this platform uniquely eliminates resilient infections and restores wound integrity that was previously unattainable with conventional azole therapies.
Graphical Abstract
具有多重耐药病原体的慢性感染伤口带来了严重的治疗挑战，往往导致长期发病和愈合受损。为了解决这个问题，我们设计了一种多功能伤口敷料，将伏立康唑负载的银/锌MOFs （VOR@Ag/Zn-MOFs）整合到透明质酸/聚乙烯吡咯烷酮（HA/PVP）基质中。通过溶剂溶解制备HA/PVP聚合物共混物，通过化学沉淀法合成双金属Ag/ zn -MOF，将VOR装入MOF纳米笼，通过化学交联巩固复合材料，然后冷冻干燥。通过SEM/EDX对MOF进行了全面的物理化学表征，确定了均匀的纳米笼结构和元素分布（Ag/Zn/F），而DLS显示颗粒尺寸可控，胶体稳定性最佳（PDI 0.694; ZP + 39.3 mV）。FTIR通过保留的聚合物峰（O - h 3400-3200, C = O 1650 cm毒血症），vo特异性的C- f （1400-1200 cm毒血症）和MOF Zn-O键（1100-1000/400-600 cm毒血症）证实了结构的完整性，证实了非共价整合而没有降解。XRD进一步验证了晶体骨架的完整性。体外释放研究显示持续的双相释放（6小时内44.2%±5.9次爆发；360小时内高达77.1%±1.8次控释）。该复合材料表现出卓越的抗菌协同作用，包括对白色念珠菌的有效抗真菌活性（MFC为1.4µg/mL，比游离VOR低214倍），显微镜下证实细胞壁破坏，以及广泛的抑菌活性（MIC范围为8,500-17,000µg/mL，对革兰氏阳性和革兰氏阴性病原体）。关键是，它在24小时内实现了完全的真菌清除。同时，它加速了组织再生，表现出出色的成纤维细胞生物相容性（IC₃₀> 3000µg/mL； 6000倍安全边际），并在伤口愈合研究中在72小时内实现了明显的伤口愈合。通过融合三重作用机制，包括金属离子协同作用（Ag + /Zn2 +）、靶向递送唑和HA/ pvp介导的促再生信号，该平台独特地消除了弹性感染，恢复了伤口完整性，这是以前传统的唑类疗法无法实现的。图形抽象
{"title":"Novel Biocompatible Hyaluronic Acid (HA)/Polyvinylpyrrolidone (PVP) Composites Containing Silver Decorated-Zinc MOF Nanoparticles: Antimicrobial Activity, Drug Delivery and Wound Healing","authors":"Eman Abdelhakeem, Sally A. Mohamed, Hanan H. Beherei, Mona Moaness, Doaa Hegazy","doi":"10.1208/s12249-025-03243-z","DOIUrl":"10.1208/s12249-025-03243-z","url":null,"abstract":"<div><p>Chronic infected wounds with multi-drug resistant pathogens present severe therapeutic challenges, often leading to prolonged morbidity and impaired healing. To address this, we engineered a multifunctional wound dressing by integrating Voriconazole-loaded silver/zinc MOFs (VOR@Ag/Zn-MOFs) into a hyaluronic acid/polyvinylpyrrolidone (HA/PVP) matrix. The composite was prepared through sequential steps, including preparing a HA/PVP polymer blend via solvent dissolution, synthesizing bimetallic Ag/Zn-MOFs through chemical precipitation, loading VOR into MOF nanocages, and consolidating the composite via chemical crosslinking followed by freeze-drying. Comprehensive physicochemical characterization to confirm MOF stability was implemented through SEM/EDX, confirming uniform nanocage architecture and elemental distribution (Ag/Zn/F), while DLS revealed controlled particle dimensions, and optimal colloidal stability (PDI 0.694; ZP + 39.3 mV). FTIR confirmed structural integrity through preserved polymer peaks (O–H 3400–3200, C = O 1650 cm⁻1), VOR-specific C-F (1400–1200 cm⁻1), and MOF Zn–O bonds (1100–1000/400–600 cm⁻1), verifying non-covalent integration without degradation. XRD further verified the crystalline framework integrity. <i>In-vitro</i> release studies demonstrated sustained biphasic release (44.2% ± 5.9 burst within 6 h; up to 77.1% ± 1.8 controlled release over 360 h). The composite demonstrated exceptional antimicrobial synergy, including potent antifungal activity against <i>Candida albicans </i>(MFC 1.4 µg/mL, 214-fold lower than free VOR) with microscopically-confirmed cell wall disruption, and broad bacteriostatic activity (MIC range 8,500–17,000 µg/mL against Gram-positive and Gram-negative pathogens). Critically, it achieved complete fungal clearance within 24 h. Simultaneously, it accelerated tissue regeneration, showing outstanding fibroblast biocompatibility (IC₃₀ > 3,000 µg/mL; 6,000-fold safety margin) and enabling marked wound closure within 72 h in the wound healing study. By converging triple-action mechanisms, including metal ion synergy (Ag⁺/Zn2⁺), targeted azole delivery, and HA/PVP-mediated pro-regenerative signaling, this platform uniquely eliminates resilient infections and restores wound integrity that was previously unattainable with conventional azole therapies.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-025-03243-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145406399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-30DOI: 10.1208/s12249-025-03264-8
Yuanyuan Ding, Zhenkun Su, Guodong Liang, Na Sai, Xin Wu, Jianping Chen, Yuheng Ma, Ruijuan Li
