Pub Date : 2026-01-08DOI: 10.1016/j.xphs.2026.104156
Xinyue Zhang , Stephanie Chow , Ho Wan Chan , Shing Fung Chow
Recent research has shown an increasing interest in nose-to-brain drug delivery due to its non-invasive nature and ability to transport therapeutics directly to the central nervous system. This approach offers significant advantages over traditional administration routes, such as the circumvention of the blood-brain barrier and avoidance of first-pass metabolism, thereby enhancing therapeutic efficacy while reducing systemic side effects. Despite promising preclinical findings, nose-to-brain delivery remains underrepresented in the pharmaceutical market, highlighting a critical gap between experimental research and clinical translation. This review critically examines the major challenges confronting nose-to-brain delivery systems, including formulation development, selection of nasal devices, and methodologies for evaluating the nasal biopharmaceutics of drugs during nose-to-brain delivery. Furthermore, strategic recommendations and research priorities are outlined to address these barriers. By identifying and analyzing factors that contribute to the translational failure of nose-to-brain drug delivery systems, it is believed that more effective delivery systems can be developed, ultimately revolutionizing treatment strategies for neurological diseases.
{"title":"Overcoming translational barriers in nose-to-brain drug delivery for clinical applications","authors":"Xinyue Zhang , Stephanie Chow , Ho Wan Chan , Shing Fung Chow","doi":"10.1016/j.xphs.2026.104156","DOIUrl":"10.1016/j.xphs.2026.104156","url":null,"abstract":"<div><div>Recent research has shown an increasing interest in nose-to-brain drug delivery due to its non-invasive nature and ability to transport therapeutics directly to the central nervous system. This approach offers significant advantages over traditional administration routes, such as the circumvention of the blood-brain barrier and avoidance of first-pass metabolism, thereby enhancing therapeutic efficacy while reducing systemic side effects. Despite promising preclinical findings, nose-to-brain delivery remains underrepresented in the pharmaceutical market, highlighting a critical gap between experimental research and clinical translation. This review critically examines the major challenges confronting nose-to-brain delivery systems, including formulation development, selection of nasal devices, and methodologies for evaluating the nasal biopharmaceutics of drugs during nose-to-brain delivery. Furthermore, strategic recommendations and research priorities are outlined to address these barriers. By identifying and analyzing factors that contribute to the translational failure of nose-to-brain drug delivery systems, it is believed that more effective delivery systems can be developed, ultimately revolutionizing treatment strategies for neurological diseases.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104156"},"PeriodicalIF":3.8,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1016/j.xphs.2026.104155
Lisa Cheng , Po-Chang Chiang , Matthew R Wright , Harvey Wong
Various changes within the gastrointestinal tract following meal intake may significantly impact oral drug absorption. Physiologically-based pharmacokinetic (PBPK) models are often used to perform early predictions of food effects on oral absorption. However, the stomach compartment within these physiological models does not wholly reflect physiology of the fed state. The current approach where the stomach compartment is fixed at pH 5 overlooks the changing gastric pH profile over time after food consumption. We suggest the integration of a multicompartment stomach that represents the various pH phases of the fed stomach to better capture ionizable drug dissolution. Ibuprofen sodium (weak acid) and posaconazole (weak base) were investigated to determine whether a PBPK model that could better capture the varying gastric pH would yield an improvement in food effect predictions. The one-compartment and multicompartment stomach models’ simulations for ibuprofen sodium exposure with and without food consumption were comparable. For posaconazole, the one-compartment stomach model predicted a smaller area under the curve and lower maximum plasma concentration than the multicompartment stomach model’s output in the fed state. Although both models accurately predicted a positive food effect, the magnitude of the simulated fed to fasted fold-changes in posaconazole exposure by the one-compartment stomach model was much less than observed fold-changes. These results suggest that a multicompartment stomach model featuring gastric re-acidification associated with food intake should be incorporated for more accurate food effect predictions for weakly basic compounds.
