Pub Date : 2026-01-23DOI: 10.1208/s12249-026-03347-0
Rosilene Ribeiro de Sousa, Matheus Oliveira do Nascimento, Leandro Josuel da Costa Santos, Francisco Gesley de Sousa Abreu, André Luiz Pinheiro de Moura, Daniele Costa Lopes, Karla Germana dos Reis Bacelar, Rita de Cássia Vianna de Carvalho, Paulline Paiva Mendes de Souza Leal, Charllyton Luis Sena da Costa, Vitória de Cássia Coelho Rodrigues, Fernando Aécio de Amorim Carvalho, Michel Muálem de Moraes Alves, André Luis Menezes Carvalho
{"title":"Correction: Amphotericin B-Loaded Bigel: Characterization and in vivo Antileishmanial Evaluation in BALB/c Mice Infected with Leishmania amazonensis","authors":"Rosilene Ribeiro de Sousa, Matheus Oliveira do Nascimento, Leandro Josuel da Costa Santos, Francisco Gesley de Sousa Abreu, André Luiz Pinheiro de Moura, Daniele Costa Lopes, Karla Germana dos Reis Bacelar, Rita de Cássia Vianna de Carvalho, Paulline Paiva Mendes de Souza Leal, Charllyton Luis Sena da Costa, Vitória de Cássia Coelho Rodrigues, Fernando Aécio de Amorim Carvalho, Michel Muálem de Moraes Alves, André Luis Menezes Carvalho","doi":"10.1208/s12249-026-03347-0","DOIUrl":"10.1208/s12249-026-03347-0","url":null,"abstract":"","PeriodicalId":6925,"journal":{"name":"AAPS PharmSciTech","volume":"27 2","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146027316","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}
Bioactive compounds in green coffee beans, such as caffeine (CF) and cafestol (CA), possess potential pharmaceutical benefits, including antioxidant and anti-inflammatory properties, but face challenges in skin penetration. This study developed a novel liposomal system combining CF and CA for the first time, formulated with either Lipoid S 75 or Phospholipon® 90 G and cholesterol (80:20 ratio), aiming to enhance skin penetration of CF and CA by encapsulating them into liposomes dermal application. Formulations with 1% CF and either 0.13% or 0.07% CA were developed and tested for skin permeation utilizing Franz diffusion cells with human cadaver skin. Receptor compartment samples were collected at 2, 4, 8, 12, and 24 h and the amount of CF penetrated (µg/cm2) was quantified using a validated HPLC method. The skin distribution in dermal and epidermal layers of both compounds were also assessed. Results showed that formulation F9 (1% CF, 0.13% CA) significantly improved skin penetration, doubling CF levels in the dermis and increasing CA levels by 5.5-fold in the dermis and 35-fold in the epidermis, despite lower CF permeability compared to the control. F9 also demonstrated high encapsulation efficiency and confirmed safety in cytotoxicity studies. These findings suggest that liposomal formulations of combining CF and CA are promising for topical applications and merit further clinical investigation.