Pramipexole dihydrochloride (PPX) is a Biopharmaceutical Classification System (BCS) Class I drug with a short half-life, and its aqueous solution is susceptible to photodegradation. To improve its dosing convenience, the aim of this study was to prepare sustained-release solid dispersion (SD) pellets via hot-melt extrusion (HME) using ethyl cellulose (EC) and polyethylene glycol 6000 (PEG6000). The preparation process was optimized using single-factor experiments and central composite design (CCD). Under optimal conditions (PPX:EC ratio 1:4, 12.5% PEG6000, preparation temperature 155°C), the PPX solid dispersion (PPX-SD) showed stable performance and sustained release characteristics. SEM, DSC, and PXRD confirmed the amorphous state of PPX, while FT-IR indicated protential hydrogen bonding interactions between PPX and the polymers. In vitro release studies showed slower and more controlled release under pH 6.8. In vivo studies in rats demonstrated that PPX-SD had a four-fold higher AUC0-∞ (41.37 ± 9.39 μg·h·mL−1) compared to the commercial formulation Sifrol® (9.52 ± 2.18 μg·h·mL−1, p < 0.05). Tissue distribution studies in rats revealed increased brain accumulation of PPX in the PPX-SD group. Thus, PPX-SD exhibited a sustained-release and markedly improved the bioavailability by maintaining supersaturated amorphous substances, inhibiting precipitation during the drug absorption phase. This formulation offers a robust scientific foundation for the treatment of Parkinson's disease.
{"title":"Preparation and Optimization of Pramipexole Hydrochloride Solid Dispersions to Improve Drug Release and Bioavailability","authors":"Yuanyuan Ding, Zhenkun Su, Guodong Liang, Na Sai, Xin Wu, Jianping Chen, Yuheng Ma, Ruijuan Li","doi":"10.1208/s12249-025-03264-8","DOIUrl":"10.1208/s12249-025-03264-8","url":null,"abstract":"<div><p>Pramipexole dihydrochloride (PPX) is a Biopharmaceutical Classification System (BCS) Class I drug with a short half-life, and its aqueous solution is susceptible to photodegradation. To improve its dosing convenience, the aim of this study was to prepare sustained-release solid dispersion (SD) pellets via hot-melt extrusion (HME) using ethyl cellulose (EC) and polyethylene glycol 6000 (PEG6000). The preparation process was optimized using single-factor experiments and central composite design (CCD). Under optimal conditions (PPX:EC ratio 1:4, 12.5% PEG6000, preparation temperature 155°C), the PPX solid dispersion (PPX-SD) showed stable performance and sustained release characteristics. SEM, DSC, and PXRD confirmed the amorphous state of PPX, while FT-IR indicated protential hydrogen bonding interactions between PPX and the polymers. <i>In vitro</i> release studies showed slower and more controlled release under pH 6.8. <i>In vivo</i> studies in rats demonstrated that PPX-SD had a four-fold higher AUC<sub>0-∞</sub> (41.37 ± 9.39 μg·h·mL<sup>−1</sup>) compared to the commercial formulation Sifrol® (9.52 ± 2.18 μg·h·mL<sup>−1</sup>, <i>p</i> < 0.05). Tissue distribution studies in rats revealed increased brain accumulation of PPX in the PPX-SD group. Thus, PPX-SD exhibited a sustained-release and markedly improved the bioavailability by maintaining supersaturated amorphous substances, inhibiting precipitation during the drug absorption phase. This formulation offers a robust scientific foundation for the treatment of Parkinson's disease.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145406259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Parkinson's disease (PD) is a common progressive neurodegenerative condition involving the degeneration of dopaminergic neurons and the accumulation of misfolded α-synuclein protein. Although standard pharmacotherapies such as levodopa provide symptomatic improvement, their effectiveness is usually compromised by issues with low bioavailability, short half-life, and limited penetration of the blood–brain barrier (BBB). Nanotechnology provides a revolutionary answer by allowing more targeted drug delivery to the brain. A broad range of nanocarriers such as liposomes, polymeric nanoparticles, and micelles have demonstrated excellent potential to enhance drug stability, target specificity, and BBB penetration. In addition, these nanocarriers can be used to deliver gene-based therapeutics and nutraceuticals in a targeted manner, potentially providing the ability to directly impact underlying pathological processes like oxidative stress, mitochondrial dysfunction, and neuroinflammation. This review emphasizes the most recent developments in the use of nanotechnology for PD management, addressing the design, therapeutic significance, and translational problems of these systems. By increasing delivery accuracy and facilitating disease modification, nanocarrier-based systems have the potential to lead the way in more effective and tailored treatments for Parkinson's disease.
