International Journal of Pharmaceutics最新文献_第7页

Rapid determination of the active pharmaceutical Ingredient (API) content of suspension formulations using Broadband acoustic resonance dissolution spectroscopy (BARDS)

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-03-04 DOI: 10.1016/j.ijpharm.2025.125433

Niamh O’Mahoney , Ewelina Chmielak , Dara Fitzpatrick

Oral suspension formulations are advantageous over other drug dosage methods due to ease of administration, swallowability and taste masking. A large market exists for this particular form of drug introduction, particularly among paediatric and geriatric patients. This paper highlights a proof of concept approach to an alternative quality control test for oral suspension formulations using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS measurements are based on reproducible changes in the compressibility of a solvent during the dispersion of a formulation, which is monitored acoustically via associated changes in the frequency of induced acoustic resonances. This study offers a new approach to tracking the loading of oral suspension formulations. Suspension formulations containing various Active Pharmaceutical Ingredients (APIs) and excipients were investigated to examine the effect of API dosage and formulation on their overall dissolution. The data shows oral suspension formulations have an intrinsic acoustic signature specific to their manufacturing and formulation composition. It was also found that the level of API present determines the acoustic response. BARDS represents a possible future surrogate for In-Process Control (IPC) testing as a Process Analytical Technology (PAT) method. It also offers an alternative approach to assessing patient compliance and for determining drug precipitation. This study represents a greener, cost-effective, and time-efficient product testing method with no requirement for organic solvents or high-end instrumentation.

{"title":"Rapid determination of the active pharmaceutical Ingredient (API) content of suspension formulations using Broadband acoustic resonance dissolution spectroscopy (BARDS)","authors":"Niamh O’Mahoney , Ewelina Chmielak , Dara Fitzpatrick","doi":"10.1016/j.ijpharm.2025.125433","DOIUrl":"10.1016/j.ijpharm.2025.125433","url":null,"abstract":"<div><div>Oral suspension formulations are advantageous over other drug dosage methods due to ease of administration, swallowability and taste masking. A large market exists for this particular form of drug introduction, particularly among paediatric and geriatric patients. This paper highlights a proof of concept approach to an alternative quality control test for oral suspension formulations using Broadband Acoustic Resonance Dissolution Spectroscopy (BARDS). BARDS measurements are based on reproducible changes in the compressibility of a solvent during the dispersion of a formulation, which is monitored acoustically via associated changes in the frequency of induced acoustic resonances. This study offers a new approach to tracking the loading of oral suspension formulations. Suspension formulations containing various Active Pharmaceutical Ingredients (APIs) and excipients were investigated to examine the effect of API dosage and formulation on their overall dissolution. The data shows oral suspension formulations have an intrinsic acoustic signature specific to their manufacturing and formulation composition. It was also found that the level of API present determines the acoustic response. BARDS represents a possible future surrogate for In-Process Control (IPC) testing as a Process Analytical Technology (PAT) method. It also offers an alternative approach to assessing patient compliance and for determining drug precipitation. This study represents a greener, cost-effective, and time-efficient product testing method with no requirement for organic solvents or high-end instrumentation.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125433"},"PeriodicalIF":5.3,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143572823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Taste-masking mechanism of brivaracetam oral solution using cyclodextrin and sodium carboxymethyl cellulose.

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-03-03 DOI: 10.1016/j.ijpharm.2025.125368

Conghui Li, Junlin Yuan, Hui Zhang, Nan Liu, Zengming Wang, Aiping Zheng, Xiaochen Bo

Brivaracetam is a novel antiepileptic medication that can be indicated for the management of epilepsy in pediatric patients over one month old. To facilitate its administration to children, an oral solution is the most suitable option. However, the inherently bitter taste of brivaracetam poses a challenge in terms of palatability, necessitating the development of a taste masking strategy for the solution. In this study, a palatable brivaracetam oral solution was prepared by meticulously screening various taste masking techniques. Then the interaction relationship between brivaracetam and pivotal excipients (sodium carboxymethyl cellulose (CMC-Na) and 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD)) within the optimized formulation was investigated by molecular dynamics simulations. It turned out that brivaracetam did not encapsulate within HP-β-CD, but instead forms a robust association through hydrogen bonding and π-stacking interactions, facilitated by the presence of CMC-Na. Further exploration through molecular docking elucidated that the optimized formulation effectively masks the bitter taste by diminishing the binding affinity of brivaracetam to bitter taste receptors. In summary, this study achieved taste masking of brivaracetam under solution conditions by investigated the interactions of brivaracetam and key excipient interactions as well as the mechanisms of taste masking of optimized formulations, providing valuable insights for similar pharmaceutical applications.

