Frontiers in drug delivery最新文献_第10页

Evaluation and Selection of the Inhaler Device for Treprostinil Palmitil Inhalation Powder 棕榈氨酯吸入性粉剂吸入器的评价与选择

Frontiers in drug delivery Pub Date : 2022-04-06 DOI: 10.3389/fddev.2022.864922

H. Gauani, T. Baker, Zhili Li, V. Malinin, W. Perkins, E. Sullivan, D. Cipolla

{"title":"Evaluation and Selection of the Inhaler Device for Treprostinil Palmitil Inhalation Powder","authors":"H. Gauani, T. Baker, Zhili Li, V. Malinin, W. Perkins, E. Sullivan, D. Cipolla","doi":"10.3389/fddev.2022.864922","DOIUrl":"https://doi.org/10.3389/fddev.2022.864922","url":null,"abstract":"Treprostinil palmitil (TP) is a prodrug of treprostinil that has been formulated as an inhaled powder, termed TPIP, for evaluation in patients with pulmonary arterial hypertension. In these characterization studies we investigated the aerosol performance of TPIP in response to changes in capsule fill, device resistance, and inspiratory flow rate to enable selection of an inhaler for clinical use. Capsules containing 8, 16 or 32 mg of TPIP (80, 160, or 320 μg TP, respectively) were evaluated using four commercially-available, breath-actuated RS01 devices (Plastiape, S. p.A., Osnago, Italy) with low, medium, high or ultra-high inspiratory resistances, creating 12 different capsule and device configurations for evaluation. Aerosol characterization was performed using the next generation impactor at compendial conditions of 23°C and 35% relative humidity and a flow rate corresponding to a 4 kPa pressure drop. The aerosol mass median aerodynamic diameter, geometric standard deviation, fine particle fraction, emitted dose and fine particle dose (FPD) were calculated from the in vitro impactor data. The TP emitted dose at 4 kPa exceeded 75% for all 12 capsule and device configurations. The FPD, an estimate of the respirable dose, varied between 61.0 and 70.6% of the loaded TP dose for all four devices with the 8 and 16 mg TPIP capsule dose. For the 32 mg TPIP capsule dose, the FPD remained above 61.0% for the high and ultra-high resistance devices but decreased to 48.5 and 52.6% for the low and medium resistance devices, respectively. Based on this initial data, the high resistance device was selected for additional characterization studies at 40 and 80 L/min corresponding to pressure drops of 1.4 and 5.4 kPa. The FPD was relatively insensitive to changes in flow rate, providing an expectation of a consistent total lung dose of TP under scenarios simulating variability in how the device is used. Based on these findings, the high resistance device was chosen for further development in human clinical trials.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42372060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

The Cell-Penetrating Peptide Tat Facilitates Effective Internalization of PSD-95 Inhibitors Into Blood–Brain Barrier Endothelial Cells but less Efficient Permeation Across the Blood–Brain Barrier In Vitro and In Vivo 细胞穿透肽可促进PSD-95抑制剂有效内化进入血脑屏障内皮细胞，但在体外和体内通过血脑屏障的效率较低

Frontiers in drug delivery Pub Date : 2022-04-06 DOI: 10.3389/fddev.2022.854703

Emma Lisa Al Humaidan, Sidse Lund Pedersen, A. Burkhart, Charlotte L. M. Rasmussen, T. Moos, P. Fuchs, E. F. A. Fernandes, B. Ozgür, K. Strømgaard, A. Bach, B. Brodin, M. Kristensen