{"title":"Expanding the Arsenal of Nanocarriers Against Parkinson Disease: Success so Far Roads Ahead","authors":"Naina Devi, Sonia Dhiman, Chander Parkash, Thakur Gurjeet Singh, Ankit Awasthi","doi":"10.1208/s12249-025-03234-0","DOIUrl":"10.1208/s12249-025-03234-0","url":null,"abstract":"<div><p>Parkinson's disease (PD) is a common progressive neurodegenerative condition involving the degeneration of dopaminergic neurons and the accumulation of misfolded α-synuclein protein. Although standard pharmacotherapies such as levodopa provide symptomatic improvement, their effectiveness is usually compromised by issues with low bioavailability, short half-life, and limited penetration of the blood–brain barrier (BBB). Nanotechnology provides a revolutionary answer by allowing more targeted drug delivery to the brain. A broad range of nanocarriers such as liposomes, polymeric nanoparticles, and micelles have demonstrated excellent potential to enhance drug stability, target specificity, and BBB penetration. In addition, these nanocarriers can be used to deliver gene-based therapeutics and nutraceuticals in a targeted manner, potentially providing the ability to directly impact underlying pathological processes like oxidative stress, mitochondrial dysfunction, and neuroinflammation. This review emphasizes the most recent developments in the use of nanotechnology for PD management, addressing the design, therapeutic significance, and translational problems of these systems. By increasing delivery accuracy and facilitating disease modification, nanocarrier-based systems have the potential to lead the way in more effective and tailored treatments for Parkinson's disease.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145406396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-24DOI: 10.1208/s12249-025-03250-0
Mai Ahmed Tawfik, Sadek Ahmed, Rania Moataz El-Dahmy, Diana E. Aziz
Agomelatine (AGO) is a dual action drug. Being serotonin receptor antagonist, AGO is orally administered for depression treatment. Here in, AGO was used for intraocular pressure management due to its agonistic activity on the melatonin receptors in the eyes. AGO is a BCS II drug, with low oral bioavailability and massive first-pass metabolism. Oleic acid enriched leciplexes were investigated as novel mucoadhesive cationic nanocarriers to improve AGO’s ocular bioavailability and prolong its pharmacological effect. Twenty-four AGO loaded leciplexes were fabricated by single-step procedure. AGO: lipid ratio, surfactant: phosphatidyl choline ratio, cationic surfactant type, permeation enhancer type were investigated. For optimization; in-vitro assessment of size, homogeneity, surface charge, drug entrapment and in-vitro release was conducted. The optimum system was further examined for crystallinity, compatibility, morphology, pH, refractive index, surface tension and stability. L20 developed at a drug: lipid ratio of 1: 20, cetyltrimethylammonium bromide and phosphatidyl choline at a ratio of 1:5 respectively and 0.25% w/v oleic acid was the optimum system with respect to shape and PS (spherical, 491 nm), PDI (0.29), ZP (31.1 mV), EE (81.8%), in-vitro release (Q2h; 34.9%, Q8h; 91.2%), crystallinity, pH (6.3), refractive index (1.24), surface tension (46.2 mN/m) and stability. AGO pharmacodynamic and histopathological studies were conducted in rabbits. Compared to AGO dispersion, elevated maximum IOP reduction (74.2%), prolonged mean residence time (12.88 h), enhanced bioavailability (3 folds) and normal histopathological micrographs proved the potential of L20 leciplex in improving and sustaining the ocular bioavailability of AGO and maintaining its safety.