{"title":"Taste-masking mechanism of brivaracetam oral solution using cyclodextrin and sodium carboxymethyl cellulose.","authors":"Conghui Li, Junlin Yuan, Hui Zhang, Nan Liu, Zengming Wang, Aiping Zheng, Xiaochen Bo","doi":"10.1016/j.ijpharm.2025.125368","DOIUrl":"https://doi.org/10.1016/j.ijpharm.2025.125368","url":null,"abstract":"<p><p>Brivaracetam is a novel antiepileptic medication that can be indicated for the management of epilepsy in pediatric patients over one month old. To facilitate its administration to children, an oral solution is the most suitable option. However, the inherently bitter taste of brivaracetam poses a challenge in terms of palatability, necessitating the development of a taste masking strategy for the solution. In this study, a palatable brivaracetam oral solution was prepared by meticulously screening various taste masking techniques. Then the interaction relationship between brivaracetam and pivotal excipients (sodium carboxymethyl cellulose (CMC-Na) and 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD)) within the optimized formulation was investigated by molecular dynamics simulations. It turned out that brivaracetam did not encapsulate within HP-β-CD, but instead forms a robust association through hydrogen bonding and π-stacking interactions, facilitated by the presence of CMC-Na. Further exploration through molecular docking elucidated that the optimized formulation effectively masks the bitter taste by diminishing the binding affinity of brivaracetam to bitter taste receptors. In summary, this study achieved taste masking of brivaracetam under solution conditions by investigated the interactions of brivaracetam and key excipient interactions as well as the mechanisms of taste masking of optimized formulations, providing valuable insights for similar pharmaceutical applications.</p>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":" ","pages":"125368"},"PeriodicalIF":5.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dextran sulfate-coated curcumin nanocrystals for the treatment of DSS-induced ulcerative colitis in mice

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-03-03 DOI: 10.1016/j.ijpharm.2025.125428

Yunmei Li , Huilin Ma , Huan Shi , Biaobiao Wang , Desheng Li , He Tian , Xifan Mei , Chao Wu

Ulcerative colitis is an inflammatory disease that primarily involves intestinal inflammation and epithelial damage. The nano-targeted drug delivery system delivers drugs to the disease site, exerting effects such as inhibiting inflammatory response and reducing reactive oxygen species expression, thereby promoting recovery from ulcerative colitis. In this experiment, dextran sulfate-coated curcumin nanocrystals (NBD) were prepared for the oral treatment of ulcerative colitis (UC). NBD not only significantly enhances the water solubility and stability of curcumin but also possesses the ability of sustained release and targeting inflammatory macrophages. The sustained release effect of NBD was demonstrated by in vitro release experiments. In simulated gastric fluid, the cumulative release amount of NBD at 2 h was 21.99 ± 1.93 %, while in simulated colonic fluid, the cumulative release amount of NBD at 12 h was 84.98 ± 2.02 %. The ability of NBD to target inflammatory macrophages was verified through the transwell system, rat one-way intestinal perfusion experiment and in vivo imaging system. The in vitro and in vivo (mice) anti-inflammatory and antioxidant capacities of NBD were validated using immunofluorescence experiment, ELISA kits and reactive oxygen species-related detection kits. The results indicated that NBD could reduce inflammatory responses, promote macrophage polarization and inhibit oxidative stress. In addition, the therapeutic effect of NBD was further confirmed in this experiment by the clostridium perfringens-induced necrotizing enteritis model in chickens. In conclusion, NBD might be a potential pharmaceutical preparation for the treatment of UC.

{"title":"Dextran sulfate-coated curcumin nanocrystals for the treatment of DSS-induced ulcerative colitis in mice","authors":"Yunmei Li , Huilin Ma , Huan Shi , Biaobiao Wang , Desheng Li , He Tian , Xifan Mei , Chao Wu","doi":"10.1016/j.ijpharm.2025.125428","DOIUrl":"10.1016/j.ijpharm.2025.125428","url":null,"abstract":"<div><div>Ulcerative colitis is an inflammatory disease that primarily involves intestinal inflammation and epithelial damage. The nano-targeted drug delivery system delivers drugs to the disease site, exerting effects such as inhibiting inflammatory response and reducing reactive oxygen species expression, thereby promoting recovery from ulcerative colitis. In this experiment, dextran sulfate-coated curcumin nanocrystals (NBD) were prepared for the oral treatment of ulcerative colitis (UC). NBD not only significantly enhances the water solubility and stability of curcumin but also possesses the ability of sustained release and targeting inflammatory macrophages. The sustained release effect of NBD was demonstrated by in vitro release experiments. In simulated gastric fluid, the cumulative release amount of NBD at 2 h was 21.99 ± 1.93 %, while in simulated colonic fluid, the cumulative release amount of NBD at 12 h was 84.98 ± 2.02 %. The ability of NBD to target inflammatory macrophages was verified through the transwell system, rat one-way intestinal perfusion experiment and in vivo imaging system. The in vitro and in vivo (mice) anti-inflammatory and antioxidant capacities of NBD were validated using immunofluorescence experiment, ELISA kits and reactive oxygen species-related detection kits. The results indicated that NBD could reduce inflammatory responses, promote macrophage polarization and inhibit oxidative stress. In addition, the therapeutic effect of NBD was further confirmed in this experiment by the clostridium perfringens-induced necrotizing enteritis model in chickens. In conclusion, NBD might be a potential pharmaceutical preparation for the treatment of UC.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125428"},"PeriodicalIF":5.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of hydrogen bonding and water clusters in deamidation of peptide in glycerol-water solutions