{"title":"A multicompartment stomach physiologically-based pharmacokinetic model capturing gastric reacidification can improve food effect predictions of weak bases","authors":"Lisa Cheng , Po-Chang Chiang , Matthew R Wright , Harvey Wong","doi":"10.1016/j.xphs.2026.104155","DOIUrl":"10.1016/j.xphs.2026.104155","url":null,"abstract":"<div><div>Various changes within the gastrointestinal tract following meal intake may significantly impact oral drug absorption. Physiologically-based pharmacokinetic (PBPK) models are often used to perform early predictions of food effects on oral absorption. However, the stomach compartment within these physiological models does not wholly reflect physiology of the fed state. The current approach where the stomach compartment is fixed at pH 5 overlooks the changing gastric pH profile over time after food consumption. We suggest the integration of a multicompartment stomach that represents the various pH phases of the fed stomach to better capture ionizable drug dissolution. Ibuprofen sodium (weak acid) and posaconazole (weak base) were investigated to determine whether a PBPK model that could better capture the varying gastric pH would yield an improvement in food effect predictions. The one-compartment and multicompartment stomach models’ simulations for ibuprofen sodium exposure with and without food consumption were comparable. For posaconazole, the one-compartment stomach model predicted a smaller area under the curve and lower maximum plasma concentration than the multicompartment stomach model’s output in the fed state. Although both models accurately predicted a positive food effect, the magnitude of the simulated fed to fasted fold-changes in posaconazole exposure by the one-compartment stomach model was much less than observed fold-changes. These results suggest that a multicompartment stomach model featuring gastric re-acidification associated with food intake should be incorporated for more accurate food effect predictions for weakly basic compounds.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104155"},"PeriodicalIF":3.8,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1016/j.xphs.2026.104154
Pradeep Valekar, Ira S. Buckner
A tabletability classification system has been previously proposed to categorize the range of tabletability behaviors of binary mixtures.1,2 Although the proposed system has been applied in several subsequent studies, the causes of each behavior have not been explained. The main objectives of this study were to investigate why different mixtures exhibit different behaviors and identify the attributes of components that would display specific behaviors in mixtures. To this end, binary mixtures comprising individual components with varied compressibility and compactibility were characterized. The component properties and mixture behaviors were compared to identify trends in the data. It was found that by combining accurate models of the compressibility and compactibility of pure components, the tabletability behavior of their mixtures can be predicted both qualitatively and quantitatively. The mixtures of components with similar tabletability profiles displayed linear behavior. The pronounced differences in both compactibility and tabletability produced negative deviations, while pronounced differences in compressibility and compactibility resulted in positive deviations.
{"title":"Explaining the underlying causes of different tabletability classifications of binary mixtures","authors":"Pradeep Valekar, Ira S. Buckner","doi":"10.1016/j.xphs.2026.104154","DOIUrl":"10.1016/j.xphs.2026.104154","url":null,"abstract":"<div><div>A tabletability classification system has been previously proposed to categorize the range of tabletability behaviors of binary mixtures.<span><span><sup>1</sup></span></span><sup>,</sup><span><span><sup>2</sup></span></span> Although the proposed system has been applied in several subsequent studies, the causes of each behavior have not been explained. The main objectives of this study were to investigate why different mixtures exhibit different behaviors and identify the attributes of components that would display specific behaviors in mixtures. To this end, binary mixtures comprising individual components with varied compressibility and compactibility were characterized. The component properties and mixture behaviors were compared to identify trends in the data. It was found that by combining accurate models of the compressibility and compactibility of pure components, the tabletability behavior of their mixtures can be predicted both qualitatively and quantitatively. The mixtures of components with similar tabletability profiles displayed linear behavior. The pronounced differences in both compactibility and tabletability produced negative deviations, while pronounced differences in compressibility and compactibility resulted in positive deviations.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104154"},"PeriodicalIF":3.8,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1016/j.xphs.2026.104153
