Targeting of Inhaled Therapeutics to the Small Airways: Nanoleucine Carrier Formulations

Current dry powder formulations for inhalation deposit a large fraction of their emitted dose in the upper respiratory tract where they contribute to off-target adverse effects and variability in lung delivery. The purpose of the current study is to design a new formulation concept that more effectively targets inhaled dry powders to the large and small airways. The formulations are based on adhesive mixtures of drug nanoparticles and nanoleucine carrier particles prepared by spray drying of a co-suspension of leucine and drug particles from a nonsolvent. The physicochemical and aerosol properties of the resulting formulations are presented. The formulations achieve 93% lung delivery in the Alberta Idealized Throat model that is independent of inspiratory flow rate and relative humidity. Largely eliminating URT deposition with a particle size larger than solution pMDIs is expected to improve delivery to the large and small airways, while minimizing alveolar deposition and particle exhalation.

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Targeting of Inhaled Therapeutics to the Small Airways: Nanoleucine Carrier Formulations

10.20944/preprints202110.0195.v1 ◽

2021 ◽

Author(s):

Danforth P. Miller ◽

Thomas E. Tarara ◽

Jeffry G. Weers

Keyword(s):

Large Fraction ◽

Small Airways ◽

Upper Respiratory Tract ◽

Dry Powders ◽

Drug Nanoparticles ◽

Lung Delivery ◽

Adhesive Mixtures ◽

New Formulation ◽

Dry Powder Formulations ◽

Emitted Dose

Current dry powder formulations for inhalation deposit a large fraction of their emitted dose in the upper respiratory tract where they contribute to off-target adverse effects and variability in lung delivery. The purpose of current study is to design a new formulation concept that more effectively targets inhaled dry powders to the large and small airways. The formulations are based on adhesive mixtures of drug nanoparticles and nanoleucine carrier particles prepared by spray drying of a co-suspension of leucine and drug particles from a nonsolvent. The physicochemical and aerosol properties of the resulting formulations are presented. The formulations achieve 93% lung delivery in the Alberta Idealized Throat model that is independent of inspiratory flow rate and relative humidity. Largely eliminating URT deposition with a particle size larger than solution pMDIs is expected to improve delivery to the large and small airways, while minimizing alveolar deposition and particle exhalation.

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The Role of the Immune Response in the Pathogenesis of Bronchiectasis

BioMed Research International ◽

10.1155/2018/6802637 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Paul T. King

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Respiratory Tract ◽

Lower Respiratory Tract ◽

Therapeutic Potential ◽

Small Airways ◽

Upper Respiratory Tract ◽

Causative Factors ◽

Triggering Factor

Bronchiectasis is a prevalent respiratory condition characterised by permanent and abnormal dilation of the lung airways (bronchi). There are a large variety of causative factors that have been identified for bronchiectasis; all of these compromise the function of the immune response to fight infection. A triggering factor may lead to the establishment of chronic infection in the lower respiratory tract. The bacteria responsible for the lower respiratory tract infection are usually found as commensals in the upper respiratory tract microbiome. The consequent inflammatory response to infection is largely responsible for the pathology of this condition. Both innate and adaptive immune responses are activated. The literature has highlighted the central role of neutrophils in the pathogenesis of bronchiectasis. Proteases produced in the lung by the inflammatory response damage the airways and lead to the pathological dilation that is the pathognomonic feature of bronchiectasis. The small airways demonstrate infiltration with lymphoid follicles that may contribute to localised small airway obstruction. Despite aggressive treatment, most patients will have persistent disease. Manipulating the immune response in bronchiectasis may potentially have therapeutic potential.

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Development of ciprofloxacin-loaded poly(vinyl alcohol) dry powder formulations for lung delivery

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2018.05.060 ◽

2018 ◽

Vol 547 (1-2) ◽

pp. 114-121 ◽

Cited By ~ 3

Author(s):

Dina M. Silva ◽

Roberto Paleco ◽

Daniela Traini ◽

Vitor Sencadas

Keyword(s):

Vinyl Alcohol ◽

Poly Vinyl Alcohol ◽

Dry Powder ◽

Lung Delivery ◽

Dry Powder Formulations

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Recombinant bovine respiratory syncytial virus with deletion of the SH gene induces increased apoptosis and pro-inflammatory cytokines in vitro, and is attenuated and induces protective immunity in calves

Journal of General Virology ◽

10.1099/vir.0.064931-0 ◽

2014 ◽

Vol 95 (6) ◽

pp. 1244-1254 ◽

Cited By ~ 24

Author(s):

Geraldine Taylor ◽

Sara Wyld ◽

Jean-Francois Valarcher ◽

Efrain Guzman ◽

Michelle Thom ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Inflammatory Cytokines ◽

Bovine Respiratory Syncytial Virus ◽

Small Airways ◽

Upper Respiratory Tract ◽

Virus Challenge ◽

Syncytial Virus ◽

Pro Inflammatory Cytokines

Bovine respiratory syncytial virus (BRSV) causes inflammation and obstruction of the small airways, leading to severe respiratory disease in young calves. The virus is closely related to human (H)RSV, a major cause of bronchiolitis and pneumonia in young children. The ability to manipulate the genome of RSV has provided opportunities for the development of stable, live attenuated RSV vaccines. The role of the SH protein in the pathogenesis of BRSV was evaluated in vitro and in vivo using a recombinant (r)BRSV in which the SH gene had been deleted. Infection of bovine epithelial cells and monocytes with rBRSVΔSH, in vitro, resulted in an increase in apoptosis, and higher levels of TNF-α and IL-1β compared with cells infected with parental, wild-type (WT) rBRSV. Although replication of rBRSVΔSH and WT rBRSV, in vitro, were similar, the replication of rBRSVΔSH was moderately reduced in the lower, but not the upper, respiratory tract of experimentally infected calves. Despite the greater ability of rBRSVΔSH to induce pro-inflammatory cytokines, in vitro, the pulmonary inflammatory response in rBRSVΔSH-infected calves was significantly reduced compared with that in calves inoculated with WT rBRSV, 6 days previously. Virus lacking SH appeared to be as immunogenic and effective in inducing resistance to virulent virus challenge, 6 months later, as the parental rBRSV. These findings suggest that rBRSVΔSH may be an ideal live attenuated virus vaccine candidate, combining safety with a high level of immunogenicity.