{"title":"The Cell-Penetrating Peptide Tat Facilitates Effective Internalization of PSD-95 Inhibitors Into Blood–Brain Barrier Endothelial Cells but less Efficient Permeation Across the Blood–Brain Barrier In Vitro and In Vivo","authors":"Emma Lisa Al Humaidan, Sidse Lund Pedersen, A. Burkhart, Charlotte L. M. Rasmussen, T. Moos, P. Fuchs, E. F. A. Fernandes, B. Ozgür, K. Strømgaard, A. Bach, B. Brodin, M. Kristensen","doi":"10.3389/fddev.2022.854703","DOIUrl":"https://doi.org/10.3389/fddev.2022.854703","url":null,"abstract":"Inhibition of the interaction between the scaffolding protein PSD-95 and the NMDA receptor has been shown to obstruct ischemic stroke-triggered excitotoxic reactions, leading to neuronal death. The peptides NR2B9c and N-dimer are inhibitors of this interaction. Delivery of the peptides to the brain is challenging due to the general low blood–brain barrier (BBB) permeability. NR2B9c and N-dimer have therefore been conjugated to the cell-penetrating peptide (CPP) Tat, to facilitate blood–brain barrier permeation. However, the BBB permeation of Tat-NR2B9c and Tat-N-dimer has not been fully elucidated. We recently demonstrated that the BBB permeation in vitro and in vivo was lowered upon conjugation of NR2B9c or N-dimer to Tat. In the present study, we aimed to further understand the impact of cargo conjugation to Tat with respect to interaction with and permeation across the BBB in vitro and in vivo. The peptides were labeled with the fluorophore TAMRA (T) and demonstrated efficient Tat-mediated uptake into BBB endothelial cells but differed in their degree of plasma membrane interaction and embedding (T-Tat-NR2B9c = T-Tat > T-Tat-N-dimer) as well as in their chemical stability (T-Tat-N-dimer = T-Tat > T-Tat-NR2B9c). The Tat conjugates all displayed a similar degree of self-association and/or plasma protein adsorption. T-Tat-NR2B9c and T-Tat affected the BBB integrity but not the permeation of the paracellular marker C14-mannitol. T-Tat-NR2B9c and T-Tat-N-dimer displayed less efficient permeation across an in vitro model representing the healthy BBB, when compared to T-Tat, and low BBB permeation in healthy rats.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44994981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Overcoming Blood-Brain Barrier Resistance: Implications for Extracellular Vesicle-Mediated Drug Brain Delivery 克服血脑屏障耐药性：细胞外囊泡介导的药物脑递送的意义

Frontiers in drug delivery Pub Date : 2022-03-24 DOI: 10.3389/fddev.2022.855017

Jean Paul Dardet, Nelson Serrano, I. András, M. Toborek

引用次数: 5

Suboptimal Inspiratory Flow Rates With Passive Dry Powder Inhalers: Big Issue or Overstated Problem? 被动干粉吸入器的次优吸入流量:大问题还是被夸大了?

Frontiers in drug delivery Pub Date : 2022-03-22 DOI: 10.3389/fddev.2022.855234

J. Weers

{"title":"Suboptimal Inspiratory Flow Rates With Passive Dry Powder Inhalers: Big Issue or Overstated Problem?","authors":"J. Weers","doi":"10.3389/fddev.2022.855234","DOIUrl":"https://doi.org/10.3389/fddev.2022.855234","url":null,"abstract":"The maximum inspiratory pressure (MIP) that a subject can achieve through the mouthpiece of a “passive” dry powder inhaler (DPI) is driven chiefly by their inspiratory muscle strength (Clark, 2015). Muscle strength increases with age, peaking at about age 25, plateauing until about age 40, after which it steadily decreases. Males achieve greater MIP values than females, and increases in disease severity may further reduce MIP. When using DPIs, patients rarely inhale with maximal effort, instead achieving peak inspiratory pressures (PIP) that are about 40–80% of their MIP (Clark, 2015 and references therein). Based on these observations, current industry guidance is that passive DPIs are inherently flow rate dependent, and that young children and elderly patients may not be able to achieve the PIP or peak inspiratory flow rates (PIFR) necessary to effectively fluidize and disperse dry powders, especially during acute exacerbations (Laube et al., 2011). For patients with COPD, it has been suggested that: “If the PIFR is less than 60 L min the patient may not achieve optimal clinical benefit (with inhaled bronchodilators), and a different delivery system such as a metered dose or soft mist inhaler or nebulized therapy should be considered” (Mahler, 2017). Based on results of multiple breathing studies in COPD patients, it was further suggested that between 19 and 78% of stable outpatients, and 32–47% of in-patients prior to discharge after admission for an exacerbation, have a suboptimal PIFR <60 L min (Mahler et al., 2013; Mahler, 2017; Mahler, 2020). More recently, Mahler has taken the argument one step further, suggesting that PIFR be used as a therapeutic biomarker to guide delivery system selection, while dropping the optimal flow rate for high resistance DPIs to 30 L min (Mahler and Halpin, 2021). This opinion reviews the available literature regarding flow rate dependence of inhaled bronchodilators when administered with passive DPIs for the treatment of asthma and COPD.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48389117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Formulation of Dry Powders for Inhalation Comprising High Doses of a Poorly Soluble Hydrophobic Drug 含有高剂量难溶疏水药物的吸入用干粉制剂

Frontiers in drug delivery Pub Date : 2022-03-15 DOI: 10.3389/fddev.2022.862336

T. Tarara, Danforth P Miller, Audrey E. Weers, Ariel R. Muliadi, J. Tso, A. Eliahu, J. Weers

引用次数: 6

Glioblastoma Vasculature: From its Critical Role in Tumor Survival to Relevant in Vitro Modelling 胶质母细胞瘤血管系统:从其在肿瘤存活中的关键作用到相关的体外建模

Frontiers in drug delivery Pub Date : 2022-02-17 DOI: 10.3389/fddev.2022.823412

Catarina C. Pacheco, Cláudia Martins, J. Monteiro, F. Baltazar, B. Costa, B. Sarmento