Zahraa Al-Tamimi , Mei Feng , Waleed Elballa , Sydney Houser , Michael J. Hageman
Despite significant advancements in peptide drug development, there is still a challenge in formulating and delivering peptide drugs orally. Current oral peptide drugs have very low bioavailability (<1%), which could be attributed, in part, to enzymatic instability, poor membrane permeability/flux, and the sequestration by intestinal colloids composed of bile acid and phospholipids that form bile acid-phospholipid mixed micelles (BAPMM). In this work, we examined the effect of perturbing the BAPMM with bile acid sequestrants (BAS) on the membrane flux and enzymatic stability of octreotide in vitro, and its potential impact on peptide absorption and bioavailability in vivo. Additionally, we tested the effect of adding cyclic E-cadherin peptide (ECP) permeation enhancers on the bioavailability of octreotide. The results suggest that using BAS decreases the bile acid levels and putatively disrupts the micellar structure, leading to a higher concentration of the free peptide to diffuse across the membrane. In vitro bile acid sequestration enhanced the overall peptide flux rate without compromising the improved enzymatic stability. Our in vivo data suggests that using the BAS, colestipol, did not have a significant impact on peptide absorption though. These results highlight the important role of BAPMM on bioaccessible drug concentration, as well as membrane permeation.
{"title":"The impact of bile acid sequestrants on octreotide absorption","authors":"Zahraa Al-Tamimi , Mei Feng , Waleed Elballa , Sydney Houser , Michael J. Hageman","doi":"10.1016/j.xphs.2026.104153","DOIUrl":"10.1016/j.xphs.2026.104153","url":null,"abstract":"<div><div>Despite significant advancements in peptide drug development, there is still a challenge in formulating and delivering peptide drugs orally. Current oral peptide drugs have very low bioavailability (<1%), which could be attributed, in part, to enzymatic instability, poor membrane permeability/flux, and the sequestration by intestinal colloids composed of bile acid and phospholipids that form bile acid-phospholipid mixed micelles (BAPMM). In this work, we examined the effect of perturbing the BAPMM with bile acid sequestrants (BAS) on the membrane flux and enzymatic stability of octreotide <em>in vitro</em>, and its potential impact on peptide absorption and bioavailability <em>in vivo</em>. Additionally, we tested the effect of adding cyclic E-cadherin peptide (ECP) permeation enhancers on the bioavailability of octreotide. The results suggest that using BAS decreases the bile acid levels and putatively disrupts the micellar structure, leading to a higher concentration of the free peptide to diffuse across the membrane. <em>In vitro</em> bile acid sequestration enhanced the overall peptide flux rate without compromising the improved enzymatic stability. Our <em>in vivo</em> data suggests that using the BAS, colestipol, did not have a significant impact on peptide absorption though. These results highlight the important role of BAPMM on bioaccessible drug concentration, as well as membrane permeation.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104153"},"PeriodicalIF":3.8,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-03DOI: 10.1016/j.xphs.2026.104152
Raja K. Rit, Venkataramasubramanian V., Deepika V., Pandiyaraj B., Umesh Waman Mali, Olivier Venier, Santoshkumar N. Patil
Prodrugs are inactive and bio-reversible derivatives of drugs or clinical candidates. Prodrugs and New Chemical Entities (NCEs) often do not show good bioavailability primarily due to poor solubility. One of the strategies to overcome this challenge is to use their salt forms. Conventional salt preparation techniques fail when applied to polar unstable prodrugs and NCEs. Herein, we have developed a simple efficient salt preparation technique using ion exchange resin chromatography. This technique involves the exchange of cations on sulfonic acid-based resin that could be applied successfully to prepare the salts of acidic prodrugs and NCEs. In this current work, phosphate/sulfate/carboxylate-prodrugs were prepared in the form of their inorganic (e.g. Na+, K+) and organic amine (e.g. erbumine, trizma, meglumine, arginine) salts with excellent control. The resin cartridge was reused for the preparation of different salts without any significant compromise in yields. Moreover, this protocol was employed to quickly switch the counterions for the pH-sensitive prodrugs, which is very useful in pharmaceutical development. This method is cost effective, operationally simple and presents a broad substrate scope. We wish this technique would help organic and pharmaceutical chemists to prepare various salt forms of prodrugs or NCEs in an efficient and controlled manner.
