Pub Date : 2022-05-04DOI: 10.3389/fddev.2022.901289
W. Finlay, D. Farina, S. Tavernini, Andrew R. Martin
To date, in vitro estimation of doses delivered by an inhaler to the different major regions of the lung has required combining particle size measurements of the inhaled aerosol with in silico deposition models. Such a two step process is labor and time intensive. Here, we describe instead the development of an apparatus that allows direct estimation of regional lung deposition by measurement of doses collected on purpose-built metal grid filters that mimic tracheobronchial deposition efficiency. Placing these filters downstream of the Alberta Idealized Throat and upstream of a final filter allows collection of doses depositing in the extrathoracic, tracheobronchial and alveolar regions. Artificial electrostatic deposition on the metal tracheobronchial filters is prevented by a custom inline electrostatic neutralizer. We use the resulting apparatus to estimate regional deposition with a variety of dry powder inhalers during realistic, time-varying inhalation maneuvers and three pMDIs with a constant flow rate of 30 l/min. These results are compared to those obtained with the traditional two step approach that combines cascade impaction with a regional deposition model. Good agreement is found between the two approaches, indicating that the present direct method may be an efficient, time-saving alternative method for in vitro estimation of regional lung doses.
{"title":"In Vitro Estimation of Tracheobronchial and Alveolar Doses Using Filters","authors":"W. Finlay, D. Farina, S. Tavernini, Andrew R. Martin","doi":"10.3389/fddev.2022.901289","DOIUrl":"https://doi.org/10.3389/fddev.2022.901289","url":null,"abstract":"To date, in vitro estimation of doses delivered by an inhaler to the different major regions of the lung has required combining particle size measurements of the inhaled aerosol with in silico deposition models. Such a two step process is labor and time intensive. Here, we describe instead the development of an apparatus that allows direct estimation of regional lung deposition by measurement of doses collected on purpose-built metal grid filters that mimic tracheobronchial deposition efficiency. Placing these filters downstream of the Alberta Idealized Throat and upstream of a final filter allows collection of doses depositing in the extrathoracic, tracheobronchial and alveolar regions. Artificial electrostatic deposition on the metal tracheobronchial filters is prevented by a custom inline electrostatic neutralizer. We use the resulting apparatus to estimate regional deposition with a variety of dry powder inhalers during realistic, time-varying inhalation maneuvers and three pMDIs with a constant flow rate of 30 l/min. These results are compared to those obtained with the traditional two step approach that combines cascade impaction with a regional deposition model. Good agreement is found between the two approaches, indicating that the present direct method may be an efficient, time-saving alternative method for in vitro estimation of regional lung doses.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42114652","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}
Pub Date : 2022-04-28DOI: 10.3389/fddev.2022.901281
Yuwei Wang, D. Grainger
Nearly a half-century after original liposome discovery as a prospective lipid pharmaceutical carrier, the global liposomal drug delivery market has increased dramatically, with an annual market growth rate of 13.2%, valued at ∼$6,993 million by 2027. As an intrinsically complex delivery system, liposomal formulations face much greater characterization and regulatory review challenges than traditional small molecule drugs and biologics. Due to rapid liposomal drug development, both European Medicines Agency (EMA) and US Food and Drug Administration (FDA) now provide regulatory guidance for new liposomal drug application reviews. The expanding global liposome drug market and associated driving forces for increased research and development (R&D) in novel liposomal products are key factors propelling liposomal drug interests. We review and compare EU and US regulations on liposomal drug submissions, and provide insights into regulatory strategies throughout the entire liposomal drug development process. This addresses current gaps noted between liposome-based drug development in research labs and current regulatory guidance for liposomal drug approvals in order to facilitate more efficient, less costly, and less risky complex drug development.