{"title":"Oleic acid Enriched Leciplexes as Novel Mucoadhesive Cationic Nanocarriers of Agomelatine for Glaucoma Treatment","authors":"Mai Ahmed Tawfik, Sadek Ahmed, Rania Moataz El-Dahmy, Diana E. Aziz","doi":"10.1208/s12249-025-03250-0","DOIUrl":"10.1208/s12249-025-03250-0","url":null,"abstract":"<div><p>Agomelatine (AGO) is a dual action drug. Being serotonin receptor antagonist, AGO is orally administered for depression treatment. Here in, AGO was used for intraocular pressure management due to its agonistic activity on the melatonin receptors in the eyes. AGO is a BCS II drug, with low oral bioavailability and massive first-pass metabolism. Oleic acid enriched leciplexes were investigated as novel mucoadhesive cationic nanocarriers to improve AGO’s ocular bioavailability and prolong its pharmacological effect. Twenty-four AGO loaded leciplexes were fabricated by single-step procedure. AGO: lipid ratio, surfactant: phosphatidyl choline ratio, cationic surfactant type, permeation enhancer type were investigated. For optimization; in-vitro assessment of size, homogeneity, surface charge, drug entrapment and in-vitro release was conducted. The optimum system was further examined for crystallinity, compatibility, morphology, pH, refractive index, surface tension and stability. L20 developed at a drug: lipid ratio of 1: 20, cetyltrimethylammonium bromide and phosphatidyl choline at a ratio of 1:5 respectively and 0.25% w/v oleic acid was the optimum system with respect to shape and PS (spherical, 491 nm), PDI (0.29), ZP (31.1 mV), EE (81.8%), in-vitro release (Q<sub>2h</sub>; 34.9%, Q<sub>8h</sub>; 91.2%), crystallinity, pH (6.3), refractive index (1.24), surface tension (46.2 mN/m) and stability. AGO pharmacodynamic and histopathological studies were conducted in rabbits. Compared to AGO dispersion, elevated maximum IOP reduction (74.2%), prolonged mean residence time (12.88 h), enhanced bioavailability (3 folds) and normal histopathological micrographs proved the potential of L20 leciplex in improving and sustaining the ocular bioavailability of AGO and maintaining its safety.\u0000</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-025-03250-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145352293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-24DOI: 10.1208/s12249-025-03251-z
Ikki Shibazaki, Yuri Ikeuchi-Takahashi, Mayumi Ikegami-Kawai, Yasuko Obata
Nanoemulsions are considered to have an advantage in improving the oral bioavailability of poorly absorbed drugs. However, studies on additives such as surfactants used as emulsifiers, essential for the preparation of nanoemulsions, are relatively limited, and their safety and usefulness require further investigation. In this study, the utility of polyoxyethylene sorbitan monostearate (PS60) and polyglyceryl-10 oleate (PGFE), used as nonionic surfactants, was evaluated by using them as emulsifiers for nanoemulsions containing fexofenadine (FXD), a P-glycoprotein (P-gp) substrate. The median diameter of droplets in FXD nanoemulsions was smaller with PGFE compared with PS60. In the drug release study, all FXD nanoemulsions suppressed the drug release at gastric pH and the cumulative amount of drug released increased at intestinal pH. In an in vivo study, PS60-containing nanoemulsions exhibited a higher area under the plasma concentration–time curve, indicating their potential as an effective formulation for improving the gastrointestinal absorption of FXD. In PS60-containing nanoemulsions, we hypothesize that the absorptive transport of FXD was increased due to the combined effects of improved drug dissolution properties, increased paracellular and/or transcellular transport due to emulsification, and decreased secretory transport due to inhibition of P-gp. In PGFE-containing nanoemulsions, the increased bioavailability of the P-gp substrate drug was lower than PS60-containing nanoemulsions. However, data indicate that PGFE has a weaker P-gp inhibitory potential than PS60 in the cellular transport of digoxin, and it may serve as a surfactant with minimal P-gp interaction in the gastrointestinal tract when used in combination with P-gp substrate drugs.
