Pub Date : 2026-01-10DOI: 10.1016/j.xphs.2026.104157
Bernhardt L. Trout , Steven J. Burcat , Rohan P. Kadambi , Lorenzo J. Stratta , Richard D. Braatz , Roberto Pisano , Alexander H. Slocum
Pharmaceutical lyophilization (vacuum freeze-drying) removes water from aqueous drug products to stabilize formulations. This work presents a continuous final-dose pharmaceutical lyophilizer that can integrate with continuous production chains, increasing process quality, speed, and flexibility. Performance is assessed by freeze-drying various model formulations, and the cakes produced showed no visual defects, low residual moisture, and no loss in bioactivity. Moreover, this system moves vials via magnetic levitation and includes process analytical technologies (PAT) to monitor the sublimation rate and temperature of every vial in the system, enabling the possibility of real time release and model-based feedback control to optimize drying conditions. The modular design of this continuous lyophilizer provides a direct link between laboratory and production-scale equipment, greatly simplifying the scale-up difficulty found in the traditional batch process.
{"title":"Continuous lyophilization of suspended vials with per-vial inline analytics","authors":"Bernhardt L. Trout , Steven J. Burcat , Rohan P. Kadambi , Lorenzo J. Stratta , Richard D. Braatz , Roberto Pisano , Alexander H. Slocum","doi":"10.1016/j.xphs.2026.104157","DOIUrl":"10.1016/j.xphs.2026.104157","url":null,"abstract":"<div><div>Pharmaceutical lyophilization (vacuum freeze-drying) removes water from aqueous drug products to stabilize formulations. This work presents a continuous final-dose pharmaceutical lyophilizer that can integrate with continuous production chains, increasing process quality, speed, and flexibility. Performance is assessed by freeze-drying various model formulations, and the cakes produced showed no visual defects, low residual moisture, and no loss in bioactivity. Moreover, this system moves vials via magnetic levitation and includes process analytical technologies (PAT) to monitor the sublimation rate and temperature of every vial in the system, enabling the possibility of real time release and model-based feedback control to optimize drying conditions. The modular design of this continuous lyophilizer provides a direct link between laboratory and production-scale equipment, greatly simplifying the scale-up difficulty found in the traditional batch process.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104157"},"PeriodicalIF":3.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959439","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 : 2026-01-10DOI: 10.1016/j.xphs.2026.104161
Praval Shah, Maria Fischer, Taylour Treadwell , Sandipan Sinha , Kai Zheng
Intravenous (IV) administration is a common delivery route for protein therapeutics, especially when used for oncology indications. Typically, multiple components, including IV bags with diluents and infusion sets, are used for IV administration, where proteins encounter various surfaces and materials, leading to potential physical and chemical degradations. Thus, it is important to evaluate the compatibility of the drug product with IV diluents, and IV administration sets to ensure product quality. In this study, when the compatibility of an IgG4 monoclonal antibody was assessed for two kinds of infusion sets after diluting in IV bags containing 0.9% sodium chloride, an increase in subvisible particles was observed post-infusion through one of the sets. Both infusion sets equipped with in-line PES filters with the same pore size (0.2 µm) and similar nominal filtration area (10 cm2), except for the shape of the filter (rectangular vs cylindrical). To understand the cause of increases in subvisible particles post infusion, a thorough assessment was conducted to evaluate the potential impact of infusion rate, infusion set tubing, in-line filter (particle shedding, location, contact surface area of the filter), and polysorbate 20 concentration in the drug product formulation. The results showed that the pore structure and contact surface area of the filter have an impact on surfactant adsorption which can lead to subvisible particle formation. The results from this study underscores the importance of conducting thorough in-use compatibility studies with different infusion materials during formulation development to identify an appropriate level of surfactant, which can mitigate the risk of subvisible particle formation during IV infusion.