{"title":"Application of ion-exchange chromatographic technique using resins to prepare the salts of polar unstable prodrugs and new chemical entities (NCEs)","authors":"Raja K. Rit, Venkataramasubramanian V., Deepika V., Pandiyaraj B., Umesh Waman Mali, Olivier Venier, Santoshkumar N. Patil","doi":"10.1016/j.xphs.2026.104152","DOIUrl":"10.1016/j.xphs.2026.104152","url":null,"abstract":"<div><div>Prodrugs are inactive and bio-reversible derivatives of drugs or clinical candidates. Prodrugs and New Chemical Entities (NCEs) often do not show good bioavailability primarily due to poor solubility. One of the strategies to overcome this challenge is to use their salt forms. Conventional salt preparation techniques fail when applied to polar unstable prodrugs and NCEs. Herein, we have developed a simple efficient salt preparation technique using ion exchange resin chromatography. This technique involves the exchange of cations on sulfonic acid-based resin that could be applied successfully to prepare the salts of acidic prodrugs and NCEs. In this current work, phosphate/sulfate/carboxylate-prodrugs were prepared in the form of their inorganic (e.g. Na<sup>+</sup>, K<sup>+</sup>) and organic amine (e.g. erbumine, trizma, meglumine, arginine) salts with excellent control. The resin cartridge was reused for the preparation of different salts without any significant compromise in yields. Moreover, this protocol was employed to quickly switch the counterions for the pH-sensitive prodrugs, which is very useful in pharmaceutical development. This method is cost effective, operationally simple and presents a broad substrate scope. We wish this technique would help organic and pharmaceutical chemists to prepare various salt forms of prodrugs or NCEs in an efficient and controlled manner.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104152"},"PeriodicalIF":3.8,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.xphs.2025.104149
Richieline S. Cual, Tajmarah Ayyah M. Sandato, Mae Quenie T. Pontanar
Insulin, a pancreatic hormone regulating blood glucose, is available in forms of syringe, pen, or implants; however, these methods presented challenges related to skin adverse reactions and patient compliance. Oral insulin delivery has long been explored due to higher compliance and reduced costs. Similar to natural insulin secretion, but prone to GIT breakdown and low bioavailability. SNEDDS has been investigated to address these in protein formulations. This study formulated Insulin into SNEDDS with trimethyl chitosan and spray-dried for stability, then analyzed for properties and drug release. The study successfully prepared Insulin-TMC SNEDDS with a 36.17±4.02 s emulsification time, forming a Grade B nanoemulsion. Droplet sizes remained nanoscale (134.20–287.20 nm for liquid, 188.77–214.93 nm for solid), preserving characteristics post–spray drying. Stability was confirmed in TMC-free formulations, while TMC variants showed sedimentation over time. TMC-containing Solid-SNEDDS showed moisture content below 5 %, indicating good stability. Insulin release varied with pH—highest at pH 2.5 with 3 mg/mL TMC (105.48 % cumulative percent drug release), while lower releases were seen at pH 6.6 (61.73±1.38 %) and 7.0 (61.73±1.38 %) without TMC. The study supports TMC-based SNEDDS and spray drying as a potential method for oral insulin delivery.