{"title":"Effect of Surfactants on Oral Delivery of Nanoemulsions Containing Fexofenadine, a Substrate for P-glycoprotein","authors":"Ikki Shibazaki, Yuri Ikeuchi-Takahashi, Mayumi Ikegami-Kawai, Yasuko Obata","doi":"10.1208/s12249-025-03251-z","DOIUrl":"10.1208/s12249-025-03251-z","url":null,"abstract":"<div><p>Nanoemulsions are considered to have an advantage in improving the oral bioavailability of poorly absorbed drugs. However, studies on additives such as surfactants used as emulsifiers, essential for the preparation of nanoemulsions, are relatively limited, and their safety and usefulness require further investigation. In this study, the utility of polyoxyethylene sorbitan monostearate (PS60) and polyglyceryl-10 oleate (PGFE), used as nonionic surfactants, was evaluated by using them as emulsifiers for nanoemulsions containing fexofenadine (FXD), a P-glycoprotein (P-gp) substrate. The median diameter of droplets in FXD nanoemulsions was smaller with PGFE compared with PS60. In the drug release study, all FXD nanoemulsions suppressed the drug release at gastric pH and the cumulative amount of drug released increased at intestinal pH. In an <i>in vivo</i> study, PS60-containing nanoemulsions exhibited a higher area under the plasma concentration–time curve, indicating their potential as an effective formulation for improving the gastrointestinal absorption of FXD. In PS60-containing nanoemulsions, we hypothesize that the absorptive transport of FXD was increased due to the combined effects of improved drug dissolution properties, increased paracellular and/or transcellular transport due to emulsification, and decreased secretory transport due to inhibition of P-gp. In PGFE-containing nanoemulsions, the increased bioavailability of the P-gp substrate drug was lower than PS60-containing nanoemulsions. However, data indicate that PGFE has a weaker P-gp inhibitory potential than PS60 in the cellular transport of digoxin, and it may serve as a surfactant with minimal P-gp interaction in the gastrointestinal tract when used in combination with P-gp substrate drugs.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145352291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-24DOI: 10.1208/s12249-025-03239-9
Najam ul Hassan Jawa, Nasir Abbas, Hafiza Nasreen Aslam, Hafsa Afzal, Misbah Hameed, Nadeem Irfan Bukhari, Sumera Latif
Quercetin (QUC), an extensively investigated nutraceutical, demonstrates various clinical and therapeutic effects such as anti-oxidant, anti-inflammatory, anti-malarial, anti-viral, anti-carcinogenic and cytoprotective properties. However, the effectiveness of QUC is off-set by its poor solubility, stability, permeability, and absorption. In current research, a cocrystal nanonization strategy, integrating the cocrystallization and nanosizing techniques, has been tested to address intrinsic issues of QUC. A cocrystal of QUC with ascorbic acid (as co-former) synthesized by solvent evaporation was transformed into nano-cocrystal (NCC) by top-down homogenization technique using 0.045% Poloxamer 188 (as stabilizer). NCC was characterized by SEM and Zetasizer and appeared to be blocked-shaped with mean particle size of 300 ± 80 nm. Further characterization was undertaken using powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared spectroscopy. The properties of cocrystal and NCC were explored by solubility, In-vitro dissolution, anti-oxidant, and cytotoxicity studies against Vero and MCF-7 cells. NCC presented 17 and 5 times enhanced solubility and dissolution of QUC in distilled water and 1.6 times enhanced anti-oxidant activity compared to free QUC, and substantial mortality against MCF-7 cells. NCC remained stable in gel for six months at 4 ± 2ºC and 30 ± 2ºC/60 ± 5%RH. The gel released 98.91% QUC after 5 h. Hence, the topical formulation by combining the advantages of cocrystals and nanonization (nano-cocrystals) might be a promising strategy in treating various skin ailments by virtue of ameliorated physicochemical profile, anti-oxidant activity and stability.