{"title":"Skin Penetration of Caffeine and Cafestol using Liposomes: Exploring the Benefits of a Combined Delivery System","authors":"Nubul Albayati, Amitkumar Virani, Sesha Rajeswari Talluri, Bozena Michniak-Kohn","doi":"10.1208/s12249-025-03310-5","DOIUrl":"10.1208/s12249-025-03310-5","url":null,"abstract":"<div><p>Bioactive compounds in green coffee beans, such as caffeine (CF) and cafestol (CA), possess potential pharmaceutical benefits, including antioxidant and anti-inflammatory properties, but face challenges in skin penetration. This study developed a novel liposomal system combining CF and CA for the first time, formulated with either Lipoid S 75 or Phospholipon® 90 G and cholesterol (80:20 ratio), aiming to enhance skin penetration of CF and CA by encapsulating them into liposomes dermal application. Formulations with 1% CF and either 0.13% or 0.07% CA were developed and tested for skin permeation utilizing Franz diffusion cells with human cadaver skin. Receptor compartment samples were collected at 2, 4, 8, 12, and 24 h and the amount of CF penetrated (µg/cm<sup>2</sup>) was quantified using a validated HPLC method. The skin distribution in dermal and epidermal layers of both compounds were also assessed. Results showed that formulation F9 (1% CF, 0.13% CA) significantly improved skin penetration, doubling CF levels in the dermis and increasing CA levels by 5.5-fold in the dermis and 35-fold in the epidermis, despite lower CF permeability compared to the control. F9 also demonstrated high encapsulation efficiency and confirmed safety in cytotoxicity studies. These findings suggest that liposomal formulations of combining CF and CA are promising for topical applications and merit further clinical investigation.</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 2","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-025-03310-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146026833","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}
The work aims to improve the solubility and dissolution rate of the cardiovascular drug carvedilol (CVD) of II class BCS by a co-crystallization approach. The slurry method was used to preparation of CVD cocrystals. The existence of new solid phases was confirmed by PXRD, DSC, TGA, FTIR and UV–vis spectroscopy. The dissolution kinetics of two component systems in a model buffer solution was studied by the classical shake flask method. The process of CVD release from co-crystals tablets were studied in accordance with Pharmacopoeia standard using a dissolution tester. Pharmaceutical cocrystals of CVD with two coformers, 2-hydroxybenzamide (2OHBZA) and 4-hydroxybenzamide (4OHBZA) in molar ratio 1:1, have been obtained for the first time. Thermodynamic characteristics of the cocrystallization reaction of the active pharmaceutical ingredient with the selected coformers have been experimentally determined for the synthesized CVD/2OHBZA and CVD/4OHBZA cocrystals. It has been shown that the process of cocrystal formation is enthalpy-determined, which is typical for most two-component crystals. Kinetic solubility profiles of new solid phases have been determined in a buffer solution pH 7.4, simulating the pH of blood plasma. It was found that the equilibrium solubility of co-crystal forms of carvedilol significantly exceeds the solubility of original drug. In vitro study of the release of CVD from co-crystal tablets showed a improving of the drug release rate into solution to 67% for CVD/2OHBZA and 43% for CVD/4OHBZA, that by 2.6 and 1.7 times higher then the raw drug. Considering the significant enhancement of carvedilol solubility in two-component systems and their stability in aqueous medium, co-crystallization is a promising approach for the development of new dosage forms of this drug with improved bioavailability.
{"title":"Carvedilol Pharmaceutical Cocrystals: Preparation, Advanced Characterization and Dissolution Behavior","authors":"Angelica Sharapova, Marina Ol’khovich, Svetlana Blokhina","doi":"10.1208/s12249-025-03317-y","DOIUrl":"10.1208/s12249-025-03317-y","url":null,"abstract":"<div><p>The work aims to improve the solubility and dissolution rate of the cardiovascular drug carvedilol (CVD) of II class BCS by a co-crystallization approach. The slurry method was used to preparation of CVD cocrystals. The existence of new solid phases was confirmed by PXRD, DSC, TGA, FTIR and UV–vis spectroscopy. The dissolution kinetics of two component systems in a model buffer solution was studied by the classical shake flask method. The process of CVD release from co-crystals tablets were studied in accordance with Pharmacopoeia standard using a dissolution tester. Pharmaceutical cocrystals of CVD with two coformers, 2-hydroxybenzamide (2OHBZA) and 4-hydroxybenzamide (4OHBZA) in molar ratio 1:1, have been obtained for the first time. Thermodynamic characteristics of the cocrystallization reaction of the active pharmaceutical ingredient with the selected coformers have been experimentally determined for the synthesized CVD/2OHBZA and CVD/4OHBZA cocrystals. It has been shown that the process of cocrystal formation is enthalpy-determined, which is typical for most two-component crystals. Kinetic solubility profiles of new solid phases have been determined in a buffer solution pH 7.4, simulating the pH of blood plasma. It was found that the equilibrium solubility of co-crystal forms of carvedilol significantly exceeds the solubility of original drug. <i>In vitro</i> study of the release of CVD from co-crystal tablets showed a improving of the drug release rate into solution to 67% for CVD/2OHBZA and 43% for CVD/4OHBZA, that by 2.6 and 1.7 times higher then the raw drug. Considering the significant enhancement of carvedilol solubility in two-component systems and their stability in aqueous medium, co-crystallization is a promising approach for the development of new dosage forms of this drug with improved bioavailability.</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 2","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146007043","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 : 2026-01-21DOI: 10.1208/s12249-025-03314-1
Jiyaur Rahaman, Dhrubojyoti Mukherjee Ph.D.