{"title":"Preparation and characterization of oral insulin-trimethyl chitosan complex-loaded solid self-nanoemulsifying drug delivery systems (SNEDDS)","authors":"Richieline S. Cual, Tajmarah Ayyah M. Sandato, Mae Quenie T. Pontanar","doi":"10.1016/j.xphs.2025.104149","DOIUrl":"10.1016/j.xphs.2025.104149","url":null,"abstract":"<div><div>Insulin, a pancreatic hormone regulating blood glucose, is available in forms of syringe, pen, or implants; however, these methods presented challenges related to skin adverse reactions and patient compliance. Oral insulin delivery has long been explored due to higher compliance and reduced costs. Similar to natural insulin secretion, but prone to GIT breakdown and low bioavailability. SNEDDS has been investigated to address these in protein formulations. This study formulated Insulin into SNEDDS with trimethyl chitosan and spray-dried for stability, then analyzed for properties and drug release. The study successfully prepared Insulin-TMC SNEDDS with a 36.17±4.02 s emulsification time, forming a Grade B nanoemulsion. Droplet sizes remained nanoscale (134.20–287.20 nm for liquid, 188.77–214.93 nm for solid), preserving characteristics post–spray drying. Stability was confirmed in TMC-free formulations, while TMC variants showed sedimentation over time. TMC-containing Solid-SNEDDS showed moisture content below 5 %, indicating good stability. Insulin release varied with pH—highest at pH 2.5 with 3 mg/mL TMC (105.48 % cumulative percent drug release), while lower releases were seen at pH 6.6 (61.73±1.38 %) and 7.0 (61.73±1.38 %) without TMC. The study supports TMC-based SNEDDS and spray drying as a potential method for oral insulin delivery.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104149"},"PeriodicalIF":3.8,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-30DOI: 10.1016/j.xphs.2025.104151
Weronika Śliżewska , Filomena Martins , Rodrigo F.M. de Almeida , Joaquim T. Marquês
Tuberculosis is one of the most important causes of death in the world. The emergence and increased prominence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), non-susceptible to currently available therapies, has toughened the fight to eradicate this disease. This study focuses on further investigating the therapeutic potential of promising antitubercular compounds, namely, isoniazid (INH), and three INH derivatives, N'-decanoylisonicotinohydrazide (INH-C10), N'-(E)-(4-phenoxybenzylidene)isonicotinohydrazide (N34) and N’-(4-phenoxybenzyl)isonicotinohydrazide (N34red). INH-C10 and N34 have been selected due to their high selectivity index against the Mtb mutant bearing the primary mutation responsible for INH drug resistance. In opposition, N34red, which differs from N34 only in the saturation of the N′ = C bond, exhibits a poor selectivity index. Moreover, INH-C10 and N34 interact with human serum albumin and model lipid membranes mimicking the plasma membrane of human cells, showing their promising potential. In the current study, the interaction of these compounds with models of the lung surfactant (LS) and of the mycolic acid (MA)-enriched Mtb cell wall was assessed, in order to further explore their ability to interact with and cross the various biological barriers to be encountered on their way to the molecular target inside Mtb. We show that all the INH derivatives were able to interact with both the LS and the mycolic acid-enriched cell wall models. INH-C10 and N34 had a smaller impact than N34red on the pulmonary surfactant model. On the other hand, INH-C10 promoted the most extensive perturbation of the MA-enriched cell wall model, which correlates well with the previously shown ability of this compound to incorporate into and disturb gel-phase lipid bilayers. This indicates that INH-C10 may penetrate a MA rich barrier more easily, reaching higher intracellular levels, and increase its permeability. These traits contribute to explain the high antimicrobial activity of this derivative against the most common drug-resistant Mtb mutant.