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-03-02 DOI: 10.1016/j.ijpharm.2025.125420

Tapiwa Chiura , Dana Filoti , Markus Hollman , Christian Schöneich , Shaoxin Feng , Evgenyi Shalaev

The study is part of investigations on relationships between water content, structure, and rates of chemical reactions in amorphous systems. This paper reports Asn deamidation of a hexapeptide in an amorphous liquid matrix, glycerol with water concentration of 1 to 30 wt%, at 50 °C. Using an amorphous liquid system allows focusing on the chemical and structural features of water effects, by minimizing the “molecular mobility” aspect. High-performance liquid chromatography (HPLC) is used to quantify both the loss of the parent compound and the accumulation of the cyclic succinimide intermediate and the hydrolysis products, Asp and iso-Asp. The rate constants for succinimide formation (k₁) and succinimide hydrolysis (k₂ and k₃) are determined by fitting the HPLC data to specific kinetic models. The apparent pH of the solutions is confirmed to be independent of water content by using two orthogonal approaches. The experimental studies are complemented by molecular dynamics (MD) simulations of the hydrogen-bonding network around the Asn. This work reveals two water-content regions with distinct effects on deamidation. The first region shows a nearly constant k₁ for water concentrations up to 8 wt%, whereas a significant increase in k₁ with increased water content is observed in the second region above 12 wt% water. The water content threshold for the deamidation rate coincides with the spectroscopically determined thresholds for hydrogen bonding and water clustering in glycerol/water mixtures, as reported previously by a range of techniques including Raman spectroscopy. The study highlights relevance of hydrogen bonding and water clustering pattern for chemical processes including deamidation, and provides a basis for follow-up studies on the role of amorphous structure in deamidation in amorphous freeze-dried peptide and protein formulations.

{"title":"Role of hydrogen bonding and water clusters in deamidation of peptide in glycerol-water solutions","authors":"Tapiwa Chiura , Dana Filoti , Markus Hollman , Christian Schöneich , Shaoxin Feng , Evgenyi Shalaev","doi":"10.1016/j.ijpharm.2025.125420","DOIUrl":"10.1016/j.ijpharm.2025.125420","url":null,"abstract":"<div><div>The study is part of investigations on relationships between water content, structure, and rates of chemical reactions in amorphous systems. This paper reports Asn deamidation of a hexapeptide in an amorphous liquid matrix, glycerol with water concentration of 1 to 30 wt%, at 50 °C. Using an amorphous liquid system allows focusing on the chemical and structural features of water effects, by minimizing the “molecular mobility” aspect. High-performance liquid chromatography (HPLC) is used to quantify both the loss of the parent compound and the accumulation of the cyclic succinimide intermediate and the hydrolysis products, Asp and <em>iso</em>-Asp. The rate constants for succinimide formation (<em>k</em><sub>1</sub>) and succinimide hydrolysis (<em>k</em><sub>2</sub> and <em>k</em><sub>3</sub>) are determined by fitting the HPLC data to specific kinetic models. The apparent pH of the solutions is confirmed to be independent of water content by using two orthogonal approaches. The experimental studies are complemented by molecular dynamics (MD) simulations of the hydrogen-bonding network around the Asn. This work reveals two water-content regions with distinct effects on deamidation. The first region shows a nearly constant <em>k</em><sub>1</sub> for water concentrations up to 8 wt%, whereas a significant increase in <em>k</em><sub>1</sub> with increased water content is observed in the second region above 12 wt% water. The water content threshold for the deamidation rate coincides with the spectroscopically determined thresholds for hydrogen bonding and water clustering in glycerol/water mixtures, as reported previously by a range of techniques including Raman spectroscopy. The study highlights relevance of hydrogen bonding and water clustering pattern for chemical processes including deamidation, and provides a basis for follow-up studies on the role of amorphous structure in deamidation in amorphous freeze-dried peptide and protein formulations.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125420"},"PeriodicalIF":5.3,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GB05, a safe and effective IFNα1b inhalation solution for treating respiratory syncytial virus infection

