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Biologic Drug Substance and Drug Product Manufacture
Published in Anthony J. Hickey, Sandro R.P. da Rocha, Pharmaceutical Inhalation Aerosol Technology, 2019
Ajit S. Narang, Mary E. Krause, Shelly Pizarro, Joon Chong Yee
Biologic drug products are marketed in several different configurations, including liquid (solution) filled vials or prefilled syringes, lyophilized powder in a vial, or concentrated solutions intended for either dilution in a parenteral fluid before administration or for direct subcutaneous injection using novel delivery devices. Proteins and peptides for parenteral administration are typically formulated as ready-to-use aqueous solutions or as a lyophilized solid mass that is reconstituted with water, isotonic dextrose solution, or isotonic sodium chloride solution immediately before administration; while proteins and peptides for inhalation and nasal routes of administration are typically formulated as dry powders (Mahato and Narang 2018). For stable molecules, nebulization of aqueous solutions is also a viable strategy. For example, Pulmozyme® (dornase alpha) is a solution which is aerosolized by a nebulizer during administration. It contains a CHO-produced recombinant human deoxyribonuclease I, an enzyme which cleaves the DNA present in the mucus of cystic fibrosis patients and reduces viscosity in the lungs, resulting in better clearance of secretions.
Neonatal and pediatric inhalation drug delivery
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Many pediatric conditions are treated with inhaled medications. Albuterol, ipratropium bromide, and inhaled corticosteroids are used for the treatment of asthma (19). Hypertonic saline is used in cystic fibrosis, and in bronchiolitis (20,21). Antibiotics are used in cystic fibrosis, in tracheostomized patients experiencing tracheitis, and in intubated patients suffering pneumonia (20,22). Dornase alfa is used in cystic fibrosis patients, but also off label for the treatment of atelectasis (20,23). Vasodilators are used in the treatment of pulmonary hypertension (17). Racemic epinephrine and budesonide are used in croup (24,25).
Plastic bronchitis
Published in Alisa McQueen, S. Margaret Paik, Pediatric Emergency Medicine: Illustrated Clinical Cases, 2018
Plastic bronchitis is a rare disease that mainly occurs in children and is characterized by the expectoration or bronchoscopic removal of complex, branching bronchial casts. Unlike other diseases with mucous plugging such as allergic bronchopulmonary aspergillosis (ABPA) and asthma, these casts are large, rubbery, and branching on gross inspection and acellular on histopathology. The disease may be related to abnormalities in lymphatic drainage. Frequently patients with plastic bronchitis have an underlying systemic illness, with congenital heart disease, particularly after corrective surgery, being the most common (Dori et al., 2014). Patients present with cough, dyspnea, and airway obstruction and are often misdiagnosed initially as having reactive airway disease or pneumonia. Standard treatment for reactive airway disease and mucous plugging with albuterol, steroids, acetylcysteine, and dornase alfa are typically ineffective. Other therapies such as tissue plasminogen activator, and pulmonary vasodilators, such as sildenafil, have been used. Thoracic duct ligation and selective lymphatic collateral embolization have been shown to be curative (Caruthers et al., 2013). Acute bronchoscopic removal of casts causing airway obstruction may be lifesaving.
Adults with cystic fibrosis: spiritual coping with lifelong disease
Published in Journal of Health Care Chaplaincy, 2020
Daniel H. Grossoehme, Adam G. Cole, Katrina Lewis, Sophia M. Stamper, Alexis Teeters, Patricia M. Joseph
Participants’ prescriptions for airway clearance and to dornase alfa, if prescribed, were obtained by chart review. Adherence behavior data were obtained by the Daily Phone Diary (DPD) (Modi et al., 2006; Quittner & Opipari, 1994). The DPD uses a cued recall system in which participants are asked to recollect all events of at least 5 min duration in the last 24 h. Recollection of all events theoretically blinds participants to the behavior of interest and minimizes the likelihood of providing socially desirable responses. Participants completed two DPDs in the 3 weeks following enrollment and were scheduled to include one weekend day and one weekday (Ball et al., 2013). The DPD is frequently used to study CF treatment adherence and its psychometric properties are well-established, including test-retest reliabilitya interrater reliability (Quittner et al., 1998) and convergent validity (Quittner, Modi, Lemanek, Ievers-Landis, & Rapoff, 2008; Quittner & Opipari, 1994). Two co-authors (DHG and SMS) were previously trained on the use of the DPD by its owner. The ratio of treatments completed obtained from DPD data to the number of prescribed treatments is the adherence rate.
The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis lung disease
Published in Expert Opinion on Therapeutic Targets, 2018
Patrick J. Moore, Robert Tarran
CF sputum contains large amounts of extracellular DNA that is released by infiltrating inflammatory cells such as neutrophils. Nebulization of recombinant human deoxyribonuclease (rhDNase) is a commonly used method to mobilize CF sputum [146]. Dornase alfa (Pulmozyme; Genentech) is a purified rhDNase that cleaves extracellular DNA, thereby reducing the viscosity of the mucus layer [146,147]. Daily treatment with rhDNase reduces the number of pulmonary exacerbations, improves lung function, and is well tolerated [148,149]. Use of Dornase alfa would not affect ASL hydration or ENaC activity directly but would likely be complementary to an inhaled ENaC antagonist, since the latter would likely facilitate mucus hydration/clearance. Clinical trials have demonstrated that rhDNase significantly improves lung function [147,150]. However, variations in clinical response to rhDNase have been observed in CF patients [151,152] which have been attributed to treatment regimens and optimal timing [153,154].
Designing inhaled protein therapeutics for topical lung delivery: what are the next steps?
Published in Expert Opinion on Drug Delivery, 2018
Elsa Bodier-Montagutelli, Alexie Mayor, Laurent Vecellio, Renaud Respaud, Nathalie Heuzé-Vourc’h
Although proteins can be formulated as dry powders for aerosolization, 75% of the inhaled protein therapeutics in clinical development have been developed as liquids for nebulization (Table 1). Accordingly, this editorial will mainly comment on advances in protein nebulization for topical lung delivery. Protein nebulization is often the first step in the development process because it offers several advantages over dry powders: it avoids drying steps, it is suitable for all clinical situations, and it enables greater pulmonary deposition than dry powder inhalers. Nebulizers have been significantly improved in recent years, and can deliver a 70% lung dose versus a maximum of 30% with current dry powder inhalers or the 50% expected with next-generation devices [4,5]. Indeed, dornase alfa is administered daily (2.5 mg per session) by nebulization. Nevertheless, nebulization exposes proteins to stressful conditions by generating a huge air–liquid interface (ALI) and, in some cases, high temperatures and/or shear forces. These conditions may cause protein unfolding, aggregation, oxidation, deamidation, or glycation, which may lead to changes in biological activity and safety concerns. In this prospect, nebulizers and formulations constitute two relevant tools to optimize protein stability during nebulization.