The current study aims to develop a polymer hybrid scaffold functionalized with Eudragit nanoparticles, having an inherent effect on bone tissue regeneration. Thiolated sodium alginate (TSA) was combined with β-cyclodextrin (β-CD) and polyethylene glycol (PEG) as the interlinking polymer to design the hydrogel scaffold. The freeze–thaw technique was followed to develop the scaffold, and the scaffold was functionalized with Eudragit nanoparticles during freeze-thawing. The Eudragit nanoparticle was characterized by SEM, AFM, and DLS. The prepared nanoparticle-embedded polymeric scaffold was characterized by FTIR, XRD, gel fraction, swelling, water vapor transmission, SEM, and optical profilometry. The polymeric interlinking in the scaffold during the freeze-thawing method was confirmed by FTIR and XRD analysis. The developed scaffold showed swelling degree within a limit of 0.140 ± 0.100 to 0.195 ± 0.100 within 8 h, and gel fraction ranged from 36.67 ± 2.12% and 44.40 ± 2.06%. The surface smoothness and porous structure of the hydrogel scaffold were confirmed by optical profilometry. In vitro, cell line study indicated no toxicity, and molecular docking studies exhibited optimum binding energy with target proteins bone morphogenetic protein-2 and Integrin αvβ3, suggesting potential bone tissue engineering applications of the developed scaffolds.
{"title":"Characterization of Eudragit Nanoparticle-Tailored β-Cyclodextrin/Thiolated Sodium Alginate/Polyethyleneglycol Polymer Hybrid as a Potential Bone Tissue Engineering Scaffold","authors":"Jiyaur Rahaman, Dhrubojyoti Mukherjee Ph.D.","doi":"10.1208/s12249-025-03314-1","DOIUrl":"10.1208/s12249-025-03314-1","url":null,"abstract":"<div><p>The current study aims to develop a polymer hybrid scaffold functionalized with Eudragit nanoparticles, having an inherent effect on bone tissue regeneration. Thiolated sodium alginate (TSA) was combined with β-cyclodextrin (β-CD) and polyethylene glycol (PEG) as the interlinking polymer to design the hydrogel scaffold. The freeze–thaw technique was followed to develop the scaffold, and the scaffold was functionalized with Eudragit nanoparticles during freeze-thawing. The Eudragit nanoparticle was characterized by SEM, AFM, and DLS. The prepared nanoparticle-embedded polymeric scaffold was characterized by FTIR, XRD, gel fraction, swelling, water vapor transmission, SEM, and optical profilometry. The polymeric interlinking in the scaffold during the freeze-thawing method was confirmed by FTIR and XRD analysis. The developed scaffold showed swelling degree within a limit of 0.140 ± 0.100 to 0.195 ± 0.100 within 8 h, and gel fraction ranged from 36.67 ± 2.12% and 44.40 ± 2.06%. The surface smoothness and porous structure of the hydrogel scaffold were confirmed by optical profilometry. <i>In vitro</i>, cell line study indicated no toxicity, and molecular docking studies exhibited optimum binding energy with target proteins bone morphogenetic protein-2 and Integrin αvβ3, suggesting potential bone tissue engineering applications of the developed scaffolds.</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 2","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146007041","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 : 2026-01-21DOI: 10.1208/s12249-025-03312-3
Namık Bilici, Ferhat Bozduman
Fluconazole (FCZ) is an antifungal drug of the triazole class and is widely used in the treatment of systemic and superficial fungal infections. However, resistance development is high in triazoles. Zinc undecylenate (ZU), on the other hand, has fungistatic properties and inhibits Candida albicans biofilm formation. This study aimed to develop a new compound that would utilize the sequential pharmacodynamic effects of FCZ and ZU to overcome FCZ resistance, eliminate biofilm formation, and reduce infection recurrence. Solid Lipid Nanoparticle-Fluconazole (SLNP-FCZ) suspension was prepared, and the surface of ZU powders was coated using low-pressure radio frequency plasma-chemical vapor deposition (LPRFP-CVD). The resulting SLNP-FCZ-ZU composition was characterized by nuclear magnetic resonance (NMR), optical emission spectroscopy (OES), scanning electron microscopy (SEM), zeta potential, and particle size analyses. Statistical evaluations compared the difference between the ZU and coated form using correlation. A significant difference was observed in the correlation analysis (p < 0.001), and the effect size was found to be high (d = 1.03). The antifungal efficacy of SLNP-FCZ-coated ZU preparations was supported by their sequential mechanism of action. The results obtained demonstrate that the LPRFP technique can combine pharmacotherapeutic agents into a single pharmaceutical preparation. The combination of SLNP-FCZ and ZU can shorten the treatment time and improve patient well-being in persistent Candida infections by reducing resistance and biofilm formation. This approach can be considered an innovative strategy in antifungal therapies.