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The role of the solid state and physical properties of the carrier in adhesive mixtures for lung delivery

Expert Opinion on Drug Delivery ◽

10.1080/17425247.2017.1371132 ◽

2017 ◽

Vol 15 (7) ◽

pp. 665-674 ◽

Cited By ~ 5

Author(s):

Andrea Della Bella ◽

Enrico Salomi ◽

Francesca Buttini ◽

Ruggero Bettini

Keyword(s):

Solid State ◽

Physical Properties ◽

Lung Delivery ◽

Adhesive Mixtures

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Sustained-release microparticle dry powders of chloramphenicol palmitate or thiamphenicol palmitate prodrugs for lung delivery as aerosols

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2019.105028 ◽

2019 ◽

Vol 138 ◽

pp. 105028

Author(s):

Siti Nani Nurbaeti ◽

Julien Brillault ◽

Frédéric Tewes ◽

Jean-Christophe Olivier

Keyword(s):

Sustained Release ◽

Dry Powders ◽

Lung Delivery

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Prolonged effects of viral infections of the upper respiratory tract upon small airways

The American Journal of Medicine ◽

10.1016/0002-9343(72)90079-4 ◽

1972 ◽

Vol 52 (6) ◽

pp. 738-746 ◽

Cited By ~ 55

Author(s):

John J. Picken ◽

Dennis E. Niewoehner ◽

Edward H. Chester

Keyword(s):

Respiratory Tract ◽

Viral Infections ◽

Small Airways ◽

Upper Respiratory Tract ◽

Upper Respiratory

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Bronchiolitis

Pediatrics in Review ◽

10.1542/pir.7.7.219 ◽

1986 ◽

Vol 7 (7) ◽

pp. 219-222

Author(s):

Peter F. Wright

Keyword(s):

Respiratory Tract ◽

Lymphocytic Infiltration ◽

Goblet Cells ◽

Small Airways ◽

Upper Respiratory Tract ◽

Whole Process ◽

Ciliary Function ◽

Upper Respiratory ◽

Diagnosis Therapy ◽

Submucosal Edema

Bronchiolitis is an acute respiratory disease of early childhood characterized clinically by upper respiratory tract signs of rhinitis and congestion and by lower respiratory tract signs of tachypnea, retractions, wheezing, and rales. The presence of wheezing differentiates bronchiolitis from many of the other entities to be considered in the child with respiratory distress. Fever and other systemic signs are not prominent components of bronchiolitis. Radiographically, there is evidence of hyperexpansion of the chest, thickening of the bronchial walls, and areas of atelectasis or interstitial pneumonia. Physiologically, there is evidence of hypoxia and hypercarbia with disequilibrium of perfuson-ventilation. Pathologically, there is evidence of damage to the mucosal epithelium with loss of ciliary function. There is an increased production of mucus, with a proliferation of goblet cells. Submucosal edema and lymphocytic infiltration are common. These changes are seen throughout the respiratory tract but are particularly prominent in the cells and submucosal lining of the bronchioles, with resultant obstruction of the small airways (Fig 1). The pathologic events are obviously central to the whole process of the illness. An understanding of the mechanisms by which the pathologic changes in bronchiolitis evolve, and their implications for diagnosis, therapy, prognosis, and, ultimately, prevention, will be the focus of this review.

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A Contribution on Quasi-Static Mooring Line Damping

Journal of Offshore Mechanics and Arctic Engineering ◽

10.1115/1.533734 ◽

1999 ◽

Vol 122 (2) ◽

pp. 125-133 ◽

Cited By ~ 19

Author(s):

Christian Bauduin ◽

Mamoun Naciri

Keyword(s):

Finite Element ◽

Large Fraction ◽

Low Frequency ◽

Mooring Line ◽

Floating Structure ◽

Mooring Lines ◽

Mooring Cable ◽

Static Approach ◽

Numerical Tools ◽

New Formulation

Since the pioneering work of Huse (1986, “Influence of Mooring Line Damping Upon Rig Motions,” Proc., 18th OTC Conference), it is well known that mooring lines may account for a large fraction of the overall damping present in a moored floating structure. This paper is concerned with the mooring line damping induced by the low-frequency, quasi-static, horizontal motion of the mooring line fairlead. The main advantage of the quasi-static approach is that it is much faster than the more accurate finite element methods, and, secondly, that it does not require any finite element modeling skills. A new formulation is proposed and is compared to the results of Liu et al. (1998, “Improvement on Huse’s Model for Estimating Mooring Cable-Induced Damping,” Proc., 17th OMAE Conference), as well as to time domain results obtained with FLEXRISER. The improvement with respect to the previous quasi-static methods is quite notable and our results are closer to FLEXRISER predictions. Finally, quasi-static results are compared to mooring line damping values measured during model tests for full mooring systems. The agreement between the two is very encouraging and suggests that the simpler quasi-static approach may, in some circumstances, be a valuable substitute for the more complex and time-consuming numerical tools. [S0892-7219(00)00102-3]

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