{"title":"Novel Quercetin-Ascorbic Acid Nano Cocrystals: A Carrier-free Strategy for Enhancement of Solubility, Topical Anti-oxidant Activity and Cytotoxicity","authors":"Najam ul Hassan Jawa, Nasir Abbas, Hafiza Nasreen Aslam, Hafsa Afzal, Misbah Hameed, Nadeem Irfan Bukhari, Sumera Latif","doi":"10.1208/s12249-025-03239-9","DOIUrl":"10.1208/s12249-025-03239-9","url":null,"abstract":"<div><p>Quercetin (QUC), an extensively investigated nutraceutical, demonstrates various clinical and therapeutic effects such as anti-oxidant, anti-inflammatory, anti-malarial, anti-viral, anti-carcinogenic and cytoprotective properties. However, the effectiveness of QUC is off-set by its poor solubility, stability, permeability, and absorption. In current research, a cocrystal nanonization strategy, integrating the cocrystallization and nanosizing techniques, has been tested to address intrinsic issues of QUC. A cocrystal of QUC with ascorbic acid (as co-former) synthesized by solvent evaporation was transformed into nano-cocrystal (NCC) by top-down homogenization technique using 0.045% Poloxamer 188 (as stabilizer). NCC was characterized by SEM and Zetasizer and appeared to be blocked-shaped with mean particle size of 300 ± 80 nm. Further characterization was undertaken using powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared spectroscopy. The properties of cocrystal and NCC were explored by solubility, <i>In-vitro</i> dissolution, anti-oxidant, and cytotoxicity studies against Vero and MCF-7 cells. NCC presented 17 and 5 times enhanced solubility and dissolution of QUC in distilled water and 1.6 times enhanced anti-oxidant activity compared to free QUC, and substantial mortality against MCF-7 cells. NCC remained stable in gel for six months at 4 ± 2ºC and 30 ± 2ºC/60 ± 5%RH. The gel released 98.91% QUC after 5 h. Hence, the topical formulation by combining the advantages of cocrystals and nanonization (nano-cocrystals) might be a promising strategy in treating various skin ailments by virtue of ameliorated physicochemical profile, anti-oxidant activity and stability.\u0000</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145352292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-23DOI: 10.1208/s12249-025-03254-w
Sukannika Tubtimsri, Yotsanan Weerapol
Corneal fungal infections are a leading cause of blindness worldwide; however, poor ocular drug absorption limits current topical antifungal treatments. Itraconazole (ICZ), a potent antifungal agent, exhibits low aqueous solubility and limited permeability. This study aimed to develop self-emulsifying drug delivery systems (SEDDS) to enhance the solubility, permeability, and ocular cell uptake of ICZ, providing a more effective topical therapy. ICZ solubility was evaluated in various vehicles (Tween 80, Tween 60, Span 20, coconut oil, and olive oil). Ten optimized SEDDS formulations were prepared, with particle sizes ranging from 514 to 1,384 nm (tenfold dilution). In vitro drug permeation was assessed using Franz diffusion cells with a parallel artificial membrane permeability assay. Cellular uptake was evaluated in ocular cell lines, and drug diffusion kinetics were analyzed using the Higuchi model. Formulation stability was assessed over a 6-month period. Formulation F1 achieved the highest permeation (96.71% ± 1.99%), followed by F3 (96.33% ± 3.24%) and F2 (80.98% ± 2.85%), whereas ICZ-PEG showed minimal permeation (11.55% ± 2.80%). The Higuchi model indicated diffusion-controlled transport. Cellular uptake was highest for F3, followed by F1 and F2, with approximately 50.3-, 38.6-, and 12.3-fold higher uptake than ICZ-PEG, respectively. All ICZ-SEDDS formulations remained stable for > 6 months. ICZ-SEDDS markedly improved the solubility, permeability, and ocular cell uptake of ICZ compared with ICZ-PEG. The superior performance of formulation F3 highlights the potential of SEDDS as an effective strategy for overcoming limitations in topical antifungal therapy for corneal fungal infections.