{"title":"Interaction of isoniazid derivatives active against drug-resistant tuberculosis with models of the lung surfactant and of the Mycobacterium tuberculosis cell wall","authors":"Weronika Śliżewska , Filomena Martins , Rodrigo F.M. de Almeida , Joaquim T. Marquês","doi":"10.1016/j.xphs.2025.104151","DOIUrl":"10.1016/j.xphs.2025.104151","url":null,"abstract":"<div><div>Tuberculosis is one of the most important causes of death in the world. The emergence and increased prominence of multidrug-resistant strains of <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>), non-susceptible to currently available therapies, has toughened the fight to eradicate this disease. This study focuses on further investigating the therapeutic potential of promising antitubercular compounds, namely, isoniazid (INH), and three INH derivatives, <em>N</em>'-decanoylisonicotinohydrazide (INH-C10), <em>N</em>'-(<em>E</em>)-(4-phenoxybenzylidene)isonicotinohydrazide (N34) and <em>N</em>’-(4-phenoxybenzyl)isonicotinohydrazide (N34red). INH-C10 and N34 have been selected due to their high selectivity index against the <em>Mtb</em> mutant bearing the primary mutation responsible for INH drug resistance. In opposition, N34red, which differs from N34 only in the saturation of the <em>N</em>′ = C bond, exhibits a poor selectivity index. Moreover, INH-C10 and N34 interact with human serum albumin and model lipid membranes mimicking the plasma membrane of human cells, showing their promising potential. In the current study, the interaction of these compounds with models of the lung surfactant (LS) and of the mycolic acid (MA)-enriched <em>Mtb</em> cell wall was assessed, in order to further explore their ability to interact with and cross the various biological barriers to be encountered on their way to the molecular target inside <em>Mtb</em>. We show that all the INH derivatives were able to interact with both the LS and the mycolic acid-enriched cell wall models. INH-C10 and N34 had a smaller impact than N34red on the pulmonary surfactant model. On the other hand, INH-C10 promoted the most extensive perturbation of the MA-enriched cell wall model, which correlates well with the previously shown ability of this compound to incorporate into and disturb gel-phase lipid bilayers. This indicates that INH-C10 may penetrate a MA rich barrier more easily, reaching higher intracellular levels, and increase its permeability. These traits contribute to explain the high antimicrobial activity of this derivative against the most common drug-resistant <em>Mtb</em> mutant.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104151"},"PeriodicalIF":3.8,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recombinant adeno-associated virus (rAAV) is widely used as a gene delivery vector. Sedimentation velocity analytical ultracentrifugation (SV–AUC) is the gold standard for quantifying the ratio of full particles (FPs) to the sum of empty particles (EPs) and FPs (F/E ratio) of rAAVs. Here, we experimentally determined the molar extinction coefficients (ε) and mass extinction coefficients of highly purified FPs and EPs of AAV serotypes 2, 5, 6, 8, and 9 using SV–AUC with interference and multi-wavelength absorbance detection. At 230 nm, the difference in ε between EPs and FPs was the smallest, although the ε of FPs remained 1.2-fold higher than that of EPs. Expectedly, the differences in ε between FPs and EPs were almost identical across serotypes with the same genome length and increased linearly in a genome length-dependent manner, although both sets of ε differed across serotypes. Consequently, accurate quantification of F/E ratio requires the use of distinct ε values for EPs and FPs. The ε per base of single-stranded DNA was independent of serotype and genome length, allowing estimation of the ε of FPs from that of EPs. Coupling these ε values with SV–AUC enables the determination of absolute rAAV concentrations. This study provides practical guidance for accurate absorbance-based rAAV quantification.
