Aerosol, chemical and physical properties of dry powder synthetic lung surfactant for noninvasive treatment of neonatal respiratory distress syndrome

AbstractInhalation of dry powder synthetic lung surfactant may assist spontaneous breathing by providing noninvasive surfactant therapy for premature infants supported with nasal continuous positive airway pressure. Surfactant was formulated using spray-drying with different phospholipid compositions (70 or 80 total weight% and 7:3 or 4:1 DPPC:POPG ratios), a surfactant protein B peptide analog (KL4, Super Mini-B, or B-YL), and Lactose or Trehalose as excipient. KL4 surfactant underperformed on initial adsorption and surface activity at captive bubble surfactometry. Spray-drying had no effect on the chemical composition of Super Mini-B and B-YL peptides and surfactant with these peptides had excellent surface activity with particle sizes and fine particle fractions that were well within the margins for respiratory particles and similar solid-state properties. Prolonged exposure of the dry powder surfactants with lactose as excipient to 40 °C and 75% humidity negatively affected hysteresis during dynamic cycling in the captive bubble surfactometer. Dry powder synthetic lung surfactants with 70% phospholipids (DPPC and POPG at a 7:3 ratio), 25% trehalose and 3% of SMB or B-YL showed excellent surface activity and good short-term stability, thereby qualifying them for potential clinical use in premature infants.

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Interaction of transferrin saturated with iron with lung surfactant in respiratory failure

Journal of Applied Physiology ◽

10.1152/jappl.1994.77.2.757 ◽

1994 ◽

Vol 77 (2) ◽

pp. 757-766 ◽

Cited By ~ 16

Author(s):

M. Hallman ◽

A. Sarnesto ◽

K. Bry

Keyword(s):

Respiratory Failure ◽

Surface Activity ◽

Lung Surfactant ◽

Protein A ◽

Surfactant Protein ◽

Lung Damage ◽

Epithelial Lining ◽

Surface Absorption ◽

Epithelial Lining Fluid

Proteins that decrease the surface activity of surfactant accumulate in epithelial lining fluid in respiratory failure. The aim of this study was to isolate a surfactant inhibitor from the airways of rabbits in acute respiratory failure induced by bronchoalveolar lavage (BAL). This inhibitor was identified as being transferrin (TF). Unlike serum TF, TF recovered in respiratory failure was saturated with iron (Fe(3+)-TF). Fe(3+)-TF decreased the surface activity of normal surfactant in vitro, whereas iron-free TF had no effect. In the presence of H2O2 and a reducing agent, Fe(+3)-TF inactivated the surfactant complex: the surface absorption rate was decreased, immunoreactive surfactant protein A was decreased, and malondialdehyde was formed. The acute effects of Fe(3+)-TF and iron-free TF applied to the airways were studied in animal models. In respiratory failure induced by BAL, Fe(3+)-TF deteriorated respiratory failure, whereas iron-free TF had no effect. In respiratory failure induced by hyperoxia for 48 h, administration of iron-free TF ameliorated the respiratory failure and improved the surface activity in BAL. We propose that Fe(3+)-TF accumulating in epithelial lining fluid during lung damage contributes to surfactant inhibition and promotes the formation of free radicals that inactivate the surfactant system.

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Lipid composition greatly affects the in vitro surface activity of lung surfactant protein mimics

Colloids and Surfaces B Biointerfaces ◽

10.1016/j.colsurfb.2007.01.001 ◽

2007 ◽

Vol 57 (1) ◽

pp. 37-55 ◽

Cited By ~ 16

Author(s):

Shannon L. Seurynck-Servoss ◽

Nathan J. Brown ◽

Michelle T. Dohm ◽

Cindy W. Wu ◽

Annelise E. Barron

Keyword(s):