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-03-02 DOI: 10.1016/j.ijpharm.2025.125426

Wenjun Zhang, Jingan Yang, Meiqi Hao, Xinrong Zhou, Kaiqing Sun, Lijun Yang, Bo Wang, Hengxin Peng, Yi Yu, Qiongying You, Huiming Li, Suofu Qin

Human respiratory syncytial virus (HRSV) infection is linked to significant morbidity and mortality in infants and young children worldwide, yet no effective treatment is available. Interferon α (IFNα), a major subtype among the IFN family, has demonstrated antiviral effects by activating the human immune system. Aerosol inhalation is a way of IFN administration that can enhance efficacy while decreasing serum IFNα concentrations and systemic exposure, thereby minimizing the risk of systemic toxicity. However, at present, human interferon α1b (IFNα1b) injection solution is used off-label for inhalation, raising safety concerns for infants. Additionally, natural IFNα1b contains a free sulfhydryl group from cysteine residue, increasing the risk of structural instability. Human serum albumin (HSA), an excipient in IFNα1b formulations, may pose safety risks to infants. To address these concerns, we developed GB05-human IFNα1b inhalation solution with optimized molecular design, expression system and formulation. First, GB05 protein was expressed in the periplasmic space to achieve easier purification. GB05 was engineered with a C86S mutation to prevent the formation of intermolecular disulfide bonds. Furthermore, GB05 was formulated according to regulations for inhalation solution, with a minimal HSA of 0.1 %, to ensure safety while preserving biological activity and stability. Plasma concentrations of GB05 following nebulization in cynomolgus macaques were significantly lower than those in the lungs, suggesting a reduced risk of systemic adverse events. Finally, GB05 showed good efficacy against HRSV infection in vitro and in vivo. In summary, GB05 is the first reported IFN inhalation solution manufactured in compliance with regulatory standards, to our knowledge, exhibiting safety and efficacy due to effectively local delivery. GB05 will fill the gap in the treatment of HRSV infection.

{"title":"GB05, a safe and effective IFNα1b inhalation solution for treating respiratory syncytial virus infection","authors":"Wenjun Zhang, Jingan Yang, Meiqi Hao, Xinrong Zhou, Kaiqing Sun, Lijun Yang, Bo Wang, Hengxin Peng, Yi Yu, Qiongying You, Huiming Li, Suofu Qin","doi":"10.1016/j.ijpharm.2025.125426","DOIUrl":"10.1016/j.ijpharm.2025.125426","url":null,"abstract":"<div><div>Human respiratory syncytial virus (HRSV) infection is linked to significant morbidity and mortality in infants and young children worldwide, yet no effective treatment is available. Interferon α (IFNα), a major subtype among the IFN family, has demonstrated antiviral effects by activating the human immune system. Aerosol inhalation is a way of IFN administration that can enhance efficacy while decreasing serum IFNα concentrations and systemic exposure, thereby minimizing the risk of systemic toxicity. However, at present, human interferon α1b (IFNα1b) injection solution is used off-label for inhalation, raising safety concerns for infants. Additionally, natural IFNα1b contains a free sulfhydryl group from cysteine residue, increasing the risk of structural instability. Human serum albumin (HSA), an excipient in IFNα1b formulations, may pose safety risks to infants. To address these concerns, we developed GB05-human IFNα1b inhalation solution with optimized molecular design, expression system and formulation. First, GB05 protein was expressed in the periplasmic space to achieve easier purification. GB05 was engineered with a C86S mutation to prevent the formation of intermolecular disulfide bonds. Furthermore, GB05 was formulated according to regulations for inhalation solution, with a minimal HSA of 0.1 %, to ensure safety while preserving biological activity and stability. Plasma concentrations of GB05 following nebulization in cynomolgus macaques were significantly lower than those in the lungs, suggesting a reduced risk of systemic adverse events. Finally, GB05 showed good efficacy against HRSV infection <em>in vitro</em> and <em>in vivo.</em> In summary, GB05 is the first reported IFN inhalation solution manufactured in compliance with regulatory standards, to our knowledge, exhibiting safety and efficacy due to effectively local delivery. GB05 will fill the gap in the treatment of HRSV infection.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"673 ","pages":"Article 125426"},"PeriodicalIF":5.3,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evaluation of Calibration Burden for Monitoring of a Pharmaceutical Continuous Manufacturing Line using Near-Infrared Spectroscopy

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-03-02 DOI: 10.1016/j.ijpharm.2025.125419

Adam J. Rish , Cassidy Kurt , Joao Marcos Assis , Owen Rehrauer , Raúl S. Rangel-Gil , Edward Taylor