{"title":"Experimental determination of extinction coefficients by sedimentation velocity analytical ultracentrifugation for accurate quantification of recombinant adeno-associated virus","authors":"Yuki Yamaguchi , Takahiro Maruno , Takaaki Kurinomaru , Risa Shibuya , Mitsuko Fukuhara , Yasuo Tsunaka , Susumu Uchiyama","doi":"10.1016/j.xphs.2025.104150","DOIUrl":"10.1016/j.xphs.2025.104150","url":null,"abstract":"<div><div>Recombinant adeno-associated virus (rAAV) is widely used as a gene delivery vector. Sedimentation velocity analytical ultracentrifugation (SV–AUC) is the gold standard for quantifying the ratio of full particles (FPs) to the sum of empty particles (EPs) and FPs (F/E ratio) of rAAVs. Here, we experimentally determined the molar extinction coefficients (<em>ε</em>) and mass extinction coefficients of highly purified FPs and EPs of AAV serotypes 2, 5, 6, 8, and 9 using SV–AUC with interference and multi-wavelength absorbance detection. At 230 nm, the difference in <em>ε</em> between EPs and FPs was the smallest, although the <em>ε</em> of FPs remained 1.2-fold higher than that of EPs. Expectedly, the differences in <em>ε</em> between FPs and EPs were almost identical across serotypes with the same genome length and increased linearly in a genome length-dependent manner, although both sets of <em>ε</em> differed across serotypes. Consequently, accurate quantification of F/E ratio requires the use of distinct <em>ε</em> values for EPs and FPs. The <em>ε</em> per base of single-stranded DNA was independent of serotype and genome length, allowing estimation of the <em>ε</em> of FPs from that of EPs. Coupling these <em>ε</em> values with SV–AUC enables the determination of absolute rAAV concentrations. This study provides practical guidance for accurate absorbance-based rAAV quantification.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104150"},"PeriodicalIF":3.8,"publicationDate":"2025-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-26DOI: 10.1016/j.xphs.2025.104148
Shun Takayama , Yukiko Nagai , Tomomi Sugiyama , Fumiyuki Ito , Jun Miyazaki
Light-sensitive pharmaceuticals are susceptible to alteration or degradation under ambient light conditions, such as sunlight or artificial lighting, requiring pharmacists and patients to prevent exposure of these drugs to light. However, the transition from fluorescent to light-emitting diode (LED) light has altered the ambient light characteristics within buildings. Dacarbazine, chemically known as 5-(3,3-dimethyl-1-triazen-1-yl)-1H-imidazole-4-carboxamide (DTIC), is a light-sensitive anticancer drug. Its photodegradation product, Diazo-IC (5-diazoimidazole-4-carboxamide) is known to cause vascular pain in patients during infusion. Utilizing UV/Vis spectroscopy, this study examines the photodegradation of DTIC in aqueous solution under fluorescent and light-emitting diode (LED) lighting conditions, which are both prevalent in contemporary buildings. Results indicate that DTIC remained stable when exposed to LED light, with no decomposition observed, whereas photodegradation occurred under fluorescent light. The residual ratio revealed that DTIC remained stable for 240 min under LED illumination, indicating that LED light exposure does not induce DTIC photodegradation. These findings suggest that the ongoing replacement of fluorescent lighting with LED in healthcare settings and patient residences may eliminate vascular pain associated with DTIC photodegradation in the near future.
{"title":"Photodegradation of dacarbazine irradiated by common lighting sources: An examination of the differences between light-emitting diode (LED) and fluorescent light","authors":"Shun Takayama , Yukiko Nagai , Tomomi Sugiyama , Fumiyuki Ito , Jun Miyazaki","doi":"10.1016/j.xphs.2025.104148","DOIUrl":"10.1016/j.xphs.2025.104148","url":null,"abstract":"<div><div>Light-sensitive pharmaceuticals are susceptible to alteration or degradation under ambient light conditions, such as sunlight or artificial lighting, requiring pharmacists and patients to prevent exposure of these drugs to light. However, the transition from fluorescent to light-emitting diode (LED) light has altered the ambient light characteristics within buildings. Dacarbazine, chemically known as 5-(3,3-dimethyl-1-triazen-1-yl)-1<em>H</em>-imidazole-4-carboxamide (DTIC), is a light-sensitive anticancer drug. Its photodegradation product, Diazo-IC (5-diazoimidazole-4-carboxamide) is known to cause vascular pain in patients during infusion. Utilizing UV/Vis spectroscopy, this study examines the