Surface Activity ◽

Lipid Composition ◽

Lung Surfactant ◽

Surfactant Protein ◽

Protein Mimics ◽

Lung Surfactant Protein

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Surfactant Protein A, Phosphatidylcholine, and Surfactant Inhibitors in Epithelial Lining Fluid: Correlation with Surface Activity, Severity of Respiratory Distress Syndrome, and Outcome in Small Premature Infants

American Review of Respiratory Disease ◽

10.1164/ajrccm/144.6.1376 ◽

1991 ◽

Vol 144 (6) ◽

pp. 1376-1384 ◽

Cited By ~ 114

Author(s):

Mikko Hallman ◽

T. Allen Merritt ◽

Toyoaki Akino ◽

Kristina Bry

Keyword(s):

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Surface Activity ◽

Premature Infants ◽

Distress Syndrome ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Epithelial Lining ◽

Epithelial Lining Fluid

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Aerosol delivery of dry powder synthetic lung surfactant to surfactant-deficient rabbits and preterm lambs on non-invasive respiratory support

Gates Open Research ◽

10.12688/gatesopenres.12899.2 ◽

2019 ◽

Vol 3 ◽

pp. 6 ◽

Cited By ~ 3

Author(s):

Frans J. Walther ◽

Monik Gupta ◽

Michael M. Lipp ◽

Holly Chan ◽

John Krzewick ◽

...

Keyword(s):

Lung Function ◽

Surface Activity ◽

Lung Surfactant ◽

Respiratory Support ◽

Low Flow ◽

Synthetic Surfactant ◽

Aerosol Delivery ◽

Dry Powder ◽

Non Invasive

Background: The development of synthetic lung surfactant for preterm infants has focused on peptide analogues of native surfactant proteins B and C (SP-B and SP-C). Non-invasive respiratory support with nasal continuous positive airway pressure (nCPAP) may benefit from synthetic surfactant for aerosol delivery. Methods: A total of three dry powder (DP) surfactants, consisting of phospholipids and the SP-B analogue Super Mini-B (SMB), and one negative control DP surfactant without SMB, were produced with the Acorda Therapeutics ARCUS® Pulmonary Dry Powder Technology. Structure of the DP surfactants was compared with FTIR spectroscopy, in vitro surface activity with captive bubble surfactometry, and in vivo activity in surfactant-deficient adult rabbits and preterm lambs. In the animal experiments, intratracheal (IT) aerosol delivery was compared with surfactant aerosolization during nCPAP support. Surfactant dosage was 100 mg/kg of lipids and aerosolization was performed using a low flow inhaler. Results: FTIR spectra of the three DP surfactants each showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to that previously noted for surface-active SMB in other lipids. The DP surfactants with SMB demonstrated in vitro surface activity <1 mN/m. Oxygenation and lung function increased quickly after IT aerosolization of DP surfactant in both surfactant-deficient rabbits and preterm lambs, similar to improvements seen with clinical surfactant. The response to nCPAP aerosol delivery of DP surfactant was about 50% of IT aerosol delivery, but could be boosted with a second dose in the preterm lambs. Conclusions: Aerosol delivery of DP synthetic surfactant during non-invasive respiratory support with nCPAP significantly improved oxygenation and lung function in surfactant-deficient animals and this response could be enhanced by giving a second dose. Aerosol delivery of DP synthetic lung surfactant has potential for clinical applications.

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Content-dependent activity of lung surfactant protein B in mixtures with lipids

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00431.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. L897-L906 ◽

Cited By ~ 14

Author(s):

Z. Wang ◽

J. E. Baatz ◽

B. A. Holm ◽

R. H. Notter

Keyword(s):