{"title":"Surface Modification of Zinc Undecylenate with Nanoparticle Fluconazole Using Low-Pressure RF Plasma-Assisted CVD: A New Generation Antifungal Compound","authors":"Namık Bilici, Ferhat Bozduman","doi":"10.1208/s12249-025-03312-3","DOIUrl":"10.1208/s12249-025-03312-3","url":null,"abstract":"<div><p>Fluconazole (FCZ) is an antifungal drug of the triazole class and is widely used in the treatment of systemic and superficial fungal infections. However, resistance development is high in triazoles. Zinc undecylenate (ZU), on the other hand, has fungistatic properties and inhibits Candida albicans biofilm formation. This study aimed to develop a new compound that would utilize the sequential pharmacodynamic effects of FCZ and ZU to overcome FCZ resistance, eliminate biofilm formation, and reduce infection recurrence. Solid Lipid Nanoparticle-Fluconazole (SLNP-FCZ) suspension was prepared, and the surface of ZU powders was coated using low-pressure radio frequency plasma-chemical vapor deposition (LPRFP-CVD). The resulting SLNP-FCZ-ZU composition was characterized by nuclear magnetic resonance (NMR), optical emission spectroscopy (OES), scanning electron microscopy (SEM), zeta potential, and particle size analyses. Statistical evaluations compared the difference between the ZU and coated form using correlation. A significant difference was observed in the correlation analysis (<i>p</i> < 0.001), and the effect size was found to be high (d = 1.03). The antifungal efficacy of SLNP-FCZ-coated ZU preparations was supported by their sequential mechanism of action. The results obtained demonstrate that the LPRFP technique can combine pharmacotherapeutic agents into a single pharmaceutical preparation. The combination of SLNP-FCZ and ZU can shorten the treatment time and improve patient well-being in persistent Candida infections by reducing resistance and biofilm formation. This approach can be considered an innovative strategy in antifungal 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 2","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146006973","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 : 2026-01-15DOI: 10.1208/s12249-025-03306-1
Li Ying Kam, Jia Woei Wong, Kah Hay Yuen
Many compounds with high aqueous solubility, limited absorption in the upper gastrointestinal tract, poor oral bioavailability, and pH-dependent chemical stability can benefit from sustained and gastric-specific delivery systems to improve oral absorption. Intragastric floating systems represent a promising strategy to address these challenges. However, their use is limited by factors such as long floating lag time (FLT), the reliance on high viscosity hydroxypropylmethyl cellulose (HPMC), complex formulations and non-biocompatible excipients. In this study, floating tablets were developed using different grades of HPMC, sodium alginate and sodium carboxymethylcellulose and a gas generating agent. The effects of formulation variables on the in vitro drug release, floating behavior, release mechanism and physical properties were evaluated. High viscosity HPMC 2208, when used as the predominant polymer, provided sustained drug release for up to 12 h. However, it exhibited an excessively long FLT (> 6 min), increasing the risk of premature gastric expulsion which could lead to incomplete absorption and reduced therapeutic efficacy. Incorporation of HPMC 2910 and increasing its proportion within the matrix gradually reduced FLT, enabling faster buoyancy while preserving sustained release characteristics. FLT could also be optimized by fine-tuning the content of sodium bicarbonate (NaHCO3). A higher NaHCO3 content resulted in shorter floating lag time and shifted the release mechanism towards matrix erosion.