{"title":"Enhanced Ocular Delivery of Itraconazole via a Self-Emulsifying Drug Delivery System: Improved Antifungal Activity and Cellular Uptake","authors":"Sukannika Tubtimsri, Yotsanan Weerapol","doi":"10.1208/s12249-025-03254-w","DOIUrl":"10.1208/s12249-025-03254-w","url":null,"abstract":"<div><p>Corneal fungal infections are a leading cause of blindness worldwide; however, poor ocular drug absorption limits current topical antifungal treatments. Itraconazole (ICZ), a potent antifungal agent, exhibits low aqueous solubility and limited permeability. This study aimed to develop self-emulsifying drug delivery systems (SEDDS) to enhance the solubility, permeability, and ocular cell uptake of ICZ, providing a more effective topical therapy. ICZ solubility was evaluated in various vehicles (Tween 80, Tween 60, Span 20, coconut oil, and olive oil). Ten optimized SEDDS formulations were prepared, with particle sizes ranging from 514 to 1,384 nm (tenfold dilution). <i>In vitro</i> drug permeation was assessed using Franz diffusion cells with a parallel artificial membrane permeability assay. Cellular uptake was evaluated in ocular cell lines, and drug diffusion kinetics were analyzed using the Higuchi model. Formulation stability was assessed over a 6-month period. Formulation F1 achieved the highest permeation (96.71% ± 1.99%), followed by F3 (96.33% ± 3.24%) and F2 (80.98% ± 2.85%), whereas ICZ-PEG showed minimal permeation (11.55% ± 2.80%). The Higuchi model indicated diffusion-controlled transport. Cellular uptake was highest for F3, followed by F1 and F2, with approximately 50.3-, 38.6-, and 12.3-fold higher uptake than ICZ-PEG, respectively. All ICZ-SEDDS formulations remained stable for > 6 months. ICZ-SEDDS markedly improved the solubility, permeability, and ocular cell uptake of ICZ compared with ICZ-PEG. The superior performance of formulation F3 highlights the potential of SEDDS as an effective strategy for overcoming limitations in topical antifungal therapy for corneal fungal infections.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145341164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-14DOI: 10.1208/s12249-025-03237-x
Esraa Al Shawakri, Eman A. Ashour, Rasha M. Elkanayati, Mashan Almutairi, Sundus Omari, Nouf AlShammari, Michael A. Repka
Famotidine suffers from low oral bioavailability due to poor aqueous solubility, short half-life, and limited gastric retention. This study aimed to develop gastro-retentive floating tablets of famotidine using hot-melt extrusion (HME) and fused deposition modeling (FDM) 3D printing approach to enhance its solubility, prolong gastric residence, and achieve extended drug release. Famotidine was incorporated into various polymeric carriers, including hydroxypropyl cellulose (HPC LF) and hydroxypropyl methylcellulose (HPMC E5), to produce drug-loaded filaments using an 11 mm twin-screw co-rotating extruder. The filaments were subsequently 3D-printed into low-density, hollow tablets to achieve prolonged gastric floatation. The solid-state characterization by differential scanning calorimetry (DSC) revealed the absence of famotidine’s crystalline melting peak in both filaments and 3D-printed tablets, suggesting amorphization within the polymer matrix. FTIR spectroscopy indicated hydrogen bonding interactions between famotidine and polymer hydroxyl groups, supporting the stabilization of the solid dispersion. The lead formulation demonstrated excellent buoyancy of about nine hours and extended drug release in 0.1 N HCl, confirming the potential of the system for extended gastric retention. This work highlights the utility of HME-FDM 3D printing for developing tailored, gastro-retentive dosage forms that enhance the performance of poorly soluble drugs like famotidine through amorphous solid dispersion and formulation-driven design.