{"title":"Regulatory Considerations Specific to Liposome Drug Development as Complex Drug Products","authors":"Yuwei Wang, D. Grainger","doi":"10.3389/fddev.2022.901281","DOIUrl":"https://doi.org/10.3389/fddev.2022.901281","url":null,"abstract":"Nearly a half-century after original liposome discovery as a prospective lipid pharmaceutical carrier, the global liposomal drug delivery market has increased dramatically, with an annual market growth rate of 13.2%, valued at ∼$6,993 million by 2027. As an intrinsically complex delivery system, liposomal formulations face much greater characterization and regulatory review challenges than traditional small molecule drugs and biologics. Due to rapid liposomal drug development, both European Medicines Agency (EMA) and US Food and Drug Administration (FDA) now provide regulatory guidance for new liposomal drug application reviews. The expanding global liposome drug market and associated driving forces for increased research and development (R&D) in novel liposomal products are key factors propelling liposomal drug interests. We review and compare EU and US regulations on liposomal drug submissions, and provide insights into regulatory strategies throughout the entire liposomal drug development process. This addresses current gaps noted between liposome-based drug development in research labs and current regulatory guidance for liposomal drug approvals in order to facilitate more efficient, less costly, and less risky complex drug development.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48152722","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}
Nicotine, the major component of tobacco smoke (TS) and electronic cigarette (e-cig) vape, has been reported in some cases to be prodromal to cerebrovascular toxicity as well as a promoting factor for the onset of various neurological diseases. In some conditions, pre-exposure to nicotine can lead to a state of compromised blood-brain barrier (BBB) integrity, including altered BBB-related protein expression, BBB leakage, and defective ion and glucose homeostasis within the brain. Moreover, drugs used to treat central nervous system disorders (CNS) have been reported to interact with nicotine and other components of TS/e-cig through both transporter and enzyme-based mechanisms. Herein we discuss nicotine’s potential toxicity at the brain cerebrovasculature and explain how nicotine (from smoking/vaping) may interfere with the uptake of CNS drugs through a CNS drug interaction perspective.
{"title":"Effects of Nicotine Exposure From Tobacco Products and Electronic Cigarettes on the Pathogenesis of Neurological Diseases: Impact on CNS Drug Delivery","authors":"Sejal Sharma, Sabrina Rahman Archie, Vrajesh Kanchanwala, Kyle Mimun, Md. Ashrafur Rahman, Yong Zhang, T. Abbruscato","doi":"10.3389/fddev.2022.886099","DOIUrl":"https://doi.org/10.3389/fddev.2022.886099","url":null,"abstract":"Nicotine, the major component of tobacco smoke (TS) and electronic cigarette (e-cig) vape, has been reported in some cases to be prodromal to cerebrovascular toxicity as well as a promoting factor for the onset of various neurological diseases. In some conditions, pre-exposure to nicotine can lead to a state of compromised blood-brain barrier (BBB) integrity, including altered BBB-related protein expression, BBB leakage, and defective ion and glucose homeostasis within the brain. Moreover, drugs used to treat central nervous system disorders (CNS) have been reported to interact with nicotine and other components of TS/e-cig through both transporter and enzyme-based mechanisms. Herein we discuss nicotine’s potential toxicity at the brain cerebrovasculature and explain how nicotine (from smoking/vaping) may interfere with the uptake of CNS drugs through a CNS drug interaction perspective.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48882072","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}
Pub Date : 2022-04-13DOI: 10.3389/fddev.2022.871147
A. Clark
The last half century of pulmonary product development is reviewed in the context of the main drivers of innovation, technology development, and the advancement of science. A perspective on development timeframes, patent lifetimes, and the odds of success of developing of new inhaler technologies is presented.
{"title":"Half a Century of Technological Advances in Pulmonary Drug Delivery: A Personal Perspective","authors":"A. Clark","doi":"10.3389/fddev.2022.871147","DOIUrl":"https://doi.org/10.3389/fddev.2022.871147","url":null,"abstract":"The last half century of pulmonary product development is reviewed in the context of the main drivers of innovation, technology development, and the advancement of science. A perspective on development timeframes, patent lifetimes, and the odds of success of developing of new inhaler technologies is presented.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43076108","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}
Pub Date : 2022-04-06DOI: 10.3389/fddev.2022.864922
H. Gauani, T. Baker, Zhili Li, V. Malinin, W. Perkins, E. Sullivan, D. Cipolla
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.
{"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}
Pub Date : 2022-04-06DOI: 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
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.
{"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}
Pub Date : 2022-03-24DOI: 10.3389/fddev.2022.855017
Jean Paul Dardet, Nelson Serrano, I. András, M. Toborek
Drug delivery across the blood–brain barrier (BBB) has several challenges, especially toward targeting neurological diseases, due to tight and selective barrier function of the BBB. Several structural and functional components of this barrier contribute to restricting drug entry, such as interendothelial tight junctions (TJs), efflux transporters, drug-metabolizing enzymes, and crosstalk between the cells of the neurovascular unit. Among different strategies to overcome BBB resistance to therapeutic drug delivery, the use of extracellular vesicles (EVs) gained attention in recent years. This review discusses the BBB structural and functional resistance, as well as potential avenues to overcome this challenge using EVs as drug delivery vehicles into the brain.