{"title":"Evaluating the impact of in-line PES filters on subvisible particle formation during IV administration of IgG4 monoclonal antibody","authors":"Praval Shah, Maria Fischer, Taylour Treadwell , Sandipan Sinha , Kai Zheng","doi":"10.1016/j.xphs.2026.104161","DOIUrl":"10.1016/j.xphs.2026.104161","url":null,"abstract":"<div><div>Intravenous (IV) administration is a common delivery route for protein therapeutics, especially when used for oncology indications. Typically, multiple components, including IV bags with diluents and infusion sets, are used for IV administration, where proteins encounter various surfaces and materials, leading to potential physical and chemical degradations. Thus, it is important to evaluate the compatibility of the drug product with IV diluents, and IV administration sets to ensure product quality. In this study, when the compatibility of an IgG4 monoclonal antibody was assessed for two kinds of infusion sets after diluting in IV bags containing 0.9% sodium chloride, an increase in subvisible particles was observed post-infusion through one of the sets. Both infusion sets equipped with in-line PES filters with the same pore size (0.2 µm) and similar nominal filtration area (10 cm<sup>2</sup>), except for the shape of the filter (rectangular vs cylindrical). To understand the cause of increases in subvisible particles post infusion, a thorough assessment was conducted to evaluate the potential impact of infusion rate, infusion set tubing, in-line filter (particle shedding, location, contact surface area of the filter), and polysorbate 20 concentration in the drug product formulation. The results showed that the pore structure and contact surface area of the filter have an impact on surfactant adsorption which can lead to subvisible particle formation. The results from this study underscores the importance of conducting thorough in-use compatibility studies with different infusion materials during formulation development to identify an appropriate level of surfactant, which can mitigate the risk of subvisible particle formation during IV infusion.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104161"},"PeriodicalIF":3.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959484","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}
Peristaltic pumps are widely used in fill and finish operations for parenteral drugs, especially biologics. These pumps are believed to work as volumetric pumps and to deliver a constant flow rate. However, this is only true within a limited range of backpressure. In this article, we show that if the backpressure exceeds a certain threshold, which depends on the pump tuning, the flow decreases progressively until it completely vanishes at a certain backpressure. We demonstrate that this behavior may have practical consequences on the various operations, including the filtration of biologic solutions and the filling accuracy especially for viscous solutions.
{"title":"Characterization of peristaltic pumps and application to fill & finish operations: Part I","authors":"Mostafa Nakach , Lionel Bardet , Fabian Voll , Doriane Calvet , Jean-René Authelin","doi":"10.1016/j.xphs.2026.104162","DOIUrl":"10.1016/j.xphs.2026.104162","url":null,"abstract":"<div><div>Peristaltic pumps are widely used in fill and finish operations for parenteral drugs, especially biologics. These pumps are believed to work as volumetric pumps and to deliver a constant flow rate. However, this is only true within a limited range of backpressure. In this article, we show that if the backpressure exceeds a certain threshold, which depends on the pump tuning, the flow decreases progressively until it completely vanishes at a certain backpressure. We demonstrate that this behavior may have practical consequences on the various operations, including the filtration of biologic solutions and the filling accuracy especially for viscous solutions.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 2","pages":"Article 104162"},"PeriodicalIF":3.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959502","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 : 2026-01-10DOI: 10.1016/j.xphs.2026.104159
Elham Taherian , Mirjam Crul , Reza Nejadnik
The majority of monoclonal antibodies (mAbs) are administered through intravenous infusion, typically in hospitals. A shift towards home-based therapy, initially driven by the COVID-19 pandemic, has been underway in recent years. Elastomeric pumps are devices that can be used for home-based therapy. They have been used for analgesics and antibiotics but not for delicate APIs such as proteins. While there is interest in using elastomeric pumps for administration of mAbs, and a few reports indicate that some hospitals have already started using them, valid stability data are lacking. This study aimed to investigate the stability of two marketed antibodies, Erbitux (cetuximab) and Herzuma (trastuzumab), during infusion using an elastomeric pump. High-performance size exclusion chromatography (HPSEC), flow imaging microscopy (FIM), dynamic light scattering (DLS), UV-VIS spectroscopy, and nanoparticle tracking analysis (NTA) were employed to assess subvisible particles and aggregation. Results show high stability and no degradation in form of aggregation in HPSEC. FIM data revealed that particle counts were the same before and after infusion using the pump. DLS and NTA data exhibited uniform particle sizes across samples, suggesting undetectable aggregation. Overall, findings support the technical feasibility of utilizing this combination of elastomeric pump and conditions for administration of cetuximab and trastuzumab, providing valuable insights into maintaining product stability outside traditional healthcare settings.