{"title":"Fabrication of Gastroretentive and Extended-Release Famotidine Floating Tablets via Fused Deposition Modeling","authors":"Esraa Al Shawakri, Eman A. Ashour, Rasha M. Elkanayati, Mashan Almutairi, Sundus Omari, Nouf AlShammari, Michael A. Repka","doi":"10.1208/s12249-025-03237-x","DOIUrl":"10.1208/s12249-025-03237-x","url":null,"abstract":"<div><p>Famotidine suffers from low oral bioavailability due to poor aqueous solubility, short half-life, and limited gastric retention. This study aimed to develop gastro-retentive floating tablets of famotidine using hot-melt extrusion (HME) and fused deposition modeling (FDM) 3D printing approach to enhance its solubility, prolong gastric residence, and achieve extended drug release. Famotidine was incorporated into various polymeric carriers, including hydroxypropyl cellulose (HPC LF) and hydroxypropyl methylcellulose (HPMC E5), to produce drug-loaded filaments using an 11 mm twin-screw co-rotating extruder. The filaments were subsequently 3D-printed into low-density, hollow tablets to achieve prolonged gastric floatation. The solid-state characterization by differential scanning calorimetry (DSC) revealed the absence of famotidine’s crystalline melting peak in both filaments and 3D-printed tablets, suggesting amorphization within the polymer matrix. FTIR spectroscopy indicated hydrogen bonding interactions between famotidine and polymer hydroxyl groups, supporting the stabilization of the solid dispersion. The lead formulation demonstrated excellent buoyancy of about nine hours and extended drug release in 0.1 N HCl, confirming the potential of the system for extended gastric retention. This work highlights the utility of HME-FDM 3D printing for developing tailored, gastro-retentive dosage forms that enhance the performance of poorly soluble drugs like famotidine through amorphous solid dispersion and formulation-driven design.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-025-03237-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-09DOI: 10.1208/s12249-025-03236-y
Hendrik Küllmar, Martin Schöler, Jonas Brügmann, Claudia S. Leopold
Dustiness and the spatial distribution of dust are major problems when working with highly active pharmaceutical ingredients. Therefore, the aim of this study was to develop a chamber setup that allows a reproducible atomization of small powder quantities and the detection of not only dustiness but also the spatial distribution of airborne dust at extremely low concentrations, to prove that an emission site may be localized with stationary sampling even in a confined space. For this purpose, the time required for evacuation of the chamber setup was determined with fuming sulfuric acid. In subsequent atomization experiments, the safe surrogate acetaminophen was used. The spatial distribution of the surrogate was detected with nine IOM samplers (Institute of Occupational Medicine) and its quantification was carried out via HPLC. A linear tendency of the quantity of aerosol formed in dependence of the sample mass was demonstrated. In addition, significant differences between individual spots of detection and thus a spatial distribution in the detection chamber was observed. These results indicated a strong convective mass transport within the chamber setup. To verify these results, the airflow used for atomization was simulated using Computational Fluid Dynamics, confirming the convective mass transport and the spatial distribution of the airborne acetaminophen dust. In summary, it was shown that an emission site may be localized based on stationary exposure data even at concentrations as low as those mandatory in the contained manufacture of HPAPI-containing pharmaceuticals.
{"title":"Investigations on the Spatial Dust Distribution for Emission Site Localization in Containment","authors":"Hendrik Küllmar, Martin Schöler, Jonas Brügmann, Claudia S. Leopold","doi":"10.1208/s12249-025-03236-y","DOIUrl":"10.1208/s12249-025-03236-y","url":null,"abstract":"<div><p>Dustiness and the spatial distribution of dust are major problems when working with highly active pharmaceutical ingredients. Therefore, the aim of this study was to develop a chamber setup that allows a reproducible atomization of small powder quantities and the detection of not only dustiness but also the spatial distribution of airborne dust at extremely low concentrations, to prove that an emission site may be localized with stationary sampling even in a confined space. For this purpose, the time required for evacuation of the chamber setup was determined with fuming sulfuric acid. In subsequent atomization experiments, the safe surrogate acetaminophen was used. The spatial distribution of the surrogate was detected with nine IOM samplers (Institute of Occupational Medicine) and its quantification was carried out via HPLC. A linear tendency of the quantity of aerosol formed in dependence of the sample mass was demonstrated. In addition, significant differences between individual spots of detection and thus a spatial distribution in the detection chamber was observed. These results indicated a strong convective mass transport within the chamber setup. To verify these results, the airflow used for atomization was simulated using Computational Fluid Dynamics, confirming the convective mass transport and the spatial distribution of the airborne acetaminophen dust. In summary, it was shown that an emission site may be localized based on stationary exposure data even at concentrations as low as those mandatory in the contained manufacture of HPAPI-containing pharmaceuticals.\u0000</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"26 8","pages":""},"PeriodicalIF":4.0,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-025-03236-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145256118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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