Process analytical technology (PAT) tools are an important part of process monitoring and control in pharmaceutical continuous manufacturing (CM) that help ensure product quality. However, there is hesitancy to adopt PAT due, in part, to the high start-up costs. A portion of the cost is the calibration burden associated with developing an appropriate multivariate data analysis (MVDA) method to extract the desired information from the spectral outputs of spectroscopic PAT tools. This has generated research interest in reduced calibration burden MVDA methods, such as iterative optimization technology (IOT) algorithms, as alternatives to conventional modeling approaches like partial least squares (PLS) regression. The goal of the presented research is to compare the calibration burden of three different MVDA methods (direct IOT, indirect IOT, PLS regression) at two drug loading levels (low and high) of pharmaceutical powder blends in a CM line. The blends were binary mixtures consisting of an active pharmaceutical ingredient and a coprocessed excipient blend. The coprocessed excipient blend was leveraged to reduce formulation complexity and streamline process development, benefiting the application of IOT algorithm. Calibration burden was assessed in terms of time, material, and financial costs. Utilizing a near-infrared spectroscopic PAT tool, it was found that MVDA methods that utilized IOT algorithms demonstrated a notably reduced calibration burden compared to the PLS models, while predicting blend potency with similar accuracy.

{"title":"Evaluation of Calibration Burden for Monitoring of a Pharmaceutical Continuous Manufacturing Line using Near-Infrared Spectroscopy","authors":"Adam J. Rish , Cassidy Kurt , Joao Marcos Assis , Owen Rehrauer , Raúl S. Rangel-Gil , Edward Taylor","doi":"10.1016/j.ijpharm.2025.125419","DOIUrl":"10.1016/j.ijpharm.2025.125419","url":null,"abstract":"<div><div>Process analytical technology (PAT) tools are an important part of process monitoring and control in pharmaceutical continuous manufacturing (CM) that help ensure product quality. However, there is hesitancy to adopt PAT due, in part, to the high start-up costs. A portion of the cost is the calibration burden associated with developing an appropriate multivariate data analysis (MVDA) method to extract the desired information from the spectral outputs of spectroscopic PAT tools. This has generated research interest in reduced calibration burden MVDA methods, such as iterative optimization technology (IOT) algorithms, as alternatives to conventional modeling approaches like partial least squares (PLS) regression. The goal of the presented research is to compare the calibration burden of three different MVDA methods (direct IOT, indirect IOT, PLS regression) at two drug loading levels (low and high) of pharmaceutical powder blends in a CM line. The blends were binary mixtures consisting of an active pharmaceutical ingredient and a coprocessed excipient blend. The coprocessed excipient blend was leveraged to reduce formulation complexity and streamline process development, benefiting the application of IOT algorithm. Calibration burden was assessed in terms of time, material, and financial costs. Utilizing a near-infrared spectroscopic PAT tool, it was found that MVDA methods that utilized IOT algorithms demonstrated a notably reduced calibration burden compared to the PLS models, while predicting blend potency with similar accuracy.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"673 ","pages":"Article 125419"},"PeriodicalIF":5.3,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143549813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Material-sparing degradation-kinetics model for thermolabile drug stability assessment during twin-screw melt granulation – Insights with gabapentin

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-03-02 DOI: 10.1016/j.ijpharm.2025.125421

Adwait Pradhan , Fengyuan Yang , Kapish Karan , Thomas Durig , Quyen Schwing , Brian Haight , Mark Costello , Mark Anderson , Feng Zhang

Twin-Screw Melt Granulation (TSMG) has emerged as a viable manufacturing process for continuous granulation due to short residence time (<1 min) while maintaining drug crystallinity. However, TSMG relies on heat and shear, making it challenging to process thermolabile drugs like gabapentin (GABA). The absence of a material-sparing model to evaluate TSMG feasibility for such drugs has limited adoption. This study aims to develop an empirical model based on the degradation kinetics of thermolabile drugs. In this work, GABA-HPC (Hydroxypropylcellulose) model system with gabalactam (GABA-L) as degradant was selected. In-process sampling using screw pullout indicated GABA degradation followed different rates in pre-granulation (before kneading zone) and granulation sections(kneading zone to discharge) due to the granule growth and attrition downstream of kneading zone. Leveraging DSC and ball-milling to simulate the stresses encountered during TSMG, a model was developed linking the GABA degradation kinetics of milled and unmilled blends to granule temperature and residence time, providing a comprehensive approach for calculating GABA-L. One key finding was that only 10–30 % GABA-L degraded in pre-granulation while majority of degradation occurred in the granulation section despite its shorter residence time (30–35 % of total) highlighting the importance of a deeper mechanistic understanding of TSMG. The combined model encapsulating both sections showed promise as predicted %GABA-L correlated well with actual %GABA-L after TSMG (R2 = 0.927) for various granulation runs conducted with 30° and 60° kneading block configurations. This work represents one of the first attempts at developing a material-sparing model for feasibility evaluation studies for TSMG of thermolabile drugs.