{"title":"Glioblastoma Vasculature: From its Critical Role in Tumor Survival to Relevant in Vitro Modelling","authors":"Catarina C. Pacheco, Cláudia Martins, J. Monteiro, F. Baltazar, B. Costa, B. Sarmento","doi":"10.3389/fddev.2022.823412","DOIUrl":"https://doi.org/10.3389/fddev.2022.823412","url":null,"abstract":"Biochemical and biophysical cues governing glioblastoma (GBM) progression are complex and dynamic. Tumor blood vessels, often recognized only by their transport functions, are more deeply involved in this process. Vessels are involved in tumor immune evasion, matrix alterations and stem cell stimulation, contributing for tumor treatment resistance and patients’ poor survival. Given blood vessel complex and dynamic nature, they are hardly represented in conventional GBM monolayered in vitro models. However, other in vitro approaches, such as three-dimensional (3D) models, incorporating extracellular matrix (ECM), malignant and stromal cells, and promoting their communication, can resemble neovascularization, growing blood vessels in a tumor-like microenvironment. These models mimic GBM physiological architecture and key biochemical and biophysical environments, allowing the investigation of the impact of vascularization in tumor progression. For researchers in neuro-oncology field, 3D vascularized GBM models are of great interest. They are promising tools to evaluate individual driven neovascularization and identify mediators involved in those processes. Moreover, they may be used to test potential anti-GBM therapies targeting blood vessels or influenced by them. This review will discuss the significance of blood vessels in GBM and review novel 3D pre-clinical vascular models.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42487929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Optimization and Characterization of a Liposomal Azithromycin Formulation for Alternative Macrophage Activation. 阿奇霉素脂质体替代巨噬细胞活化配方的优化与表征。

Frontiers in drug delivery Pub Date : 2022-01-01 Epub Date: 2022-07-05 DOI: 10.3389/fddev.2022.908709

Abdullah A Masud, Fahd M Alsharif, Jarrod W Creameans, Jasmine Perdeh, David J Feola, Vincent J Venditto

{"title":"Optimization and Characterization of a Liposomal Azithromycin Formulation for Alternative Macrophage Activation.","authors":"Abdullah A Masud, Fahd M Alsharif, Jarrod W Creameans, Jasmine Perdeh, David J Feola, Vincent J Venditto","doi":"10.3389/fddev.2022.908709","DOIUrl":"https://doi.org/10.3389/fddev.2022.908709","url":null,"abstract":"Liposomal azithromycin (L-AZM) promotes macrophage polarization toward an M2-like phenotype in the context of myocardial infarction that results in improved cardiovascular outcomes in mice. To improve upon this formulation, we sought to identify optimized formulation, stability, and biological activity parameters necessary to enhance the immunomodulatory activity and efficacy of L-AZM. While our parent formulation contains a mixture of long-chain saturated phosphatidylcholine and phosphatidylglycerol lipids, we evaluated a series of formulations with different amounts of unsaturated lipids and cholesterol with the goal of improving the loading capacity and stability of the formulations. We also introduce fusogenic lipids to improve the cytosolic delivery to enhance the immune modulatory properties of the drug. To achieve these goals, we initially prepared a library of 24 formulations using thin film hydration and assessed the resultant liposomes for size and polydispersity. Five lead formulations were identified based on low polydispersity (<0.3) and stability over time. The lead formulations were then evaluated for stability in serum using dialysis and macrophage polarization activity in vitro as measured by decreased IL-12 expression. Collectively, our data indicate that the formulation components drive the balance between encapsulation efficiency and stability and that all the lead liposomal formulations improve in vitro alternative macrophage activation as compared to free AZM.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9670256/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40699731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Localized PD-1 Blockade in a Mouse Model of Renal Cell Carcinoma. 局部PD-1阻断在肾细胞癌小鼠模型中的作用。

Frontiers in drug delivery Pub Date : 2022-01-01 Epub Date: 2022-05-09 DOI: 10.3389/fddev.2022.838458

Ngoc B Pham, Nevil Abraham, Ketki Y Velankar, Nathan R Schueller, Errol J Philip, Yasmeen Jaber, Ellen S Gawalt, Yong Fan, Sumanta K Pal, Wilson S Meng