photodegradation of DTIC in aqueous solution under fluorescent and light-emitting diode (LED) lighting conditions, which are both prevalent in contemporary buildings. Results indicate that DTIC remained stable when exposed to LED light, with no decomposition observed, whereas photodegradation occurred under fluorescent light. The residual ratio revealed that DTIC remained stable for 240 min under LED illumination, indicating that LED light exposure does not induce DTIC photodegradation. These findings suggest that the ongoing replacement of fluorescent lighting with LED in healthcare settings and patient residences may eliminate vascular pain associated with DTIC photodegradation in the near future.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104148"},"PeriodicalIF":3.8,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-25DOI: 10.1016/j.xphs.2025.104146
Masato Takahashi, Shintaro Sakamoto, Nao Sakamoto, Sora Nishimura, Seonho Hwang, Jihyun Kim, Masakiyo Hosokawa
Ester-based prodrugs are often prematurely hydrolyzed by intestinal carboxylesterases, leading to reduced bioavailability and potential gastrointestinal (GI) toxicity. To overcome this limitation, a series of diester, carbonate-linked ester, and carbamate-linked ester prodrugs were synthesized and evaluated using human liver microsomes (HLM), human intestinal microsomes (HIM), and recombinant carboxylesterases (CES1A1 and CES2A1). Under strongly acidic conditions (pH 1.2), all prodrugs remained highly stable (>98% remaining after 6 h). In human plasma, however, diester prodrugs showed relatively rapid degradation (approximately 50% remaining after 6 h), whereas carbonate- and carbamate-linked esters displayed enhanced stability. Diester and carbonate-linked ester prodrugs were hydrolyzed by both HLM and HIM, indicating non-selective activation. By contrast, several carbamate-linked ester prodrugs showed high HLM/HIM selectivity, with CES1A1/CES2A1 hydrolysis rate ratios exceeding 50. Docking simulations showed favorable active-site binding of carbamate-linked ester prodrugs to CES1A1 but not to CES2A1, supporting the selectivity of CES1A1. These findings suggest that carbamate-based prodrug strategies can be employed to improve intestinal stability and enable controlled systemic activation, potentially reducing off-target effects and enhancing oral drug delivery. This strategy may also be applicable to liver- or lung-targeted prodrug design.
{"title":"Design and synthesis of carbamate-linked ester prodrugs selectively activated by carboxylesterase 1 with enhanced stability against intestinal hydrolysis","authors":"Masato Takahashi, Shintaro Sakamoto, Nao Sakamoto, Sora Nishimura, Seonho Hwang, Jihyun Kim, Masakiyo Hosokawa","doi":"10.1016/j.xphs.2025.104146","DOIUrl":"10.1016/j.xphs.2025.104146","url":null,"abstract":"<div><div>Ester-based prodrugs are often prematurely hydrolyzed by intestinal carboxylesterases, leading to reduced bioavailability and potential gastrointestinal (GI) toxicity. To overcome this limitation, a series of diester, carbonate-linked ester, and carbamate-linked ester prodrugs were synthesized and evaluated using human liver microsomes (HLM), human intestinal microsomes (HIM), and recombinant carboxylesterases (CES1A1 and CES2A1). Under strongly acidic conditions (pH 1.2), all prodrugs remained highly stable (>98% remaining after 6 h). In human plasma, however, diester prodrugs showed relatively rapid degradation (approximately 50% remaining after 6 h), whereas carbonate- and carbamate-linked esters displayed enhanced stability. Diester and carbonate-linked ester prodrugs were hydrolyzed by both HLM and HIM, indicating non-selective activation. By contrast, several carbamate-linked ester prodrugs showed high HLM/HIM selectivity, with CES1A1/CES2A1 hydrolysis rate ratios exceeding 50. Docking simulations showed favorable active-site binding of carbamate-linked ester prodrugs to CES1A1 but not to CES2A1, supporting the selectivity of CES1A1. These findings suggest that carbamate-based prodrug strategies can be employed to improve intestinal stability and enable controlled systemic activation, potentially reducing off-target effects and enhancing oral drug delivery. This strategy may also be applicable to liver- or lung-targeted prodrug design.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104146"},"PeriodicalIF":3.8,"publicationDate":"2025-12-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145846798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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