{"title":"Overcoming Blood-Brain Barrier Resistance: Implications for Extracellular Vesicle-Mediated Drug Brain Delivery","authors":"Jean Paul Dardet, Nelson Serrano, I. András, M. Toborek","doi":"10.3389/fddev.2022.855017","DOIUrl":"https://doi.org/10.3389/fddev.2022.855017","url":null,"abstract":"Drug delivery across the blood–brain barrier (BBB) has several challenges, especially toward targeting neurological diseases, due to tight and selective barrier function of the BBB. Several structural and functional components of this barrier contribute to restricting drug entry, such as interendothelial tight junctions (TJs), efflux transporters, drug-metabolizing enzymes, and crosstalk between the cells of the neurovascular unit. Among different strategies to overcome BBB resistance to therapeutic drug delivery, the use of extracellular vesicles (EVs) gained attention in recent years. This review discusses the BBB structural and functional resistance, as well as potential avenues to overcome this challenge using EVs as drug delivery vehicles into the brain.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46806446","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}
Pub Date : 2022-03-22DOI: 10.3389/fddev.2022.855234
J. Weers
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.
受试者通过“被动”干粉吸入器(DPI)的吸口所能达到的最大吸气压力(MIP)主要由其吸气肌力量驱动(Clark, 2015)。肌肉力量随着年龄的增长而增加，在25岁左右达到顶峰，直到40岁左右趋于平稳，之后逐渐下降。男性的MIP值高于女性，疾病严重程度的增加可能进一步降低MIP。当使用dpi时，患者很少以最大的努力吸气，而是达到峰值吸气压力(PIP)，约为其MIP的40-80% (Clark, 2015和其中的参考文献)。基于这些观察结果，目前的行业指导是，被动dpi固有地依赖于流量，幼儿和老年患者可能无法达到有效流化和分散干粉所需的PIP或峰值吸气流量(PIFR)，特别是在急性加重期间(Laube等人，2011)。对于COPD患者，有研究表明:“如果PIFR小于60 L min，患者可能无法获得最佳临床获益(使用吸入式支气管扩张剂)，应考虑使用不同的给药系统，如计量或软雾吸入器或雾化治疗”(Mahler, 2017)。基于COPD患者的多项呼吸研究结果，进一步表明，19 - 78%的稳定门诊患者和32-47%的住院患者在入院后加重出院前的PIFR <60 L min为次优(Mahler等，2013;马勒,2017;马勒,2020)。最近，Mahler进一步提出，PIFR可作为一种治疗性生物标志物来指导给药系统的选择，同时将高阻力dpi的最佳流速降至30 L min (Mahler和Halpin, 2021)。这一观点回顾了现有的关于被动dpi治疗哮喘和COPD时吸入支气管扩张剂流速依赖性的文献。
{"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}
Pub Date : 2022-03-15DOI: 10.3389/fddev.2022.862336
T. Tarara, Danforth P Miller, Audrey E. Weers, Ariel R. Muliadi, J. Tso, A. Eliahu, J. Weers
Spray-dried formulations of a hydrophobic, crystalline drug, GDC-A, were prepared using the suspension-PulmoSphere™ technology. Increases in drug loading resulted in decreases in the primary particle size distribution and increases in tapped density. This enabled fine particle doses of up to 25 mg to be achieved with a portable dry powder inhaler from a size three capsule. The powders were physically and chemically stable, with no changes in physical form or degradants observed during processing or on storage in an open configuration at 40°C for 1 month. The potential benefits of the suspension-based spray drying process relative to solution-based spray drying in terms of stability, lung targeting, and safety/tolerability are discussed.
{"title":"Formulation of Dry Powders for Inhalation Comprising High Doses of a Poorly Soluble Hydrophobic Drug","authors":"T. Tarara, Danforth P Miller, Audrey E. Weers, Ariel R. Muliadi, J. Tso, A. Eliahu, J. Weers","doi":"10.3389/fddev.2022.862336","DOIUrl":"https://doi.org/10.3389/fddev.2022.862336","url":null,"abstract":"Spray-dried formulations of a hydrophobic, crystalline drug, GDC-A, were prepared using the suspension-PulmoSphere™ technology. Increases in drug loading resulted in decreases in the primary particle size distribution and increases in tapped density. This enabled fine particle doses of up to 25 mg to be achieved with a portable dry powder inhaler from a size three capsule. The powders were physically and chemically stable, with no changes in physical form or degradants observed during processing or on storage in an open configuration at 40°C for 1 month. The potential benefits of the suspension-based spray drying process relative to solution-based spray drying in terms of stability, lung targeting, and safety/tolerability are discussed.","PeriodicalId":73079,"journal":{"name":"Frontiers in drug delivery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48639190","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}
Pub Date : 2022-02-17DOI: 10.3389/fddev.2022.823412
Catarina C. Pacheco, Cláudia Martins, J. Monteiro, F. Baltazar, B. Costa, B. Sarmento
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.
{"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}
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