{"title":"Localized PD-1 Blockade in a Mouse Model of Renal Cell Carcinoma.","authors":"Ngoc B Pham, Nevil Abraham, Ketki Y Velankar, Nathan R Schueller, Errol J Philip, Yasmeen Jaber, Ellen S Gawalt, Yong Fan, Sumanta K Pal, Wilson S Meng","doi":"10.3389/fddev.2022.838458","DOIUrl":"https://doi.org/10.3389/fddev.2022.838458","url":null,"abstract":"Herein we report the impact of localized delivery of an anti-mouse PD-1-specific monoclonal antibody (aPD1) on Renca tumors in the resulting T cell responses and changes in broader immune gene expression profiles. Renca is a BALB/c mice syngeneic tumor that has been used to model human renal cell carcinoma In this study, T cell subsets were examined in tumors and draining lymph nodes of mice treated with localized PD-1 with and without the addition of adenosine deaminase (ADA), an enzyme that catabolizes adenosine (ADO), identified as an immune checkpoint in several types of human cancers. The biologics, aPD1, or aPD1 with adenosine deaminase (aPD1/ADA), were formulated with the self-assembling peptides Z15_EAK to enhance retention near the tumor inoculation site. We found that both aPD1 and aPD1/ADA skewed the local immune milieu towards an immune stimulatory phenotype by reducing Tregs, increasing CD8 T cell infiltration, and upregulating IFNɣ. Analysis of tumor specimens using bulk RNA-Seq confirmed the impact of the localized aPD1 treatment and revealed differential gene expressions elicited by the loco-regional treatment. The effects of ADA and Z15_EAK were limited to tumor growth delay and lymph node enlargement. These results support the notion of expanding the use of locoregional PD-1 blockade in solid tumors.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9486680/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33466166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lyophilization Process Engineering and Thermostability of ID93 + GLA-SE, a Single-Vial Adjuvanted Subunit Tuberculosis Vaccine Candidate for Use in Clinical Studies. ID93+GLA-SE的冻干工艺工程和热稳定性，这是一种用于临床研究的单小瓶辅助亚单位结核病候选疫苗。

Frontiers in drug delivery Pub Date : 2022-01-01 Epub Date: 2022-11-08 DOI: 10.3389/fddev.2022.1043756

Timothy S Dutill, Michelle C Archer, Joseph McCollum, Chris Press, Lisa McNeill, Linda Hawkins, Tony Phan, Erik Laursen, Richard Cabullos, Lisa Bouchard, Regie J Castro, Mong-Wu Lin, Jeralyn Roco, Cecile Blois, Babatunde Adeagbo, Jeffrey A Guderian, Alana Gerhardt, Anna Marie Beckmann, Edward H Trappler, Ryan M Kramer, Christopher B Fox

{"title":"Lyophilization Process Engineering and Thermostability of ID93 + GLA-SE, a Single-Vial Adjuvanted Subunit Tuberculosis Vaccine Candidate for Use in Clinical Studies.","authors":"Timothy S Dutill, Michelle C Archer, Joseph McCollum, Chris Press, Lisa McNeill, Linda Hawkins, Tony Phan, Erik Laursen, Richard Cabullos, Lisa Bouchard, Regie J Castro, Mong-Wu Lin, Jeralyn Roco, Cecile Blois, Babatunde Adeagbo, Jeffrey A Guderian, Alana Gerhardt, Anna Marie Beckmann, Edward H Trappler, Ryan M Kramer, Christopher B Fox","doi":"10.3389/fddev.2022.1043756","DOIUrl":"https://doi.org/10.3389/fddev.2022.1043756","url":null,"abstract":"Promising clinical efficacy results have generated considerable enthusiasm for the potential impact of adjuvant-containing subunit tuberculosis vaccines. The development of a thermostable tuberculosis vaccine formulation could have significant benefits on both the cost and feasibility of global vaccine distribution. The tuberculosis vaccine candidate ID93 + GLA-SE has reached Phase 2 clinical testing, demonstrating safety and immunogenicity as a two-vial point-of-care mixture. Earlier publications have detailed efforts to develop a lead candidate single-vial lyophilized thermostable ID93 + GLA-SE vaccine formulation. The present report describes the lyophilization process development and scale-up of the lead candidate thermostable ID93 + GLA-SE composition. The manufacture of three full-scale engineering batches was followed by one batch made and released under current Good Manufacturing Practices (cGMP). Up to 4.5 years of stability data were collected. The cGMP lyophilized ID93 + GLA-SE passed all manufacturing release test criteria and maintained stability for at least 3 months when stored at 37°C and up to 24 months when stored at 5°C. This work represents the first advancement of a thermostable adjuvant-containing subunit tuberculosis vaccine to clinical testing readiness.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10538572/pdf/nihms-1890761.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41175944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Endocytosis of insulin at the blood-brain barrier. 胰岛素在血脑屏障的内分泌作用

Frontiers in drug delivery Pub Date : 2022-01-01 Epub Date: 2022-11-24 DOI: 10.3389/fddev.2022.1062366

Sarah Pemberton, Demi C Galindo, Michael W Schwartz, William A Banks, Elizabeth M Rhea

引用次数: 0