Surface Activity ◽

Physiological Activity ◽

Lung Surfactant ◽

Dynamic Surface Tension ◽

Surfactant Protein ◽

Surface Tensions ◽

Dynamic Surface ◽

Minimum Surface ◽

Dependent Activity ◽

Lung Surfactant Protein

The content-dependent activity of surfactant protein (SP)-B was studied in mixtures with dipalmitoyl phosphatidylcholine (DPPC), synthetic lipids (SL), and purified phospholipids (PPL) from calf lung surfactant extract (CLSE). At fixed SP-B content, adsorption and dynamic surface tension lowering were ordered as PPL/SP-B ≈ SL/SP-B > DPPC/SP-B. All mixtures were similar in having increased surface activity as SP-B content was incrementally raised from 0.05 to 0.75% by weight. SP-B had small but measurable effects on interfacial properties even at very low levels ≤0.1% by weight. PPL/SP-B (0.75%) had the highest adsorption and dynamic surface activity, approaching the behavior of CLSE. All mixtures containing 0.75% SP-B reached minimum surface tensions <1 mN/m in pulsating bubble studies at low phospholipid concentration (1 mg/ml). Mixtures of PPL or SL with SP-B (0.5%) also had minimum surface tensions <1 mN/m at 1 mg/ml, whereas DPPC/SP-B (0.5%) reached <1 mN/m at 2.5 mg/ml. Physiological activity also was strongly dependent on SP-B content. The ability of instilled SL/SP-B mixtures to improve surfactant-deficient pressure-volume mechanics in excised lavaged rat lungs increased as SP-B content was raised from 0.1 to 0.75% by weight. This study emphasizes the crucial functional activity of SP-B in lung surfactants. Significant differences in SP-B content between exogenous surfactants used to treat respiratory disease could be associated with substantial activity variations.

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Aerosol delivery of dry powder synthetic lung surfactant to surfactant-deficient rabbits and preterm lambs on non-invasive respiratory support

Gates Open Research ◽

10.12688/gatesopenres.12899.1 ◽

2019 ◽

Vol 3 ◽

pp. 6 ◽

Cited By ~ 1

Author(s):

Frans J. Walther ◽

Monik Gupta ◽

Michael M. Lipp ◽

Holly Chan ◽

John Krzewick ◽

...

Keyword(s):

Lung Function ◽

Surface Activity ◽

Lung Surfactant ◽

Respiratory Support ◽

Low Flow ◽

Synthetic Surfactant ◽

Aerosol Delivery ◽

Dry Powder ◽

Non Invasive

Background: The development of synthetic lung surfactant for preterm infants has focused on peptide analogues of native surfactant proteins B and C (SP-B and SP-C). Non-invasive respiratory support with nasal continuous positive airway pressure (nCPAP) may benefit from synthetic surfactant for aerosol delivery. Methods: A total of three dry powder (DP) surfactants, consisting of phospholipids and the SP-B analogue Super Mini-B (SMB), and one negative control DP surfactant without SMB, were produced with the Acorda Therapeutics ARCUS® Pulmonary Dry Powder Technology. Structure of the DP surfactants was compared with FTIR spectroscopy, in vitro surface activity with captive bubble surfactometry, and in vivo activity in surfactant-deficient adult rabbits and preterm lambs. In the animal experiments, intratracheal (IT) aerosol delivery was compared with surfactant aerosolization during nCPAP support. Surfactant dosage was 100 mg/kg of lipids and aerosolization was performed using a low flow inhaler. Results: FTIR spectra of the three DP surfactants each showed secondary structures compatible with peptide folding as an α-helix hairpin, similar to that previously noted for surface-active SMB in other lipids. The DP surfactants with SMB demonstrated in vitro surface activity <1 mN/m. Oxygenation and lung function increased quickly after IT aerosolization of DP surfactant in both surfactant-deficient rabbits and preterm lambs, similar to improvements seen with clinical surfactant. The response to nCPAP aerosol delivery of DP surfactant was about 50% of IT aerosol delivery, but could be boosted with a second dose in the preterm lambs. Conclusions: Aerosol delivery of active DP synthetic surfactant during non-invasive respiratory support with nCPAP significantly improved oxygenation and lung function in surfactant-deficient animals and this response could be enhanced by giving a second dose. Aerosol delivery of DP synthetic lung surfactant has potential for clinical applications.

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