{"title":"HPMC Substitution Influences the Buoyancy and Release in Gastroretentive Floating Tablets","authors":"Li Ying Kam, Jia Woei Wong, Kah Hay Yuen","doi":"10.1208/s12249-025-03306-1","DOIUrl":"10.1208/s12249-025-03306-1","url":null,"abstract":"<div><p>Many compounds with high aqueous solubility, limited absorption in the upper gastrointestinal tract, poor oral bioavailability, and pH-dependent chemical stability can benefit from sustained and gastric-specific delivery systems to improve oral absorption. Intragastric floating systems represent a promising strategy to address these challenges. However, their use is limited by factors such as long floating lag time (FLT), the reliance on high viscosity hydroxypropylmethyl cellulose (HPMC), complex formulations and non-biocompatible excipients. In this study, floating tablets were developed using different grades of HPMC, sodium alginate and sodium carboxymethylcellulose and a gas generating agent. The effects of formulation variables on the <i>in vitro</i> drug release, floating behavior, release mechanism and physical properties were evaluated. High viscosity HPMC 2208, when used as the predominant polymer, provided sustained drug release for up to 12 h. However, it exhibited an excessively long FLT (> 6 min), increasing the risk of premature gastric expulsion which could lead to incomplete absorption and reduced therapeutic efficacy. Incorporation of HPMC 2910 and increasing its proportion within the matrix gradually reduced FLT, enabling faster buoyancy while preserving sustained release characteristics. FLT could also be optimized by fine-tuning the content of sodium bicarbonate (NaHCO<sub>3</sub>). A higher NaHCO<sub>3</sub> content resulted in shorter floating lag time and shifted the release mechanism towards matrix erosion.\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":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145983265","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 : 2026-01-15DOI: 10.1208/s12249-025-03300-7
Asmaa Ashraf Nemr, Abdelhamid Ibrahim Elshafey, Amir Ibrahem Mohamed Ali, Mona Mohamed Elkhatib, Mahmoud Teaima, Mohamed A. El-Nabarawi, Mai Ahmed Tawfik
Vildagliptin (VLD) is a powerful oral hypoglycemic agent used in the management of type II diabetes. The goal of the current research was to develop VLD-loaded zein protein-based nanoparticles (VLD-ZP NPs) for enhancing their oral hypoglycemic effect, achieving a sustained release profile, and addressing the issues associated with rapid metabolism and side effects. A 23 full factorial design was utilized to assess the influence of independent formulation variables on the observed responses. The independent variables considered were VLD-to-zein weight ratio (X1), ethanol-to-water volume ratio (X2), and stirring time (X3). The dependent responses evaluated were particle size (Ps), zeta potential (Zp), entrapment efficiency (EE), and percent of drug release after 2H (Q2H) and 8H (Q8H). The optimized VLD-ZP NPs formula (F04), with a desirability value of 0.94, exhibited a small Ps (149.64 ± 1.4nm), low Q2H (23.97 ± 2.1%), high Zp (− 37.67 ± 1.8mV), high EE (68.67 ± 2.3%), and sustained Q8H release (62.57 ± 2.4%). Further investigations of F04 confirmed sustained drug release, spherical vesicle morphology through TEM, and effective entrapment via DSC and X-ray diffraction. In vivo pharmacokinetic studies revealed that Cmax and AUC0-12H of F04 were enhanced by 1.25-fold and 1.8-fold compared to the marketed VLD product. Also, t1/2 and MRT were extended by 1.84-fold and 1.56-fold, respectively. These findings indicated improved oral bioavailability and prolonged residence time of VLD. Additionally, the in vivo pharmacodynamic study revealed that F04 provided markedly superior and sustained hypoglycemic effects over the marketed VLD product, with higher Rmax, longer TR½, and a 2.8-fold increase in AUC(0-24H).