{"title":"Stability of therapeutic monoclonal antibodies during infusion with elastomeric pumps intended for home-based therapy","authors":"Elham Taherian , Mirjam Crul , Reza Nejadnik","doi":"10.1016/j.xphs.2026.104159","DOIUrl":"10.1016/j.xphs.2026.104159","url":null,"abstract":"<div><div>The majority of monoclonal antibodies (mAbs) are administered through intravenous infusion, typically in hospitals. A shift towards home-based therapy, initially driven by the COVID-19 pandemic, has been underway in recent years. Elastomeric pumps are devices that can be used for home-based therapy. They have been used for analgesics and antibiotics but not for delicate APIs such as proteins. While there is interest in using elastomeric pumps for administration of mAbs, and a few reports indicate that some hospitals have already started using them, valid stability data are lacking. This study aimed to investigate the stability of two marketed antibodies, Erbitux (cetuximab) and Herzuma (trastuzumab), during infusion using an elastomeric pump. High-performance size exclusion chromatography (HPSEC), flow imaging microscopy (FIM), dynamic light scattering (DLS), UV-VIS spectroscopy, and nanoparticle tracking analysis (NTA) were employed to assess subvisible particles and aggregation. Results show high stability and no degradation in form of aggregation in HPSEC. FIM data revealed that particle counts were the same before and after infusion using the pump. DLS and NTA data exhibited uniform particle sizes across samples, suggesting undetectable aggregation. Overall, findings support the technical feasibility of utilizing this combination of elastomeric pump and conditions for administration of cetuximab and trastuzumab, providing valuable insights into maintaining product stability outside traditional healthcare settings.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104159"},"PeriodicalIF":3.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959593","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}
In vaccine therapy, there is a growing interest in novel immunostimulatory adjuvants derived from food products or dietary supplements with safe profiles. Pavlova is a microalga commonly used as a dietary supplement. Owing to its immune-activating potency and safety profiles, Pavlova offers novel possibilities as an immunostimulatory adjuvant. However, precise control of their proliferation profile and subsequent immune activation when administered to the host is difficult, limiting their practicality as adjuvants. Extracellular vesicles (EVs) are cell-derived nanoparticles containing nucleic acids and proteins. EVs exhibit biological activity without proliferating, indicating their potential in medical applications as novel cell-free materials. However, information on EVs secreted by microalgae, including Pavlova, is limited. In this study, we characterized the EVs from Pavlova as an immunostimulatory adjuvant. Heated Pavlova-derived EVs (hP-EVs) and non-heated Pavlova-derived EVs (n-hP-EVs) were purified from their culture supernatants, with heated Pavlova secreting larger amounts of EVs. These EVs exhibited a particle size of approximately 130–170 nm and a negatively-charged zeta potential. RAW264.7 macrophage cells more actively took up n-hP-EVs than hP-EVs via endocytosis. As an adjuvant activity, n-hP-EVs potently increased the production of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are indicators of enhanced innate immune response. Moreover, the effect of the storage temperature on the particle size of n-hP-EVs was small, maintaining their ability to activate innate immune responses. Thus, n-hP-EVs demonstrate attractive characteristics for use as novel cell-derived immunostimulatory adjuvants.