{"title":"Material-sparing degradation-kinetics model for thermolabile drug stability assessment during twin-screw melt granulation – Insights with gabapentin","authors":"Adwait Pradhan , Fengyuan Yang , Kapish Karan , Thomas Durig , Quyen Schwing , Brian Haight , Mark Costello , Mark Anderson , Feng Zhang","doi":"10.1016/j.ijpharm.2025.125421","DOIUrl":"10.1016/j.ijpharm.2025.125421","url":null,"abstract":"<div><div>Twin-Screw Melt Granulation (TSMG) has emerged as a viable manufacturing process for continuous granulation due to short residence time (<1 min) while maintaining drug crystallinity. However, TSMG relies on heat and shear, making it challenging to process thermolabile drugs like gabapentin (GABA). The absence of a material-sparing model to evaluate TSMG feasibility for such drugs has limited adoption. This study aims to develop an empirical model based on the degradation kinetics of thermolabile drugs. In this work, GABA-HPC (Hydroxypropylcellulose) model system with gabalactam (GABA-L) as degradant was selected. In-process sampling using screw pullout indicated GABA degradation followed different rates in pre-granulation (before kneading zone) and granulation sections(kneading zone to discharge) due to the granule growth and attrition downstream of kneading zone. Leveraging DSC and ball-milling to simulate the stresses encountered during TSMG, a model was developed linking the GABA degradation kinetics of milled and unmilled blends to granule temperature and residence time, providing a comprehensive approach for calculating GABA-L. One key finding was that only 10–30 % GABA-L degraded in pre-granulation while majority of degradation occurred in the granulation section despite its shorter residence time (30–35 % of total) highlighting the importance of a deeper mechanistic understanding of TSMG. The combined model encapsulating both sections showed promise as predicted %GABA-L correlated well with actual %GABA-L after TSMG (R2 = 0.927) for various granulation runs conducted with 30° and 60° kneading block configurations. This work represents one of the first attempts at developing a material-sparing model for feasibility evaluation studies for TSMG of thermolabile drugs.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125421"},"PeriodicalIF":5.3,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A comprehensive analytical model for predicting drug absorption in the olfactory region: Application to nose-to-brain delivery

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-03-01 DOI: 10.1016/j.ijpharm.2025.125392

Clément Rigaut , Laura Deruyver , Jonathan Goole , Pierre Lambert , Benoit Haut

Nose-to-brain drug delivery offers a promising route for administering pharmaceutical substances directly to the brain. However, this pathway faces significant challenges, such as mucociliary clearance and enzymatic activity in the nasal cavity, which limit drug absorption. Although several formulation strategies exist to enhance drug solubility, diffusion across the airway surface liquid, and protection from enzymatic degradation, there is a lack of tools to systematically evaluate which strategy is best suited for specific molecules. To address this, we developed an analytical model of the olfactory region that integrates drug dissolution, diffusion through the mucus and periciliary layers, advection by mucociliary clearance, and enzymatic degradation. This analytical model allows to estimate the fraction of a drug, formulated as a powder and deposited in the olfactory region, that is indeed dissolved in the mucus and absorbed by the cells, and to identify the most influential physicochemical properties in the absorption process. To demonstrate the model’s utility, we 3D-printed custom-made diffusion cells to measure experimentally the diffusion coefficients of caffeine, levodopa, and paliperidone palmitate, incorporating these values into our simulations. Based on these data, we predicted drug absorption levels and proposed strategies to optimise them. By applying the model to an existing formulation, we demonstrated that careful adjustments to a drug’s properties can significantly enhance the fraction absorbed in the olfactory region. Additionally, we explored how the site of drug deposition, influenced by the delivery device, impacts absorption by affecting residence time in the olfactory region. Overall, our analytical model serves as a valuable tool for the development of effective nose-to-brain formulations and the selection of optimal administration devices, streamlining the process and reducing the need for extensive in vitro and in vivo testing.