{"title":"Biopolymeric Zein Protein Nanoparticles for Oral Vildagliptin Delivery: Fabrication, Statistical Optimization, and In Vivo Pharmacokinetics and Pharmacodynamics Insights","authors":"Asmaa Ashraf Nemr, Abdelhamid Ibrahim Elshafey, Amir Ibrahem Mohamed Ali, Mona Mohamed Elkhatib, Mahmoud Teaima, Mohamed A. El-Nabarawi, Mai Ahmed Tawfik","doi":"10.1208/s12249-025-03300-7","DOIUrl":"10.1208/s12249-025-03300-7","url":null,"abstract":"<div><p>Vildagliptin (VLD) is a powerful oral hypoglycemic agent used in the management of type II diabetes. The goal of the current research was to develop VLD-loaded zein protein-based nanoparticles (VLD-ZP NPs) for enhancing their oral hypoglycemic effect, achieving a sustained release profile, and addressing the issues associated with rapid metabolism and side effects. A 2<sup>3</sup> full factorial design was utilized to assess the influence of independent formulation variables on the observed responses. The independent variables considered were VLD-to-zein weight ratio (X<sub>1</sub>), ethanol-to-water volume ratio (X<sub>2</sub>), and stirring time (X<sub>3</sub>). The dependent responses evaluated were particle size (Ps), zeta potential (Zp), entrapment efficiency (EE), and percent of drug release after 2H (Q<sub>2H</sub>) and 8H (Q<sub>8H</sub>). The optimized VLD-ZP NPs formula (F04), with a desirability value of 0.94, exhibited a small Ps (149.64 ± 1.4nm), low Q<sub>2H</sub> (23.97 ± 2.1%), high Zp (− 37.67 ± 1.8mV), high EE (68.67 ± 2.3%), and sustained Q<sub>8H</sub> release (62.57 ± 2.4%). Further investigations of F04 confirmed sustained drug release, spherical vesicle morphology through TEM, and effective entrapment <i>via</i> DSC and X-ray diffraction. <i>In vivo</i> pharmacokinetic studies revealed that C<sub>max</sub> and AUC<sub>0-12H</sub> of F04 were enhanced by 1.25-fold and 1.8-fold compared to the marketed VLD product. Also, t<sub>1/2</sub> and MRT were extended by 1.84-fold and 1.56-fold, respectively. These findings indicated improved oral bioavailability and prolonged residence time of VLD. Additionally, the <i>in vivo</i> pharmacodynamic study revealed that F04 provided markedly superior and sustained hypoglycemic effects over the marketed VLD product, with higher R<sub>max</sub>, longer TR<sub>½</sub>, and a 2.8-fold increase in AUC<sub>(0-24H)</sub>.</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":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-025-03300-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145983206","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}
Hematological malignancies like leukemia and lymphoma are severe cancers with high relapse rates. Duvelisib (DUV) is a selective dual phosphatidylinositol 3-kinase-delta and gamma inhibitor with good potential for treating hematological malignancies. However, its application is subsided by poor solubility, permeability and side effects. Herein, we have designed a human serum albumin shell and liquid-lipid core type of nanocapsule system (DUV-NCs) for effective drug loading, enhanced circulation and improved anticancer potential of DUV. The DUV-NCs were extensively optimized with DoE, resulting in a mean particle size of 188.2 ± 1.1 nm, PDI of 0.238 ± 0.018 and entrapment efficiency of 86.99 ± 1.40%. Moreover, a sustained release behaviour with around 80% release up to 48 h was observed. DUV-NCs showed an IC50 of (12.78 ± 0.66 µg/mL), which was significantly decreased (P < 0.001) than the free drug (IC50: 26.08 ± 4.04 µg/mL) in the MOLT-4 cell line. Qualitative and quantitative cellular uptake studies in MOLT-4 cells revealed considerably higher internalization of FITC-NCs than free FITC. DUV-NC-treated groups also displayed higher ROS generation, which was also evident from the increase in apoptotic bodies in MOLT-4 cells. Pharmacokinetic studies showed a 2.07-fold increase in MRT with a 3.56-fold rise in AUC0-t from DUV-NCs compared to free DUV. The DUV-NCs were found to be safe in toxicity studies with no major alterations in biomarkers compared to the control. In conclusion, DUV-NCs is a promising strategy to deliver DUV in hematological malignancies with improved efficacy and safety.