在疫苗治疗方面，人们对从安全的食品或膳食补充剂中提取的新型免疫刺激佐剂越来越感兴趣。巴甫洛娃是一种微藻，通常用作膳食补充剂。由于其免疫激活效力和安全性，巴甫洛娃作为免疫刺激佐剂提供了新的可能性。然而，当给药给宿主时，精确控制它们的增殖特征和随后的免疫激活是困难的，限制了它们作为佐剂的实用性。细胞外囊泡（EVs）是细胞衍生的含有核酸和蛋白质的纳米颗粒。电动汽车表现出不增殖的生物活性，表明其作为新型无细胞材料在医学上的应用潜力。然而，关于微藻（包括Pavlova）分泌的电动汽车的信息有限。在本研究中，我们将来自Pavlova的ev定性为免疫刺激佐剂。加热的帕夫洛娃衍生ev （hp - ev）和未加热的帕夫洛娃衍生ev （n- hp - ev）从培养上清中纯化，加热的帕夫洛娃分泌更多的ev。这些电动汽车的粒径约为130-170 nm，具有带负电的zeta电位。RAW264.7巨噬细胞通过内吞作用对n- hp - ev的吸收比hp - ev更积极。作为一种佐剂活性，n- hp - ev可显著增加炎性细胞因子肿瘤坏死因子-α (TNF-α)和白细胞介素-6 （IL-6）的产生，这是增强先天免疫应答的指标。此外，储存温度对n- hp - ev颗粒大小的影响很小，保持了它们激活先天免疫反应的能力。因此，n- hp - ev表现出作为新型细胞源性免疫刺激佐剂的有吸引力的特性。
{"title":"Extracellular vesicles from microalgae Pavlova in non-heated condition potently enhance innate immune response as a novel cell-derived immunostimulatory adjuvant","authors":"Masaki Morishita , Kotaro Yamada , Toshio Taira , Ken Nakahara , Tomonori Waku , Kotone Minato , Ken-ichi Ogawara","doi":"10.1016/j.xphs.2026.104158","DOIUrl":"10.1016/j.xphs.2026.104158","url":null,"abstract":"<div><div>In vaccine therapy, there is a growing interest in novel immunostimulatory adjuvants derived from food products or dietary supplements with safe profiles. <em>Pavlova</em> is a microalga commonly used as a dietary supplement. Owing to its immune-activating potency and safety profiles, <em>Pavlova</em> offers novel possibilities as an immunostimulatory adjuvant. However, precise control of their proliferation profile and subsequent immune activation when administered to the host is difficult, limiting their practicality as adjuvants. Extracellular vesicles (EVs) are cell-derived nanoparticles containing nucleic acids and proteins. EVs exhibit biological activity without proliferating, indicating their potential in medical applications as novel cell-free materials. However, information on EVs secreted by microalgae, including <em>Pavlova</em>, is limited. In this study, we characterized the EVs from <em>Pavlova</em> as an immunostimulatory adjuvant. Heated <em>Pavlova</em>-derived EVs (hP-EVs) and non-heated <em>Pavlova</em>-derived EVs (n-hP-EVs) were purified from their culture supernatants, with heated <em>Pavlova</em> secreting larger amounts of EVs. These EVs exhibited a particle size of approximately 130–170 nm and a negatively-charged zeta potential. RAW264.7 macrophage cells more actively took up n-hP-EVs than hP-EVs via endocytosis. As an adjuvant activity, n-hP-EVs potently increased the production of the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which are indicators of enhanced innate immune response. Moreover, the effect of the storage temperature on the particle size of n-hP-EVs was small, maintaining their ability to activate innate immune responses. Thus, n-hP-EVs demonstrate attractive characteristics for use as novel cell-derived immunostimulatory adjuvants.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"115 3","pages":"Article 104158"},"PeriodicalIF":3.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145959407","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 : 2026-01-08DOI: 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}
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