{"title":"A comprehensive analytical model for predicting drug absorption in the olfactory region: Application to nose-to-brain delivery","authors":"Clément Rigaut , Laura Deruyver , Jonathan Goole , Pierre Lambert , Benoit Haut","doi":"10.1016/j.ijpharm.2025.125392","DOIUrl":"10.1016/j.ijpharm.2025.125392","url":null,"abstract":"<div><div>Nose-to-brain drug delivery offers a promising route for administering pharmaceutical substances directly to the brain. However, this pathway faces significant challenges, such as mucociliary clearance and enzymatic activity in the nasal cavity, which limit drug absorption. Although several formulation strategies exist to enhance drug solubility, diffusion across the airway surface liquid, and protection from enzymatic degradation, there is a lack of tools to systematically evaluate which strategy is best suited for specific molecules. To address this, we developed an analytical model of the olfactory region that integrates drug dissolution, diffusion through the mucus and periciliary layers, advection by mucociliary clearance, and enzymatic degradation. This analytical model allows to estimate the fraction of a drug, formulated as a powder and deposited in the olfactory region, that is indeed dissolved in the mucus and absorbed by the cells, and to identify the most influential physicochemical properties in the absorption process. To demonstrate the model’s utility, we 3D-printed custom-made diffusion cells to measure experimentally the diffusion coefficients of caffeine, levodopa, and paliperidone palmitate, incorporating these values into our simulations. Based on these data, we predicted drug absorption levels and proposed strategies to optimise them. By applying the model to an existing formulation, we demonstrated that careful adjustments to a drug’s properties can significantly enhance the fraction absorbed in the olfactory region. Additionally, we explored how the site of drug deposition, influenced by the delivery device, impacts absorption by affecting residence time in the olfactory region. Overall, our analytical model serves as a valuable tool for the development of effective nose-to-brain formulations and the selection of optimal administration devices, streamlining the process and reducing the need for extensive in vitro and in vivo testing.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125392"},"PeriodicalIF":5.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mechanistic insights into drug supersaturation during lipid digestion in self-emulsifying drug delivery systems: A cryo-TEM and NMR study

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-03-01 DOI: 10.1016/j.ijpharm.2025.125425

Keisuke Ueda, Riku Uchiyama, Nao Kato, Kenjirou Higashi, Kunikazu Moribe

A self-emulsifying drug delivery system (SEDDS), composed of oil, surfactant, and co-surfactant, has been widely used to enhance the oral absorption of poorly water-soluble drugs. Upon oral administration, SEDDS spontaneously forms an emulsion upon contact with gastrointestinal fluids, thereby solubilizing the drug within oil droplets. Lipid digestion by lipase further facilitates the release of encapsulated drugs into the aqueous phase, generating drug supersaturation that can enhance absorption. In this study, morphological characterization at the nanometer scale using cryogenic transmission electron microscopy (Cryo-TEM) was combined with molecular-level characterization using NMR to provide a more quantitative and detailed understanding of the mechanism of drug supersaturation formation during lipid degradation. SEDDS formulations were prepared using Labrafac PG (PG), HCO-40 (HCO40), and polyethylene glycol 400, with naringenin (NAR) as a model drug. Cryo-TEM analysis revealed the transition of oil droplets into vesicles during lipid digestion in phosphate-buffered saline (PBS), whereas in fed-state simulated intestinal fluid (FeSSIF), vesicles did not form due to the solubilization of digested products by taurocholic acid (TCA)/lecithin micelles. ¹H NMR measurements of the emulsion quantitatively confirmed lipid digestion; in both PBS and FeSSIF, approximately 74 % of PG underwent lipase-mediated hydrolysis. NAR solubility measurements and permeation studies using a dialysis membrane demonstrated a reduced solubilization capacity and an increase in NAR supersaturation level during lipid digestion, particularly in FeSSIF, where TCA/lecithin micelles facilitated efficient NAR release into the aqueous phase. Conversely, vesicle retention in PBS limited NAR supersaturation. These findings highlight the importance of emulsion morphology changes in promoting drug release and supersaturation, thereby providing valuable insights for designing SEDDS formulations to enhance drug bioavailability.

{"title":"Mechanistic insights into drug supersaturation during lipid digestion in self-emulsifying drug delivery systems: A cryo-TEM and NMR study","authors":"Keisuke Ueda, Riku Uchiyama, Nao Kato, Kenjirou Higashi, Kunikazu Moribe","doi":"10.1016/j.ijpharm.2025.125425","DOIUrl":"10.1016/j.ijpharm.2025.125425","url":null,"abstract":"<div><div>A self-emulsifying drug delivery system (SEDDS), composed of oil, surfactant, and co-surfactant, has been widely used to enhance the oral absorption of poorly water-soluble drugs. Upon oral administration, SEDDS spontaneously forms an emulsion upon contact with gastrointestinal fluids, thereby solubilizing the drug within oil droplets. Lipid digestion by lipase further facilitates the release of encapsulated drugs into the aqueous phase, generating drug supersaturation that can enhance absorption. In this study, morphological characterization at the nanometer scale using cryogenic transmission electron microscopy (Cryo-TEM) was combined with molecular-level characterization using NMR to provide a more quantitative and detailed understanding of the mechanism of drug supersaturation formation during lipid degradation. SEDDS formulations were prepared using Labrafac PG (PG), HCO-40 (HCO40), and polyethylene glycol 400, with naringenin (NAR) as a model drug. Cryo-TEM analysis revealed the transition of oil droplets into vesicles during lipid digestion in phosphate-buffered saline (PBS), whereas in fed-state simulated intestinal fluid (FeSSIF), vesicles did not form due to the solubilization of digested products by taurocholic acid (TCA)/lecithin micelles. <sup>1</sup>H NMR measurements of the emulsion quantitatively confirmed lipid digestion; in both PBS and FeSSIF, approximately 74 % of PG underwent lipase-mediated hydrolysis. NAR solubility measurements and permeation studies using a dialysis membrane demonstrated a reduced solubilization capacity and an increase in NAR supersaturation level during lipid digestion, particularly in FeSSIF, where TCA/lecithin micelles facilitated efficient NAR release into the aqueous phase. Conversely, vesicle retention in PBS limited NAR supersaturation. These findings highlight the importance of emulsion morphology changes in promoting drug release and supersaturation, thereby providing valuable insights for designing SEDDS formulations to enhance drug bioavailability.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"674 ","pages":"Article 125425"},"PeriodicalIF":5.3,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143541947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Colon cancer-cell-specific drug delivery by gemcitabine conjugated with peptide chain targeting ENO1