{"title":"Human Serum Albumin-Lipid Nanocapsules of Duvelisib for Hematological Cancers: Characterization, In-Vitro Cell-Culture, Toxicity and Pharmacokinetic Studies","authors":"Srushti Mahajan, Mayur Aalhate, Anamika Sharma, Suman Karadagatla, Santosh Kumar Guru, Pankaj Kumar Singh","doi":"10.1208/s12249-025-03305-2","DOIUrl":"10.1208/s12249-025-03305-2","url":null,"abstract":"<div><p>Hematological malignancies like leukemia and lymphoma are severe cancers with high relapse rates. Duvelisib (DUV) is a selective dual phosphatidylinositol 3-kinase-delta and gamma inhibitor with good potential for treating hematological malignancies. However, its application is subsided by poor solubility, permeability and side effects. Herein, we have designed a human serum albumin shell and liquid-lipid core type of nanocapsule system (DUV-NCs) for effective drug loading, enhanced circulation and improved anticancer potential of DUV. The DUV-NCs were extensively optimized with DoE, resulting in a mean particle size of 188.2 ± 1.1 nm, PDI of 0.238 ± 0.018 and entrapment efficiency of 86.99 ± 1.40%. Moreover, a sustained release behaviour with around 80% release up to 48 h was observed. DUV-NCs showed an IC<sub>50</sub> of (12.78 ± 0.66 µg/mL), which was significantly decreased (P < 0.001) than the free drug (IC<sub>50</sub>: 26.08 ± 4.04 µg/mL) in the MOLT-4 cell line. Qualitative and quantitative cellular uptake studies in MOLT-4 cells revealed considerably higher internalization of FITC-NCs than free FITC. DUV-NC-treated groups also displayed higher ROS generation, which was also evident from the increase in apoptotic bodies in MOLT-4 cells. Pharmacokinetic studies showed a 2.07-fold increase in MRT with a 3.56-fold rise in AUC<sub>0-t</sub> from DUV-NCs compared to free DUV. The DUV-NCs were found to be safe in toxicity studies with no major alterations in biomarkers compared to the control. In conclusion, DUV-NCs is a promising strategy to deliver DUV in hematological malignancies with improved efficacy and 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":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145983266","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}
Acalabrutinib (ACL) is approved by the USFDA and classified as a BCS class II drug, primarily used for treating chronic lymphocytic leukaemia. It is characterised by low solubility, particularly at higher pH levels, which results in reduced systemic absorption. Our current research aims to repurpose ACL for breast cancer treatment by enhancing its solubility and overall bioavailability through a second-generation nanocrystal formulation (SGACNCs). SGACNCs were prepared using the Nano-Edge method, which combines microprecipitation and high-pressure homogenization. The prepared SGACNCs with a mean particle size of 250.5 ± 17nm were characterised by solid-state techniques such as FTIR, DSC, PXRD, SEM, and BET analysis. In vitro dissolution studies indicated that at pH levels of 6.8 and 7.4, there was a 99 ± 0.2% and 99 ± 0.1% release after 6 h, respectively. Furthermore, the apparent permeability of the SGACNCs were observed to be two times greater than that of ACL. The stability studies indicated that the SGACNCs remained stable for 3 months at 5 ± 3 °C. Gastroplus 10.1 software was utilized to predict the pharmacokinetic profiles of SGACNCs based on their in vitro dissolution characteristics. In vitro biological studies on MDA-MB-231 cell lines showed a 1.55-fold reduction in IC50 value in SGACNCs (36.08 ± 2.5 μM) compared to the ACL. SGACNCs showed higher cell internalisation, MMP depolarisation, ROS generation, apoptosis, reduced cell migration, and colony formation. The Nano-Edge technique for the nanonization of ACL showcased its potential to increase both the solubility and dissolution rate of ACL, which will boost its therapeutic efficacy in treating breast cancer.