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2025-02-28 DOI: 10.1016/j.ijpharm.2025.125402

Xiaoyu Hu , Jun Liu , Qingrong Wang , Qiongkun Hu , Hao Sun , Shi Wang , Yu Zhao , Liwei Gu , Jianying Shen , Qinghe Zhao , Feng Sui , Hai Ma

Gemcitabine, a chemotherapeutic agent widely approved for treating various cancers, faces significant clinical challenges, including drug resistance and poor tumor selectivity. To address the limitation of inadequate tumor targeting, a peptide chain was developed to specifically bind to colon cancer cells and conjugated to gemcitabine via aldehyde–amine condensation. This study aimed to exploit the oncogenic activity of the multifunctional protein α-Enolase (ENO1). The therapeutic efficacy of gemcitabine conjugated with the ENO1-targeting peptide (GCB-P) was evaluated through in vitro and in vivo experiments. Cytotoxicity assays and protein blotting analyses were performed on cell lines, including NCM-460, HCT116 and SW620. GCB-P exhibited significantly enhanced selectivity and potency against colon cancer cells compared to gemcitabine alone, with minimal cytotoxicity to normal colorectal cells. In addition, GCB-P demonstrated superior tumor-selective accumulation and release at the tumor site, as evidenced by in vivo metabolic analyses. These findings underscore the potential of GCB-P as an effective colon cancer treatment with reduced off-target toxicity. Furthermore, GCB-P displayed acid-responsive properties, facilitating precise delivery to tumor sites with the aid of homing peptides. These results highlight the promise of ENO1-targeted peptide modification for gemcitabine in developing targeted drug delivery systems for colon cancer.

{"title":"Colon cancer-cell-specific drug delivery by gemcitabine conjugated with peptide chain targeting ENO1","authors":"Xiaoyu Hu , Jun Liu , Qingrong Wang , Qiongkun Hu , Hao Sun , Shi Wang , Yu Zhao , Liwei Gu , Jianying Shen , Qinghe Zhao , Feng Sui , Hai Ma","doi":"10.1016/j.ijpharm.2025.125402","DOIUrl":"10.1016/j.ijpharm.2025.125402","url":null,"abstract":"<div><div>Gemcitabine, a chemotherapeutic agent widely approved for treating various cancers, faces significant clinical challenges, including drug resistance and poor tumor selectivity. To address the limitation of inadequate tumor targeting, a peptide chain was developed to specifically bind to colon cancer cells and conjugated to gemcitabine via aldehyde–amine condensation. This study aimed to exploit the oncogenic activity of the multifunctional protein α-Enolase (ENO1). The therapeutic efficacy of gemcitabine conjugated with the ENO1-targeting peptide (GCB-P) was evaluated through in vitro and in vivo experiments. Cytotoxicity assays and protein blotting analyses were performed on cell lines, including NCM-460, HCT116 and SW620. GCB-P exhibited significantly enhanced selectivity and potency against colon cancer cells compared to gemcitabine alone, with minimal cytotoxicity to normal colorectal cells. In addition, GCB-P demonstrated superior tumor-selective accumulation and release at the tumor site, as evidenced by in vivo metabolic analyses. These findings underscore the potential of GCB-P as an effective colon cancer treatment with reduced off-target toxicity. Furthermore, GCB-P displayed acid-responsive properties, facilitating precise delivery to tumor sites with the aid of homing peptides. These results highlight the promise of ENO1-targeted peptide modification for gemcitabine in developing targeted drug delivery systems for colon cancer.</div></div>","PeriodicalId":14187,"journal":{"name":"International Journal of Pharmaceutics","volume":"673 ","pages":"Article 125402"},"PeriodicalIF":5.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0