{"title":"Fabrication of Second-Generation Acalabrutinib Nanocrystals by Employing the Nano-Edge Method for Improving the Physico-Chemical Properties and Forecasting their In-Silico Pharmacokinetic Behaviour","authors":"Bharath M, Ujala Gupta, Anish Dhuri, Tanmoy Kanp, Khushi Rode, Sharon Munagalasetty, Vasundhra Bhandari, Soumyadip Mukherjee, Arvind Gulbake, Pankaj Kumar Singh","doi":"10.1208/s12249-025-03298-y","DOIUrl":"10.1208/s12249-025-03298-y","url":null,"abstract":"<div><p>Acalabrutinib (ACL) is approved by the USFDA and classified as a BCS class II drug, primarily used for treating chronic lymphocytic leukaemia. It is characterised by low solubility, particularly at higher pH levels, which results in reduced systemic absorption. Our current research aims to repurpose ACL for breast cancer treatment by enhancing its solubility and overall bioavailability through a second-generation nanocrystal formulation (SGACNCs). SGACNCs were prepared using the Nano-Edge method, which combines microprecipitation and high-pressure homogenization. The prepared SGACNCs with a mean particle size of 250.5 ± 17nm were characterised by solid-state techniques such as FTIR, DSC, PXRD, SEM, and BET analysis. <i>In vitro</i> dissolution studies indicated that at pH levels of 6.8 and 7.4, there was a 99 ± 0.2% and 99 ± 0.1% release after 6 h, respectively. Furthermore, the apparent permeability of the SGACNCs were observed to be two times greater than that of ACL<i>.</i> The stability studies indicated that the SGACNCs remained stable for 3 months at 5 ± 3 °C. Gastroplus 10.1 software was utilized to predict the pharmacokinetic profiles of SGACNCs based on their <i>in vitro</i> dissolution characteristics. <i>In vitro</i> biological studies on MDA-MB-231 cell lines showed a 1.55-fold reduction in IC<sub>50</sub> value in SGACNCs (36.08 ± 2.5 μM) compared to the ACL. SGACNCs showed higher cell internalisation, MMP depolarisation, ROS generation, apoptosis, reduced cell migration, and colony formation. The Nano-Edge technique for the nanonization of ACL showcased its potential to increase both the solubility and dissolution rate of ACL, which will boost its therapeutic efficacy in treating breast cancer.</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":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145983204","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 : 2026-01-15DOI: 10.1208/s12249-025-03316-z
Marwa Adel Abd El-Fattah
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognitive functions. It represents a global health concern with increasing prevalence and devastating outcomes for the quality of life that could ultimately lead to death. AD is associated with deposition of β-amyloid (Aβ) plaques and intracellular buildup of tau proteins forming neurofibrillary tangles (NFTs), which are the main characteristics for AD brain tissues. Approved AD therapy is based mainly on symptomatic relief, and conventional medicaments often fail due to either low bioavailability, limited solubility, or failure to cross blood–brain barrier (BBB). The complexity in AD pathophysiology opens windows for many therapeutic options. So, lecanemab was recently approved by FDA as the first disease-modifying therapy. However, drug delivery to the brain remains challenging due to the nature of BBB. Hence, more extensive research is essential to develop disease-modifying therapies and also to find drug delivery strategies to ensure simplified administration and successful brain delivery. This review article summarizes AD pathogenesis with the corresponding treatment targets. It emphasizes innovative drug delivery strategies and novel formulation approaches to deliver medicines across BBB. The use of recent advancements in drug delivery to deliver medicaments across BBB are highlighted, with focus given to novel drug delivery systems and formulation of nanoparticles for brain targeting. The use of nutraceuticals, gene therapy, and stem cell therapy are is covered.
{"title":"Challenges and Opportunities of Drug Delivery for Treatment of Alzheimer’s Disease","authors":"Marwa Adel Abd El-Fattah","doi":"10.1208/s12249-025-03316-z","DOIUrl":"10.1208/s12249-025-03316-z","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognitive functions. It represents a global health concern with increasing prevalence and devastating outcomes for the quality of life that could ultimately lead to death. AD is associated with deposition of β-amyloid (Aβ) plaques and intracellular buildup of tau proteins forming neurofibrillary tangles (NFTs), which are the main characteristics for AD brain tissues. Approved AD therapy is based mainly on symptomatic relief, and conventional medicaments often fail due to either low bioavailability, limited solubility, or failure to cross blood–brain barrier (BBB). The complexity in AD pathophysiology opens windows for many therapeutic options. So, lecanemab was recently approved by FDA as the first disease-modifying therapy. However, drug delivery to the brain remains challenging due to the nature of BBB. Hence, more extensive research is essential to develop disease-modifying therapies and also to find drug delivery strategies to ensure simplified administration and successful brain delivery. This review article summarizes AD pathogenesis with the corresponding treatment targets. It emphasizes innovative drug delivery strategies and novel formulation approaches to deliver medicines across BBB. The use of recent advancements in drug delivery to deliver medicaments across BBB are highlighted, with focus given to novel drug delivery systems and formulation of nanoparticles for brain targeting. The use of nutraceuticals, gene therapy, and stem cell therapy are is covered.</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":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1208/s12249-025-03316-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145983203","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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